A Multicenter, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of the Coadministration of SCY-078 With Voriconazole in Patients With Invasive Pulmonary Aspergillosis
Phase: PHASE2
Conditions: Invasive Pulmonary Aspergillosis
Sponsor: Scynexis, Inc.

SCYNEXIS, Inc. 
Clinical Trial Protocol
A Multicenter, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of the Coadministration of SCY-078 with Voriconazole in Patients 
with Invasive Pulmonary Aspergillosis (SCYNERGIA)
SCYNEXIS Protocol Number SCY-078-206 
EUDRA CT Number 2018-002565-18 
SCYNEXIS, Inc. 
One Evertrust Plaza, 13th Floor 
Jersey City, NJ 07302 
Original Protocol Issue Date: 
20 August 2018 (Version 1.0) 
Protocol Amendment 1 Issue Date: 
04 October 2018 (Version 2.0)  
Protocol Amendment 2 Issue Date: 
31 October 2018 (Version 3.0) 
Protocol Amendment 3 Issue Date: 
12 November 2018 (Version 4.0) 
Protocol Amendment 4 Issue Date: 
01 August 2019 (Version 5.0) 
Protocol Amendment 5 Issue Date: 
13 October 2020 (Version 6.0) 
US IND Number 107,521 
STATEMENT OF CONFIDENTIALITY 
The information in this document contains trade secrets and commercial information 
that are privileged or confidential and may not be disclosed unless such disclosure is 
required by federal or state law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure 
will apply equally to all future information supplied to you which is indicated as 
privileged or confidential. 
NCT03672292

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Investigator Agreement Statement 
PROTOCOL ID: SCY-078-206 
A Multicenter, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of 
the Coadministration of SCY-078 with Voriconazole in Patients with Invasive Pulmonary 
Aspergillosis (SCYNERGIA) 
 
I understand that all documentation provided to me by SCYNEXIS, Inc. or its designated 
representative(s) concerning this study that has not been published previously will be 
kept in the strictest confidence. This documentation includes the study protocol, 
Investigator’s Brochure, case report forms, and other scientific data. This study will not 
commence without the prior written approval of a properly constituted Institutional 
Review Board or Ethics Committee. No changes will be made to the study protocol 
without the prior written approval of SCYNEXIS, Inc. and the Institutional Review 
Board/Ethics Committee, except where necessary to eliminate an immediate hazard to the 
patient. All patients will provide a written informed consent prior to participation. 
I have read the protocol, including all appendices, and I agree that it contains all 
necessary details for me and my staff to conduct this study as described. I have read, 
understood and agree to abide by all the conditions and instructions contained in this 
protocol, and in compliance with International Conference on Harmonization (ICH) 
guidelines, Good Clinical Practices (GCP), Safety Reporting obligations and any 
applicable local requirements. 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
Principal Investigator’s Name (Printed) 
 
 
 
 

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3.0 
Table of Contents 
1.0 
Contact Information ................................................................................................ 2 
2.0 
Protocol Approvals ................................................................................................. 3 
3.0 
Table of Contents .................................................................................................... 5 
4.0 
Revision History ..................................................................................................... 9 
5.0 
Abbreviations ........................................................................................................ 20 
6.0 
Protocol Synopsis.................................................................................................. 24 
7.0 
Schematic of Study Design ................................................................................... 36 
8.0 
Background Information and Scientific Rationale ............................................... 37 
8.1 
Background Information ............................................................................... 37 
8.2 
Rationale for the Study ................................................................................. 46 
9.0 
Study Objectives ................................................................................................... 48 
9.1 
Primary Objectives........................................................................................ 48 
9.2 
Secondary Objectives.................................................................................... 48 
9.3 
Exploratory Objectives ................................................................................. 49 
10.0 
Study Endpoints .................................................................................................... 49 
10.1 
Primary Endpoints ........................................................................................ 49 
10.2 
Secondary Endpoints .................................................................................... 49 
10.3 
Exploratory Endpoints .................................................................................. 50 
11.0 
Study Design ......................................................................................................... 51 
11.1 
Overall Description of the Study .................................................................. 51 
11.1.1 
Study Visits ............................................................................................... 52 
11.1.2 
Study Assessments .................................................................................... 54 
11.2 
Blinding, Randomization and Stratification ................................................. 55 
11.3 
Study Duration/End of Study ........................................................................ 55 
11.4 
Number of Subjects and Centers ................................................................... 55 
12.0 
Study Population ................................................................................................... 56 
12.1 
Inclusion Criteria .......................................................................................... 56 
12.2 
Exclusion Criteria ......................................................................................... 57 
12.3 
Discontinuation Criteria ................................................................................ 58 
12.4 
Replacement of Dropouts ............................................................................. 59 
13.0 
Study Treatments .................................................................................................. 59 
13.1 
Study Treatment Groups ............................................................................... 59 
13.1.1 
Description of Study Groups .................................................................... 59 
13.1.2 
Treatment Duration ................................................................................... 61 
13.1.3 
Renal Insufficiency ................................................................................... 62 
13.1.4 
Voriconazole Dosing and Dose Adjustment ............................................. 62 
13.1.5 
Oral Treatment via NG or PEG Tube ....................................................... 62 
13.2 
Dietary Requirements ................................................................................... 62 
13.3 
Study Drug .................................................................................................... 63 

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13.3.1 
SCY-078 Description ................................................................................ 63 
13.3.2 
Formulation, Packaging and Labelling ..................................................... 63 
13.3.3 
Storage and Stability ................................................................................. 64 
13.4 
Drug Accountability...................................................................................... 64 
13.5 
Subject Compliance with Study Drug Dosing .............................................. 65 
14.0 
Non-Study Treatments .......................................................................................... 65 
14.1 
Prior and Concomitant Medications ............................................................. 65 
14.2 
Prohibited Medications ................................................................................. 65 
14.3 
Medications to be Administered with Caution and Monitored as Appropriate
 
66 
14.4 
Voriconazole Drug Interactions .................................................................... 66 
14.5 
Study Restrictions ......................................................................................... 67 
15.0 
Study Procedures .................................................................................................. 68 
15.1 
Informed Consent.......................................................................................... 68 
15.2 
Inclusion and Exclusion Criteria ................................................................... 68 
15.3 
Subject Enrollment and Assignment of Subject Number ............................. 68 
15.4 
Randomization .............................................................................................. 68 
15.5 
Medical History and Demographics ............................................................. 69 
15.6 
General Physical Examination, Including Visual Function Assessment ...... 69 
15.7 
Vital Signs ..................................................................................................... 69 
15.8 
Twelve-Lead Electrocardiogram .................................................................. 69 
15.9 
Pregnancy Test .............................................................................................. 70 
15.10 
Karnofsky Performance Status Scale ............................................................ 70 
15.11 
Targeted Physical Examination, Including Clinical Evaluation of Signs and 
Symptoms of Infection .................................................................................................. 70 
15.12 
Chest CT Scan............................................................................................... 70 
15.13 
Other Imaging ............................................................................................... 71 
15.14 
Mycological Testing Other than Serum GMI, Serum β-D Glucan and Plasma 
Aspergillus PCR ............................................................................................................ 71 
15.15 
Galactomannan Index Assessment ............................................................... 71 
15.16 
Serum β-D-Glucan and Plasma Aspergillus PCR Test ................................. 72 
15.17 
Safety Laboratory Tests ................................................................................ 72 
15.18 
Voriconazole Therapeutic Drug Monitoring ................................................ 74 
15.19 
Voriconazole Level Determination ............................................................... 74 
15.20 
SCY-078 Pharmacokinetic Sample Collection ............................................. 74 
15.21 
Assessment of Treatment Outcome .............................................................. 75 
15.22 
Recurrence .................................................................................................... 75 
15.23 
Survival ......................................................................................................... 75 
15.24 
Study Drug Dispensing ................................................................................. 76 
15.25 
Study Drug Dosing ....................................................................................... 76 
15.26 
Study Drug Collection and Treatment Compliance Evaluation ................... 77 
15.27 
Subject Diary Dispensing, Collection and Review ....................................... 77 
15.28 
Prior and Concomitant Medication Review .................................................. 77 
15.29 
Adverse Event Monitoring ............................................................................ 77 
16.0 
Study Schedule...................................................................................................... 79 

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17.0 
Safety Assessments and Monitoring ..................................................................... 83 
17.1 
Definition of an Adverse Event .................................................................... 83 
17.2 
Definition of a Serious Adverse Event ......................................................... 83 
17.3 
Events of Clinical Interest ............................................................................. 84 
17.4 
Overdose ....................................................................................................... 84 
17.5 
Pregnancy ...................................................................................................... 85 
17.6 
Unexpected Adverse Event ........................................................................... 85 
17.7 
Grading of Adverse Events ........................................................................... 85 
17.8 
Causality Assessment.................................................................................... 86 
17.9 
Adverse Event Collection Timeframe .......................................................... 86 
17.10 
Serious Adverse Event Reporting Requirements .......................................... 86 
17.11 
Adverse Event and Serious Adverse Event Follow-up ................................. 86 
17.12 
Serious Adverse Event Reporting – Procedures for Investigators ................ 87 
17.13 
Procedures for Emergency Unblinding ......................................................... 87 
18.0 
Data Collection, Study Monitoring and Record Management.............................. 87 
18.1 
Data Collection and Reporting...................................................................... 87 
18.2 
Study Monitoring .......................................................................................... 87 
18.3 
Investigator Study Files ................................................................................ 88 
18.4 
Retention of Records..................................................................................... 88 
19.0 
Analytical Plan ...................................................................................................... 89 
19.1 
Sample Size Determination........................................................................... 89 
19.2 
Analysis Populations ..................................................................................... 89 
19.3 
Subject Disposition, Discontinuation, and Baseline Data ............................ 90 
19.4 
Handling of Missing Data, Dose Adjustments, and Early Withdrawals....... 90 
19.5 
Prior and Concomitant Medications ............................................................. 90 
19.6 
Safety ............................................................................................................ 91 
19.6.1 
Safety Assessments ................................................................................... 91 
19.6.2 
Safety Analyses ......................................................................................... 91 
19.7 
Efficacy ......................................................................................................... 91 
19.7.1 
Efficacy Assessments................................................................................ 91 
19.7.2 
Efficacy Analyses ..................................................................................... 94 
19.8 
Pharmacokinetics .......................................................................................... 95 
19.8.1 
Pharmacokinetic Assessments .................................................................. 95 
19.8.2 
Pharmacokinetic Analyses ........................................................................ 95 
20.0 
Ethics and Protection of Human Patients.............................................................. 96 
20.1 
Ethical Conduct of the Study ........................................................................ 96 
20.2 
Institutional Review Board/Ethics Committee Review ................................ 96 
20.3 
Informed Consent.......................................................................................... 96 
20.4 
Future Use of Samples .................................................................................. 97 
20.5 
Subject Privacy and Subject Confidentiality ................................................ 97 
20.6 
Study Termination ........................................................................................ 97 
20.7 
Financial Disclosure...................................................................................... 97 
21.0 
References ............................................................................................................. 98 
22.0 
Appendices .......................................................................................................... 101 

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22.1 
Appendix A:  Prohibited Medications and Medications to be Administered 
with Caution ................................................................................................................ 101 
22.1.1 
Prohibited Medications ........................................................................... 101 
22.1.2 
Medications to be administered with Caution and Monitored as 
Appropriate ............................................................................................................. 102 
22.2 
Appendix B: Voriconazole Label ............................................................... 104 
22.3 
Appendix C: Definitions of Invasive Fungal Disease (IFD) ...................... 105 
22.4 
Appendix D: Karnofsky Performance Status Scale .................................... 107 
 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design ........................................................................... 36 
Figure 2 
Cumulative survival probability in neutropenic rabbit model of experimental 
pulmonary aspergillosis (n=6 each group) ........................................................................ 42 
Figure 3 
Galactomannan antigenemia in neutropenic rabbit model of experimental 
pulmonary aspergillosis (n=6 each group) ........................................................................ 43 
Figure 4 
Chemical Structure of SCY-078 Citrate ....................................................... 63 
LIST OF TABLES 
Table 1    
In vitro Activity of SCY-078 against Aspergillus species ............................ 39 
Table 2 In vitro activity of SCY-078 plus VOR in combination against A. fumigatus 
strains (each test performed in duplicate) ......................................................................... 40 
Table 3 Study Treatment Groups First 20 Randomized Subjectsa ............................. 60 
Table 4 Schedule of Treatment Visits and Procedures (Study SCY-078-206) .............. 79 
Table 5 Schedule of Treatment Visits and Procedures for Days 42 and 84  (Study SCY-
078-206) ........................................................................................................................... 82 
 
 
 
 

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4.0 
Revision History 
 

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Revisions to Protocol dated 01 August 2019 (Protocol Version 5.0) 
Current Version and Date: Protocol Amendment 5 (Protocol Version 6.0) dated XX 
September 2020 
Protocol Section 
Change and Rationale 
Section 1.0 Contact Information 
Deleted 
 as the CRO and added 
 as 
the CRO for Europe.  
Synopsis 
Study Design 
Amended the following paragraphs to delete the 
strikethrough text and include the bolded text: 
 
This is a multicenter, randomized, double-blind, two-arm 
study to evaluate the safety, tolerability, efficacy and PK of 
the coadministration of SCY-078 plus voriconazole 
compared to the coadministration of SCY-078 placebo plus 
voriconazole in male and female subjects 18 years of age 
and older with a possible, probable or proven IPA. based on 
EORTC MSG criteria. In addition, all subjects must be 
positive (≥0.5) for serum GMI (serum or BAL). 
Being this a Phase 2 study, multiple secondary and 
exploratory endpoints are planned, which will be evaluated 
as data allow considering the limitation of the planned 
sample size. Subjects must meet all study criteria to be 
eligible for inclusion. 
Subjects with a probable or proven IPA as defined in Section 
22.3 AND at least one positive serum or BAL GMI sample 
collected 
within 
96 
hours 
before 
enrollment 
(Baseline/Treatment Day 1) who meet all other inclusion and 
exclusion criteria will enter the Treatment Period and will be 
randomized to one of the two study treatment groups. 
The Screening Visit Period and Baseline visit (Treatment 
Day 1) may occur simultaneously for subjects who have met 
the criteria for a positive serum or BAL GMI test (Serum ≥ 
0.5 or BAL ≥1) probable or proven  at the time of IPA at 
screening diagnosis, if all other criteria are met 
Subjects with possible IPA may enter the Screening Period of 
the study. During the Screening Period, subjects will receive 
voriconazole or any other mold-active agent (e.g., 
echinocandin, amphotericin B, or other azoles for mold 
infections) as per label instructions and local standard 
practice,  and samples for serum determination of GMI will 
be collected on a daily basis. Other samples (e.g., 
bronchioalveolar lavage, cytology or histopathology) may 

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be collected as clinically indicated to confirm the IPA 
diagnosis. For subjects that only have BAL GMI, subsequent 
BAL, if done, should be sent for GMI measurements.  
Subjects may remain in the Screening Period (i.e. Screening 
Days -4 to -1) until one positive serum or BAL GMI test is 
reported the criteria of probable or proven IPA is met 
(Section 22.3), but in no case for more than 4 days of mold-
active antifungal treatment unless approved by the medical 
monitor, as explained below. This 4-day mold-active 
antifungal treatment limit prior to randomization is inclusive 
of any days of mold-active antifungal that the subject may 
have received prior to Screening.  Once the criteria for a 
probable or proven IPA is met a positive serum or BAL 
GMI test is reported and, if all other inclusion and exclusion 
criteria are met, the subject will enter the Treatment Period 
and will be randomized to one of the two study treatment 
groups. 
Subjects meeting criteria for probable or proven IPA with 
positive serum or BAL GMI results available shortly after the 
subject has reached the 4-day mold-active antifungal 
treatment limit allowance (i.e., after 4 days but no more than 
7 days of mold-active antifungal treatment) may be 
randomized into the study with the approval of the medical 
monitor, who will take into consideration the total number of 
days of mold-active agent administration up to that point as 
well as the subject´s response to therapy. If serum or BAL 
GMI the criteria for probable or proven IPA is not met 
within 7 days after initiation of mold-active antifungal 
treatment for the IPA episode results are negative, the 
subject will not be randomized and will be discontinued from 
the study. Only limited information will be collected for 
screened subjects who do not qualify for enrollment. 
This study is intended for subjects with an IPA episode that, 
in the investigator´s judgement, requires antifungal therapy 
and is reasonable to expect that be adequately treated with 
voriconazole. (i.e., the IPA is not due to a voriconazole
resistant isolate or a breakthrough infection while receiving 
a mold active azole antifungal  [voriconazole, posaconazole, 
isavuconazole or itraconazole] that requires therapy with a 
non azole antifungal agent). Subjects with breakthrough 
IPA while receiving a mold active azole antifungal 
prophylaxis may be considered for enrollment if, in the 
investigator´s judgement, the IPA episode is expected to 
be adequately treated with voriconazole. in circumstances 
in which the antifungal prophylaxis is considered not 

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optimally administered (e.g. only few doses were given, 
frequent interruptions, subject not achieving adequate 
plasma exposures) and/or if the Aspergillus spp. isolate 
(when available) is known or expected to be susceptible to 
voriconazole.    
Synopsis 
Target Population 
Male or female subjects 18 years of age and older with a 
possible, probable or proven IPA based on EORTC MSG 
criteria plus at least one positive serum GMI test. 
Synopsis 
KEY Inclusion Criteria AND 
Section 12.1 Inclusion Criteria 
Amended Inclusion #2 to delete the strikethrough text and 
include the bolded text: 
2. Subject has a possible, probable or proven IPA 
based on the protocol-specified criteria EORTC 
MSG (Section 22.3) that requires antifungal 
treatment. 
a. Note: Subjects with possible IPA may 
enter the Screening Phase of the study 
but will only be randomized after 
meeting criteria for probable or proven 
IPA.  
The Inclusion Criteria was updated to clarify the IPA 
treatment requirement. 
Synopsis 
KEY Inclusion Criteria AND 
Section 12.1 Inclusion Criteria 
Remove Inclusion #3 in entirety: 
3. Subject has a result of a serum GMI ≥0.5 OR a 
result from a BAL sample GMI ≥1.  Either result 
should be from a sample obtained within the 96 
hours preceding enrollment into the study 
(Baseline/Treatment Day 1). 
Synopsis 
KEY Inclusion Criteria AND 
Section 12.1 Inclusion Criteria 
Simplified Inclusion #6 to read as follows: 
6. For subjects who are receiving antifungal 
prophylaxis, the Subject has an IPA episode would, 
in the investigator´s judgement, requires antifungal 
therapy and may be adequately treated with 
voriconazole. (i.e., the IPA is not a breakthrough 
infection while receiving a mold active azole 
antifungal  [voriconazole, posaconazole, 
isavuconazole or itraconazole] that requires therapy 
with a non azole antifungal agent). 
The Inclusion Criteria was updated to clarify the IPA 
treatment requirement. 
Synopsis 
Study Evaluations 
Amended the following sentence with the bolded text: 
Efficacy Evaluations: Efficacy will be assessed primarily in 
terms of Global Response, ACM and GMI decrease (GMI 

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decrease will only be assessed for subjects with a serum 
GMI above 0 at Baseline). 
 
Text added to clarify the efficacy evaluation 
Section 8.1 Background 
Information 
Exposure information was updated 
Section 11.1 
Overall Description of the Study 
Amended the following paragraphs to delete the 
strikethrough text and include the bolded text: 
This is a multicenter, randomized, double-blind, two-arm 
study to evaluate the safety, tolerability, efficacy and PK of 
the coadministration of SCY-078 plus voriconazole 
compared to coadministration of SCY-078 placebo plus 
voriconazole in male and female subjects 18 years of age 
and older with possible, probable or proven IPA as defined 
in based on EORTC MSG criteria (see Section 12.122.3 
(adapted EORTC-MSG criteria)). In addition, all subjects 
must be positive (≥0.5) for serum GMI (serum or BAL).   
The primary objective of the study is to evaluate the safety 
and tolerability of the coadministration of SCY-078 plus 
voriconazole compared to the coadministration of SCY-078 
placebo plus voriconazole in the treatment of IPA. 
Secondary objectives include efficacy assessments based on 
Global Response, ACM and GMI decrease (GMI decrease 
will only be assessed for subjects with a Serum GMI 
above 0 at Baseline), and PK. Being this a Phase 2 study, 
multiple secondary and exploratory endpoints are planned, 
which will be evaluated as data allow considering the 
limitations of the planned sample size. 
This study is intended for subjects with an IPA episode that, 
in the investigator´s judgement, requires antifungal therapy 
and is reasonable to expect that be adequately treated with 
voriconazole.  (i.e., the IPA is not due to a voriconazole
resistant isolate or a breakthrough infection while receiving 
a mold active azole antifungal  [voriconazole, posaconazole, 
isavuconazole or itraconazole] that requires therapy with a 
non azole antifungal agent). Subjects with breakthrough 
IPA while receiving a mold active azole antifungal 
prophylaxis may be considered for enrollment if, in the 
investigator´s judgement, the IPA episode is expected to 
be adequately treated with voriconazole. in circumstances 
in which the antifungal prophylaxis is considered nt 
optimally administered (e.g. only few doses were given, 
frequent interruptions, subject not achieving adequate 

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plasma exposures) and/or if the Aspergillus spp. isolate 
(when available) is known or expected to be susceptible to 
voriconazole.    
The addition of the BAL GMI was made to include all 
EORTC/MSG IPA diagnostic criteria. 
BAL GMI is not required throughout the study and is thus 
not included in the secondary objective measurement of 
efficacy. 
Section 11.1.1.1 
Screening Period (Days -4 to -1) 
Amended the follow paragraphs to delete the strikethrough 
text and include the bolded text: 
Subjects with Probable or Proven IPA 
Subjects with a probable or proven IPA AND at least one 
positive serum or BAL GMI sample collected within 96 
hours before enrollment (Baseline/Treatment Day 1) who 
meet all other inclusion and exclusion criteria will enter the 
Treatment Period and will be randomized to one of the two 
study treatment groups.  
The Screening Period and Baseline visit (Treatment Day 1) 
may occur simultaneously. for subjects who have a positive 
serum or BAL GMI test (≥ 0.5 or 1 respectively) at the time 
of IPA diagnosis, if all other criteria are met. Subjects with 
a probable or proven IPA, as defined in Section 22.3 and 
who meet all other inclusion and exclusion criteria will 
enter the Treatment Period and will be randomized to 
one of the two study treatment groups. 
The Screening Visit and Baseline visit (Treatment Day 1) 
may occur simultaneously for subjects who have met the 
criteria for probable or proven  IPA at screening, if all 
other criteria are met. 
 
Subjects with Possible IPA 
Subjects with possible IPA may enter the Screening Period 
of the study. During the Screening Period, subjects will 
receive voriconazole or any other mold active agent (e.g., 
echinocandin, amphotericin B, or other azoles for mold 
infections) as per label instructions and local standard 
practice, and samples for serum determination of GMI will 
be collected on a daily basis.  For subjects that only have 
BAL GMI, subsequent BAL, if done, should be sent for 
GMI measurements.  Subjects may remain in the Screening 
Period (i.e., Screening Days 4 to 1) until one positive 
serum or BAL GMI test is reported, but in no case for more 
than 4 days of mold active antifungal treatment unless 
approved by the medical monitor, as explained below. Once 

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a positive serum or BAL GMI test is reported and if all other 
inclusion and exclusion criteria are met, the subject will 
enter the Treatment Period and will be randomized to one of 
the two study treatment groups. 
Subjects with positive serum or BAL GMI results available 
shortly after the subject has reached the 4 day mold active 
antifungal treatment limit allowance (i.e., after 4 days but no 
more than 7 days of mold active antifungal treatment) may 
be randomized into the study with the approval of the medical 
monitor, who will take into consideration the total number of 
days of mold active agent administration up to that point as 
well as the subject´s response to therapy. If serum or BAL 
GMI results are negative, the subject will not be randomized 
and will be discontinued from the study. Only limited 
information will be collected for screened subjects who do 
not qualify for enrollment Subjects with possible IPA may 
enter the Screening Period of the study. During the 
Screening Period, subjects will receive voriconazole or 
any other mold-active agent (e.g., echinocandin, 
amphotericin B, or other azoles for mold infections) as per 
label instructions and local standard practice,  and 
samples for serum determination of GMI will be collected 
on a daily basis.  Other samples (e.g., bronchioalveolar 
lavage, cytology or histopathology) may be collected as 
clinically indicated to confirm the IPA diagnosis. Subjects 
may remain in the Screening Period (i.e. Screening Days 
-4 to -1) until the criteria of probable or proven IPA is met 
(Section 22.3), but in no case for more than 4 days of 
mold-active antifungal treatment unless approved by the 
medical monitor, as explained below. This 4-day mold-
active antifungal treatment limit prior to randomization 
is inclusive of any days of mold-active antifungal that the 
subject may have received prior to Screening.  Once the 
criteria for a probable or proven IPA is met and, if all 
other inclusion and exclusion criteria are met, the subject 
will enter the Treatment Period and will be randomized 
to one of the two study treatment groups. 
Subjects meeting criteria for probable or proven IPA 
shortly after the subject has reached the 4-day mold-
active antifungal treatment limit allowance (i.e., after 4 
days but no more than 7 days of mold-active antifungal 
treatment) may be randomized into the study with the 
approval of the medical monitor, who will take into 
consideration the total number of days of mold-active 

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agent administration up to that point as well as the 
subject´s response to therapy. If the criteria for probable 
or proven IPA is not met within 7 days after initiation of 
mold-active antifungal treatment for the IPA episode, 
the subject will not be randomized and will be 
discontinued from the study. Only limited information 
will be collected for screened subjects who do not qualify 
for enrollment 
Section 11.1.1.2 
Baseline (Treatment Day 1) 
For subjects who have a probable or proven IPA AND a 
positive serum GMI test at the time of IPA diagnosis, the 
Screening Period and Baseline visit may be combined. For 
subjects who have a possible IPA at Screening Visit AND 
the criteria for upgrading the case to probable or proven 
IPA is gathered a positive serum GMI test (≥ 0.5) during 
the Screening Period, the inclusion and exclusion criteria 
will be reviewed again at Baseline to confirm eligibility. 
Section 11.1.2 
Study Assessment – Efficacy 
Assessments 
Removed the word serum and included the word PCR from 
the following bullet point: 
• 
mycological testing, including fungal cultures, 
PCR, histopathological or cytopathological analysis 
of relevant tissues or samples (e.g., lung biopsy 
sample, bronchoalveolar lavage [BAL] fluid), and 
serological testing (serum GMI). 
 
To ensure the section was aligned with the addition of BAL 
GMI. 
Section 13.1.2 
Treatment Duration 
The word serum was deleted from the following paragraph: 
Subjects who have received more than 4 days but no more 
than 7 days of voriconazole or other mold-active agent 
before inclusion criteria are met (i.e., positive serum GMI 
results become available) may be randomized into the study 
with the approval of the medical monitor, who will take into 
consideration the total number of days of mold-active agent 
administration up to that point as well as the subject´s 
response to therapy. 
 
To ensure the section was aligned with the addition of BAL 
GMI. 
Section 15.15 
Galactomannan Index Assessment 
Amended the following paragraph with the strikethrough 
and bolded text: 
Serum (or BAL, if used) GMI will be determined at all 
study visits. At Screening, at least one positive serum 
sample collected within 96 hours before enrollment must be 

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available for all subjects. For subjects with a possible IPA, 
serum samples will be collected daily for a maximum 
Screening Period of 4 days (Days -4 to -1) or until one 
positive GMI result (≥0.5) is reported.  For subjects that 
only have BAL samples, if collected per local practices, 
should be sent for GMI.., subsequent BAL if done, 
should be sent for GMI measurements.  If a positive 
serum GMI test is reported (≥ 0.5 for serum  or ≥ 1 for 
BAL) after 4 days but no more than 7  of mold active 
antifungal treatment, the case will be discussed with the 
medical monitor to evaluate eligibility. If serum GMI results 
are negative, the subject will not be randomized and will be 
discontinued from the study. 
Serum GMI samples during the Screening Period for 
evaluation of enrollment qualification will be processed 
locally (either the site laboratory or a designated regional 
laboratory). These results will be available in real time to 
make enrollment decisions. Results from GMI tests 
processed  locally should be entered into the eCRF. 
 
AND 
 
An immunoenzymatic sandwich microplate assay method 
will be generally used to determine serum GMI. Other 
methods such as lateral flow devices, which have received 
CE mark and/or FDA approval for galactomannan 
determination in serum and BAL, may be used during the 
Screening Period for evaluation of enrollment qualification. 
In these cases, enrollment qualification will be based on the 
device label recommendation for considering a serum test as 
positive, which in general should correspond to GMI ≥ 0.5 
in a immunoenzymatic sandwich microplate assay.  
 
The addition of the BAL GMI was made to include all 
EORTC/MSG IPA diagnostic criteria. 
Section 15.21 
Assessment of Treatment 
Outcome 
Included the bolded text in the following bullet point: 
o Other mycological tests, including fungal 
cultures, histopathological and cytological 
analyses, and other serological tests (including 
BAL GMI) (Section 15.14) 
To ensure the section was aligned with the addition of BAL 
GMI. 
Section 16.0 
The following Procedure was updated with the bolded text: 

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Study Schedule  
Procedure 
All Mycological Testingj  including BAL GMIl (other than 
serum GMI, serum β -D Glucan,  and plasma Aspergillus 
PCR) 
 
To ensure the section was aligned with the addition of BAL 
GMI. 
Section 16.0 
Study Schedule  
Footnotes 
Footnote l was updated with the bolded text: 
l. 
At Screening, at least one positive serum or BAL 
sample collected within 96 hours before enrollment 
must be available for all subjects. For subjects with a 
possible IPA, serum or BAL samples will be collected 
daily for a maximum Screening Period of 4 days (Days -
4 to -1) until at least one positive GMI result (≥ 0.5 for 
serum and 1 for BAL) is reported.   If a positive serum 
or BAL GMI test is reported after 4 days but no more 
than 7 days of mold-active antifungal treatment, the case 
will be discussed with the medical monitor to evaluate 
eligibility. If GMI results during the Screening period 
are negative, the subject will not be randomized and will 
be discontinued from the study. 
 
The addition of the BAL GMI was made to include all 
EORTC/MSG IPA diagnostic criteria. 
 
 
Section 19.7.1 
Efficacy Assessments 
Amended the Section with the following bolded text: 
Efficacy will be assessed primarily in terms of Global 
Response, ACM and GMI decrease (GMI decrease will 
only be assessed for subjects with a Serum GMI above 0 
at Baseline). The DRC evaluation of Global Response is 
considered the key efficacy evaluation, considering the 
expert and independent nature of the DRC assessment. In 
addition to Global Response, clinical, mycological and 
radiological outcomes will also be assessed. Exploratory 
efficacy assessments include, among others, recurrence, 
performance indicators and other serological biomarkers (β-
D-glucan and Aspergillus PCR). 
 
BAL GMI is not required throughout the study and is ths not 
included in the secondary objective measurement of 
efficacy. 
Section 19.7.1.3 
Amended the section with the following bolded text: 
GMI decrease will be assessed in terms of absolute and 
percentage reduction relative to Baseline, and in terms of 
time to achieve the GMI absolute and percentage reductions. 

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GMI decrease will be assessed in subjects with Baseline 
serum GMI above 0, only. 
 
BAL GMI is not required throughout the study and is ths not 
included in the secondary objective measurement of 
efficacy. 
Section 22.3 
Appendix C: Definitions of 
Invasive Fungal Disease (IFD) 
Amended the following section with the strikethrough and 
bolded text:  
Mycological Criteria (all available GMI results from 
serum or BAL within 7 days prior to enrollment should 
be included in the CRF) 
 
Serum galactomannan (GM) with at least one GMI value of 
≥1 0.5 OR two consecutive samples with values of ≥0.5  are 
adequate  mycological evidence for considering an IPA as 
probable in this study. 
 
BAL galactomannan (GM) with at least one GMI value 
of ≥1 
 
Cytology, direct microscopy, culture or polymerase 
chain reaction (PCR) from bronchoalveolar lavage 
(BAL) fluid, bronchial brush, or other lung samples 
indicating presence of Aspergillus spp 
o Demonstration of additional positive 
mycological criteria such us BAL GM, 
cytology, direct microscopy, culture 
from non sterile sites, antigen detection 
and polymerase chain reaction (PCR) 
may be used by the DRC to confirm 
probable or proven IPA during the 
analysis.  However, for the purpose of 
enrollment into the study, a positive 
serum GM is required. 

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5.0 
Abbreviations 
ABBREVIATION 
DEFINITION 
ACM 
all-cause mortality 
AE 
adverse event 
ALT 
alanine aminotransferase 
AMB 
amphotericin B 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve (0 to infinity) 
AUC0–24 
area under the concentration-time curve (0 to 24 hours) 
BAL 
bronchoalveolar fluid 
BID 
twice daily 
BUN 
blood urea nitrogen 
CD 
compact disk 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
clearance/fraction 
CLSI 
Clinical and Laboratory Standards Institute 
Cmax 
maximum concentration 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CSP 
caspofungin 
CT 
computed tomography 
CYP 
cytochrome P450 
DRC 
Data Review Committee 
DVD 
digital versatile disk 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECI 
event of clinical interest 
eCRF 
electronic case report form 

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ABBREVIATION 
DEFINITION 
EDC 
electronic data capture 
EORTC 
European Organization for Research and Treatment of 
Cancer 
EoT 
end of treatment 
EUCAST 
European Committee on Antimicrobial Susceptibility 
Testing 
FDA 
Food and Drug Administration 
FU 
follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
GMI 
galactomannan index  
GSI 
glucan synthase inhibitor 
GvHD 
graft-versus-host disease 
HCT 
hematopoietic stem cell transplant 
HDPE 
high density polyethylene 
HM 
hematologic malignancy  
IB 
Investigator´s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
intensive care unit 
ID 
identification 
IFD 
invasive fungal disease 
IPA 
invasive pulmonary aspergillosis 
IRB 
Institutional Review Board 
ISA 
isavuconazole 
ITT 
Intent-to-treat 
IV 
intravenous 
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 

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ABBREVIATION 
DEFINITION 
LFAB 
lipid formulation of amphotericin B 
LFT 
liver function test 
MEC 
minimal effective concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
mITT 
modified intent-to-treat 
MRI 
magnetic resonance imaging 
MSG 
Mycoses Study Group 
NG 
nasogastric 
OTC 
over-the-counter 
PBPK 
Physiologically Based Pharmacokinetic 
PD 
pharmacodynamics 
PEG 
percutaneous endoscopic gastrostomy 
PI 
principal investigator 
PK 
pharmacokinetics 
Pop PK 
population pharmacokinetics 
PP 
per protocol 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
QTcF 
QTc interval corrected for heart rate using Fridericia´s 
c rr cti n
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
standard of care 
TDM 
therapeutic drug monitoring 
TEAE 
treatment-emergent adverse event 

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ABBREVIATION 
DEFINITION 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WT 
wild type 
β-hCG 
β-human chorionic gonadotropin 
 
 
 
 

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6.0 
Protocol Synopsis 
Title: A Multicenter, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of 
the Coadministration of SCY-078 with Voriconazole in Patients with Invasive Pulmonary 
Aspergillosis (SCYNERGIA) 
Primary Objective:  
To evaluate the safety and tolerability of the coadministration of SCY-078 and voriconazole 
compared with the coadministration of SCY-078 placebo and voriconazole in the treatment of 
invasive pulmonary aspergillosis (IPA). 
Secondary Objectives: 
• 
To evaluate the efficacy of the coadministration of SCY-078 and voriconazole compared 
with that of SCY-078 placebo and voriconazole in the treatment of IPA  
o based on Global Response  
 
as determined by the Data Review Committee (DRC) 
 
as determined by the Principal Investigator  
o based on all-cause mortality (ACM) 
o based on serum galactomannan index (GMI) decrease 
o based on clinical response, mycological response and radiological response  
 as determined by the DRC 
 as determined by the Principal Investigator 
• 
To evaluate the pharmacokinetics (PK) of SCY-078 and voriconazole 
Exploratory Objectives: 
• 
To evaluate the efficacy of the coadministration of SCY-078 and voriconazole compared 
with coadministration of SCY-078 placebo and voriconazole  
o based on other biomarkers of fungal infection (i.e., serum levels of β-D-glucan and 
plasma Aspergillus PCR) 
o based on change in the performance indicator (i.e., Karnofsky score) 
o based on the rate of recurrence of IPA at Week 6 after End of Treatment (EoT) as 
determined by the DRC 
o based on the need for additional systemic antifungal treatment (other than 
secondary prophylaxis) until week 6 after EoT 
• 
To evaluate the relationship between selected endpoints to ACM at Days 42 and 84. 
• 
To evaluate healthcare resources utilization for the patients receiving the coadministration 
of SCY-078 and voriconazole compared with coadministration of SCY-078 placebo and 
voriconazole based on overall hospital stay and intensive care unit (ICU) stay. 
• 
To assess the effect of the coadministration of SCY-078 and voriconazole compared with 
coadministration of SCY-078 placebo and voriconazole on on-schedule administration of 
planned therapies for the underlying condition. 

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Primary Endpoint: 
• 
Frequency of treatment-emergent adverse events (TEAEs), drug-related adverse events 
(AEs), discontinuations due to AEs and deaths. 
Secondary Endpoints: 
• 
Global Response as measured by: 
o Percentage of subjects with Complete Response or Partial Response at EoT (key 
secondary endpoint), Day 42 and Day 84, as determined by the DRC  
o Percentage of subjects with Complete Response or Partial Response at EoT, Day 42 
and Day 84, as determined by the Principal Investigator 
• 
Overall survival, defined as the time from randomization to time of death up to Day 84 
• 
Percentage of subjects who died (any cause) at Days 42 and 84 
• 
Absolute reduction and percent change in serum GMI from Baseline to Weeks 1, 2, 4 and 
6 
• 
Percentage of subjects with the following changes in serum GMI from Baseline: 
o Fifty percent reduction or greater at Weeks 1, 2, 4 and 6 
o Twenty-five percent reduction or greater at Weeks 1, 2, 4 and 6 
o Any percent reduction at Weeks 1, 2, 4 and 6 
o Reduction equal to or greater than 0.25 at Weeks 1, 2, 4 and 6 
o Reduction to < 0.5 at Weeks 1, 2, 4 and 6 
• 
Time to achieve the following changes in serum GMI from Baseline: 
o Fifty percent reduction  
o Twenty-five percent reduction  
o Any percent reduction  
o Reduction equal to or greater than 0.25  
o Reduction to < 0.5 in 2 consecutive samples 
• 
Percentage of subjects with: 
o Clinical Response at EoT, Day 42 and Day 84, as determined by the DRC  
o Mycological Response at EoT, Day 42 and Day 84, as determined by the DRC 
o Radiological Response at EoT, Day 42 and Day 84, as determined by the DRC 
• 
Percentage of subjects with: 
o Clinical Response at EoT, Day 42 and Day 84, as determined by the Principal 
Investigator  
o Mycological Response at EoT, Day 42 and Day 84, as determined by the Principal 
Investigator 
o Radiological Response at EoT, Day 42 and Day 84, as determined by the Principal 
Investigator 
• 
SCY-078 and voriconazole plasma concentrations population PK analysis 
Exploratory Endpoints: 
• Absolute and percentage changes in serum β-D-glucan from Baseline at Weeks 1, 2, 4 and 6 
• Percentage of subjects with the following changes in serum β -D-glucan from Baseline (if 
positive): 
o Fifty percent reduction or greater at Weeks 1, 2, 4 and 6 
o Twenty-five percent reduction or greater at Weeks 1, 2, 4 and 6 
o Any percent reduction at Weeks 1, 2, 4 and 6  
o Negative serum β -D-glucan at Weeks 1, 2, 4 and 6 
• Percentage of subjects that convert from positive plasma Aspergillus PCR at Baseline to 

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negative at Weeks 1, 2, 4 and 6 
• Absolute change in Karnofsky score from Baseline to Days 42 and 84 
• Time to achieve a 10-point improvement in Karnofsky score from Baseline 
• Percentage of subjects with a recurrence of the baseline fungal infection within 42 days 
(Week 6) after EoT 
• Relationship between GMI decrease and ACM at Days 42 and 84 
• Days of hospital stay, and Days of ICU stay 
• Percentage of subjects who are able to receive on-schedule administration of the planned 
therapies for their underlying condition 
Study Design: 
This is a multicenter, randomized, double-blind, two-arm study to evaluate the safety, 
tolerability, efficacy and PK of the coadministration of SCY-078 plus voriconazole compared 
to the coadministration of SCY-078 placebo plus voriconazole in male and female subjects 18 
years of age and older with a probable or proven IPA. 
 
The primary objective of the study is to evaluate the safety and tolerability of the 
coadministration of SCY-078 plus voriconazole compared to the coadministration of SCY-078 
placebo plus voriconazole in the treatment of IPA. Secondary objectives include efficacy 
assessments based on Global Response, ACM and GMI decrease, and PK. Being this a Phase 2 
study, multiple secondary and exploratory endpoints are planned, which will be evaluated as 
data allow considering the limitation of the planned sample size. Subjects must meet all study 
criteria to be eligible for inclusion.  
 
The study will be conducted at approximately 30 sites globally. Approximately 90 subjects will 
be screened to randomize a total of approximately 60 subjects (30 subjects per group) into one 
of the two treatment groups of the study (SCY-078 plus voriconazole or  SCY-078 placebo 
plus voriconazole).  
Subjects will receive study treatment for the entire duration of the antifungal therapy (i.e., for a 
recommended minimum of 6 weeks and a maximum of 13 weeks). 
The study will consist of a Screening Period (Days -4 to -1) to assess subject eligibility; a 
Baseline visit (also considered Treatment Day 1) to confirm subject eligibility and begin study 
treatment; additional scheduled treatment visits (Treatment Days 3, 7, 10, 14 and treatment visits 
every 14 days thereafter until the EoT) to perform safety, tolerability, efficacy and PK 
assessments, an EoT visit to assess efficacy outcomes, a Follow-up (FU) visit 6 weeks after EoT 
(6-Week FU) to assess recurrence and safety, and 2 survival visits/contacts to determine survival 
status and treatment outcome. The Screening Period and Baseline visit may be combined for 
certain subjects. Unscheduled visits may also be conducted as needed. 
Subjects with a probable or proven IPA as defined in Section 22.3 who meet all other inclusion 
and exclusion criteria will enter the Treatment Period and will be randomized to one of the two 
study treatment groups. 
The Screening Visit and Baseline visit (Treatment Day 1) may occur simultaneously for subjects 

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who have met the criteria for probable or proven  IPA at screening, if all other criteria are met. 
Subjects with possible IPA may enter the Screening Period of the study. During the Screening 
Period, subjects will receive voriconazole or any other mold-active agent (e.g., echinocandin, 
amphotericin B, or other azoles for mold infections) as per label instructions and local standard 
practice,  and samples for serum determination of GMI will be collected on a daily basis.  Other 
samples (e.g., bronchioalveolar lavage, cytology or histopathology) may be collected as 
clinically indicated to confirm the IPA diagnosis. Subjects may remain in the Screening Period 
(i.e. Screening Days -4 to -1) until the criteria of probable or proven IPA is met (Section 22.3), 
but in no case for more than 4 days of mold-active antifungal treatment unless approved by the 
medical monitor, as explained below. This 4-day mold-active antifungal treatment limit prior to 
randomization is inclusive of any days of mold-active antifungal that the subject may have 
received prior to Screening.  Once the criteria for a probable or proven IPA is met and, if all 
other inclusion and exclusion criteria are met, the subject will enter the Treatment Period and 
will be randomized to one of the two study treatment groups. 
Subjects meeting criteria for probable or proven IPA shortly after the subject has reached the 4-
day mold-active antifungal treatment limit allowance (i.e., after 4 days but no more than 7 days 
of mold-active antifungal treatment) may be randomized into the study with the approval of the 
medical monitor, who will take into consideration the total number of days of mold-active agent 
administration up to that point as well as the subject´s response to therapy. If the criteria for 
probable or proven IPA is not met within 7 days after initiation of mold-active antifungal 
treatment for the IPA episode, the subject will not be randomized and will be discontinued from 
the study. Only limited information will be collected for screened subjects who do not qualify 
for enrollment. 
This study is intended for subjects with an IPA episode that, in the investigator´s judgement, 
requires antifungal therapy and is reasonable to expect that be adequately treated with 
voriconazole. Subjects with breakthrough IPA while receiving antifungal prophylaxis may be 
considered for enrollment if, in the investigator´s judgement, the IPA episode is expected to be 
adequately treated with voriconazole.  
Target Population: Male or female subjects 18 years of age and older with a probable or 
proven IPA. 
KEY Inclusion Criteria 
Subjects must fulfill all of the following KEY criteria to be eligible for study admission: 
1. Subject is a male or female adult ≥18 years of age on the day the study informed 
consent form (ICF) is signed. 
2. Subject has a probable or proven IPA based on the protocol-specified criteria (Section 
22.3) that requires antifungal treatment. 
b. Note: Subjects with possible IPA may enter the Screening Phase of the study 
but will only be randomized after meeting criteria for probable or proven IPA.  
3. Subject has one of the following: 
c. a diagnosis of a hematological malignancy or a myelodysplastic syndrome or 
aplastic anemia or has undergone hematopoietic cell transplantation, OR 
d. who either recently resolved or ongoing neutropenia (neutropenia defined as 
absolute neutrophil count < 0.5 x 109/L [< 500/mm3] for > 10 days), 

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temporally related to the onset of fungal disease OR 
e. who received treatment with other recognized T-cell immunosuppressants 
(such as cyclosporine, tacrolimus, monoclonal antibodies or nucleoside 
analogs) during the past 90 days including solid organ transplant patients. OR 
f. with inherited severe immunodeficiency (e.g. chronic granulomatous disease, 
severe combined immunodeficiency). 
4. Subject has not received more than 4 days (96 hours) of prior mold-active antifungal 
therapy for the treatment of the IPA episode in the 7 days preceding enrollment into 
the study (Baseline/Treatment Day 1). However, subjects who have received more than 
4 days but less than 7 days of prior mold-active antifungal therapy for the treatment of 
the IPA episode in the 7 days preceding enrollment into the study may be enrolled but 
will require approval from the study medical monitor, who will evaluate each subject 
on a case-by-case basis. 
5. For subjects who are receiving antifungal prophylaxis the  IPA episode would, in the 
investigator´s judgement, be adequately treated with voriconazole. 
KEY Exclusion Criteria 
A subject will be excluded from participation in the study if he or she meets any of the 
following KEY exclusion criteria:  
1. Subject has a fungal disease with central nervous system involvement suspected at 
Screening. 
2. Subject is receiving, has received or anticipates to be receiving concomitant 
medications that are listed in the prohibited medication list (Appendix A in full 
protocol) within the specified washout periods. 
3. Subject has a Karnofsky score <20. 
4. Subject is expected to die from a non-infectious cause within 30 days from the day the 
study ICF is signed. 
5. Subject is under mechanical ventilation.  
6. Subject has abnormal liver test parameters: AST or ALT ≥5 x ULN and/or total 
bilirubin >2.5 x ULN.  
Note: Subjects with unconjugated hyperbilirubinemia (< 7mg/dL) with a diagnosis of 
Gilbert’s disease are not excluded. 

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Study Drugs: SCY-078 250 mg and SCY-078 250 mg matching placebo tablets will be 
provided by the Sponsor. It is expected that voriconazole (intravenous [IV] and oral) will be 
provided by the site’s pharmacy. In extenuating circumstances, when the site’s pharmacy is not 
able to provide the SOC voriconazole, the Sponsor will assist in obtaining it.  
SCY 078 citrate drug product for oral administration will be supplied as a tablet containing 
250 mg of SCY-078 active ingredient on a free-base basis. In addition to the active ingredient, 
the tablet formulation also contains silicified microcrystalline cellulose, crospovidone, 
mannitol, colloidal silicon dioxide, magnesium stearate (non-bovine) and butylated 
hydroxyanisole.  
IV voriconazole will be supplied in a single-use vial as a sterile lyophilized powder equivalent 
to 200 mg of voriconazole. Oral voriconazole will be supplied as a 200-mg tablet. 
SCY-078 drug supplies (SCY-078 citrate and matching placebo tablets) will be packaged in 
high density polyethylene (HDPE) bottles fitted with induction seals and child-resistant 
polypropylene plastic closures. 

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Study Treatment Groups: All eligible subjects will be randomized in a 1:1 ratio to one of the  
two study treatment groups and will receive treatment for a recommended minimum of 6 
weeks and a maximum of 13 weeks.  
Once randomized, subjects will receive either voriconazole plus SCY-078 or voriconazole plus 
matching SCY-078 placebo for the entire duration of the antifungal treatment, until they reach 
EoT or a discontinuation occurs.  
Voriconazole + SCY-078 
• 
Either IV voriconazole (loading dose of 6 mg/kg BID on Day 1 followed by 
maintenance dose of 4 mg/kg BID from Day 2 onwards) OR oral voriconazole 
(loading dose of 400 mg BID on Day 1 followed by maintenance dose of 200 mg BID 
from Day 2 onwards).  
PLUS 
• 
Oral SCY-078 (loading dose of 500 mg [2 tablets of 250 mg] BID on Days 1 and 2 
followed by maintenance dose of 500 mg [2 tablets of 250 mg] QD from Day 3 
onwards). After the first 10 randomized subjects have been treated with the SCY-078 
and voriconazole for at least 7 days, an interim PK analysis will be conducted. Based 
on the data from this analysis, the oral SCY-078 dose for subjects subsequently 
randomized may be increased up to a loading dose of 750 mg (3 tablets of 250 mg) 
BID on Days 1 and 2 followed by a maintenance dose of 750 mg (3 tablets of 250 mg) 
QD from Day 3 onwards.  
 
Voriconazole + SCY-078 Placebo 
• 
Either IV voriconazole (loading dose of 6 mg/kg BID on Day 1 followed by 
maintenance dose of 4 mg/kg BID from Day 2 onwards) OR oral voriconazole 
(loading dose of 400 mg BID on Day 1 followed by maintenance dose of 200 mg BID 
from Day 2 onwards).   
PLUS 
• 
Placebo matching oral SCY-078. 
o Subjects prior to interim PK analysis: loading dose of 2 tablets given BID on Days 
1 and 2 followed by maintenance dose of 2 tablets given QD from Day 3 onwards 
o Subjects subsequently randomized (depending on interim PK analysis): loading 
dose of up to 3 tablets given BID on Days 1 and 2 followed by a maintenance dose 
of up to 3 tablets given QD from Day 3 onwards 
Subjects will receive the administration of voriconazole as per label instructions and local 
standard practice. The individual dose of voriconazole may be adjusted by the investigator 
according to results from standard of care voriconazole drug monitoring evaluations. Subjects 
should be instructed to take oral voriconazole 1 hour before or after a meal, every 12 hours.  
The dose of SCY-078 will not be adjusted for a particular subject. Subjects will be instructed to 
take the oral SCY-078 preferably with meal, twice a day (BID) approximately 12 hours apart 
the first 2 days (loading dose) and once daily (QD) subsequently (maintenance dose).  The 
dose of SCY-078 may be adjusted for subjects randomized after the interim PK analysis.  Until 
a decision to adjust the dose is made based on data from this analysis, subjects will continue 
receiving SCY-078 500 mg doses. 

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Study Blinding, Randomization and Stratification: This is a double-blind study. All site and 
sponsor personnel will be blinded to treatment assignment. Subject randomization will be 
performed using an Interactive Web Response System (IWRS). Eligible subjects will be 
stratified to one of these groups at randomization: 
• 
Hematological malignancies and /or hematopoietic cell transplantation recipients  
• 
Solid organ transplant recipients 
• 
Other immunocompromising conditions  
In the event that the web-based IWRS system is not available, emergency unblinding can occur 
by contacting the Endpoint help-desk as follows: http://www.endpointclinical.com/help-desk. 
Study Evaluations  
Safety Evaluations: Subjects will be evaluated for safety and tolerability throughout the study, 
including parameters such as physical exam including visual function assessment, vital signs, 
12-lead electrocardiograms (ECGs), safety laboratory tests (hematology, blood chemistry and 
urinalysis), concomitant medications, AEs and treatment discontinuations. Electrolyte 
disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be 
monitored and corrected, if necessary, prior to initiation and during voriconazole therapy.  
AEs will be collected and evaluated from Baseline (Treatment Day 1) ), after the first dose of 
SCY-078 and SOC voriconazole and through the end of the study. AEs will also be collected at 
any unscheduled visits. A general physical exam will be conducted at Screening and Baseline 
(Treatment Day 1), at EoT and at the 6-Week FU visit. The physical examination will include 
an abbreviated assessment of general appearance, skin, eyes, heart, chest and abdomen. An 
overall visual function assessment will also be conducted as part of the physical exam to 
investigate visual acuity, visual field and color perception at Screening or Baseline. This visual 
function assessment will be repeated at approximately Treatment Day 28 if voriconazole 
treatment continues beyond 28 days. Vital signs, including blood pressure (systolic and 
diastolic), heart rate, respiratory rate and body temperature will be measured at Screening and 
Baseline (Treatment Day 1), at EoT and at unscheduled visits, if applicable. Safety laboratory 
tests (hematology, blood chemistry and urinalysis) will be performed at Screening and Baseline 
(Treatment Day 1), and on Treatment Days 7 and 14, at EoT and 6-Week FU. In addition, serum 
transaminase levels, bilirubin levels, serum electrolytes (potassium, magnesium and calcium) 
and amylase and lipase should be monitored at initiation of voriconazole therapy (Day 1) and 
then weekly during the first month of treatment (Day 7, Day 14, around Day 21 and Day 28). 
Monitoring frequency of these laboratory parameters may be reduced to monthly intervals during 
continued use of voriconazole if no clinically significant changes are noted. All medications 
(including prescription and over the counter [OTC] medications, supplements, and herbal 
products) taken from 28 days before Screening through the EoT will be recorded on the eCRF. 
Only the use of antifungal medications, antibiotics for any reason or medications to treat an AE 
will be recorded after EoT and through the 6-Week FU visit. 
Efficacy Evaluations: Efficacy will be assessed primarily in terms of Global Response, ACM 
and GMI decrease (GMI decrease will only be assessed for subjects with a positive serum GMI 
at Baseline). In addition to Global Response, clinical, mycological and radiological outcomes 
will also be assessed. Exploratory efficacy assessments include, among others, recurrence, 

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performance indicators and other serological biomarkers (β-D-glucan and Aspergillus PCR). 
The following treatment outcome definitions will be used for the assessment of efficacy: 
Global Response will be assessed based on the following definitions: 
• 
Global Response 
• 
Complete Response: Survival and resolution of all attributable symptoms and signs 
of disease; plus, successful radiological outcome; plus, documented mycological 
eradication of infected sites that are accessible to repeated sampling or presumed 
eradication of sites that are not accessible to repeated sampling.  
• 
Partial Response: Survival and improvement of attributable symptoms and signs of 
disease; plus at least 25% reduction in diameter of radiological lesion(s); plus, 
documented mycological eradication of infected sites that are accessible to repeated 
sampling or presumed eradication of sites that are not accessible to repeated 
sampling. In cases of radiological stabilization (defined as 0%-25% reduction in the 
diameter of the lesion), resolution of attributable symptoms and signs of fungal 
disease can be equated with a partial response. In cases of radiological stabilization, 
biopsy of an infected site (e.g., lung biopsy) showing no evidence of hyphae and 
negative culture results can be equated with a partial response.  
• 
Stable response: Survival and no improvement in any attributable symptoms and 
signs of disease; plus, radiological stabilization (defined as a 0%-25% reduction in 
the diameter of the lesion); or persistent isolation of mold or histological presence 
of invasive hyphae in infected sites.  
• 
Progression of disease: Worsening clinical symptoms and signs of disease; plus, 
new sites of disease or radiological worsening of preexisting lesions; or persistent 
isolation of mold species from infected sites.  
• 
Death: Death during the prespecified period of evaluation regardless of attribution. 
 
Clinical, mycological and radiological outcome will be assessed based on the following 
definitions:  
• 
Clinical response 
 
Success: 
• 
Resolution of all attributable clinical symptoms and physical findings 
• 
Partial resolution of attributable clinical symptoms and physical findings 
 
Failure: 
• 
No resolution of any attributable clinical symptoms and physical findings and/or 
worsening 
 
Not applicable: 
• 
No attributable signs and symptoms present at Baseline and no symptoms 
attributable to invasive fungal disease developed post Baseline 
• 
Mycological response 
 
Success: 
• 
Eradication 
• 
Presumed eradication 
 
Failure: 

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• 
Persistence 
• 
Presumed persistence  
 
Not applicable: 
• 
No mycological evidence available at Baseline  
 
• 
Radiological response 
 
Day 42: 
• 
Success (improvement of at least 25% from Baseline) 
• 
Failure 
• 
No post Baseline radiology available for patient with baseline evidence of 
radiological disease 
• 
Radiology not applicable at Baseline 
 
Day 84: 
• 
Success (improvement of at least 50% from Baseline) 
• 
Failure 
• 
No post Baseline radiology available for patient with baseline evidence of 
radiological disease 
• 
Radiology not applicable at Baseline 
 
EoT: 
• 
Success (improvement of at least 25% from Baseline if EoT occurs prior to Day 42; 
if EoT occurs after Day 42, at least 50% improvement from Baseline) 
• 
Failure 
• 
No post Baseline radiology available for patient with baseline evidence of 
radiological disease 
• 
Radiology not applicable at Baseline 
Pharmacokinetic Evaluations: Voriconazole level determination as well as SCY-078 PK will 
be performed for all study subjects. Therapeutic drug monitoring (TDM) for voriconazole will 
be conducted as per local standard practice and samples for voriconazole TDM will be 
analyzed at the local laboratory. The target trough plasma concentration should be above 
1.5 mg/L.   
For the first 20 randomized subjects, blood PK samples will be collected predose on Treatment 
Days 1, 3, 7 and 14, approximately within 1 hour before dosing, and on Treatment Days 1, 7 
and 14 at 2-4 hours and 6-8 hours after dosing for SCY-078 and voriconazole central lab PK 
testing. The PK data from the first 20 subjects will be assessed in an interim PK analysis that 
will keep the study team blinded. 
For subsequent randomized subjects, blood PK samples will be collected predose on Treatment 
Days 1, 3, 7 and 14, approximately within 1 hour before dosing, and on Treatment Days 1, 7 
and 14 at 4-8 hours after dosing for SCY-078 and voriconazole central lab PK testing.  Results 
for plasma concentrations of SCY-078 and voriconazole analyzed by the central laboratory will 
not be available in real time. 
Statistical Analyses: 
All statistical processing will be performed using SAS® version 9.3 or later, unless otherwise 
stated. Descriptive statistics (i.e., number of subjects, mean, standard deviation, median, 
minimum, maximum) will be presented for all continuous variables; number and percentage of 

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subjects will be presented for categorical variables. For parameters measured over time, 
observed data and changes from baseline will be described for each time point. A Statistical 
Analysis Plan (SAP) describing all statistical analyses in detail will be provided as a separate 
document. 
Sample Size Determination 
This is an exploratory study with safety as a primary objective.  As a result, no formal sample 
size calculations are defined and the data from this study will provide safety data for SCY-078 
in patients along with a preliminary view of efficacy data, which can be used to design future 
studies. 
Analysis Populations  
The study populations used for the analyses are as follows: 
Intent-to-Treat (ITT)/Safety Population: The ITT Population will include all randomized 
subjects who receive at least one dose of randomized study medication. The Safety Population 
will be the same as the ITT population. 
Modified Intent-to-Treat (mITT) Population: The mITT population will be a subset of the 
ITT population that will include subjects who have a probable or proven IPA at baseline, per 
DRC, with at least one positive serum GMI at baseline. 
Per-Protocol (PP) Population: The PP Population will be a subset of the ITT population and 
will include subjects who have a probable or proven IPA at baseline, per DRC, with at least 
one positive serum GMI at baseline, have completed at least 14 days of randomized study 
treatment and have at least one efficacy assessment post Baseline (Treatment Day 1) and no 
major protocol deviations. 
PK Population: The PK Population will include all enrolled subjects who provide at least one 
PK sample. 
Handling of Missing Data, Dose Adjustments and Early Withdrawals 
For the efficacy analyses, subjects who do not have an EoT assessment will be assigned an 
indeterminate outcome, so will be classed as treatment failures for the corresponding efficacy 
analyses. For subjects who withdraw from the study early, every effort will be made to collect 
EoT visit information at the point of withdrawal. 
Safety Analyses 
All safety analyses will be conducted using the ITT/safety population; all safety variables will 
be listed. 
The incidence and severity of TEAEs and serious adverse events (SAEs) and their relationship 
to treatment will be summarized.  AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 19.1 or higher and presented by system organ class 
and preferred term.   
Early discontinuation of study drug treatment will be presented and will include the reasons for 
and timing of such discontinuations.  
Prior and concomitant medications will be summarized; medications will be classified based 
on the World Health Organization´s Drug Dictionary terminology. 
Abnormal physical examinations will be listed.  Laboratory evaluations will be summarized as 
observed values and changes from Baseline; shifts with respect to the laboratory reference 
range will be summarized. Events of clinical interest will be summarized. 
Vital signs and ECG evaluations will be summarized as observed values and changes from 

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Baseline. 
Efficacy Analyses 
The secondary efficacy endpoint, the percentage of subjects with successful Global Response 
(Complete Response or Partial Response) at EoT, Day 42 and Day 84 as determined by the 
DRC and the Principal Investigator will be presented by treatment group along with an 
estimate of the difference between treatment groups.  The response rate will be calculated for 
each treatment group as the number of successes divided by the total number of patients 
(success + failure + indeterminate). The difference in response rates between treatments will be 
presented along with a 95% confidence interval (CI), calculated using the method of Miettinen 
and Nurminen. The secondary analysis of ACM at Day 42 and Day 84 will be presented by 
treatment group along with an estimate of the difference between treatment groups. In addition, 
a Kaplan Meier plot will be produced to summarize overall survival over time. 
The remaining secondary and exploratory endpoints will be summarized by treatment group. 
Provided sufficient data are available to allow meaningful presentation, results of the key 
efficacy parameters will also be presented by oral SCY-078 dose level; by baseline Aspergillus 
species; by baseline minimum inhibitory concentration (MIC) and minimal effective 
concentration (MEC) for voriconazole and SCY-078, respectively; and by baseline neutropenia 
and persistent neutropenia at Week 2. 
Considering the exploratory nature of this study, further analysis may be defined in the statistical 
analysis plan, as deemed appropriate.  For example, if the data are heterogeneous within this 
randomized study, attempts may be made to match patients across the treatment groups on key 
disease criteria, provided sufficient data are available, to better understand the comparability of 
the randomized groups. 
Pharmacokinetic Analyses 
The sparse samples collected in this study will be analyzed using Population PK (Pop PK) 
analysis methods to estimate PK parameters (Cmax, AUC, clearance/fraction absorbed [CL/F]) 
as applicable. Key collection and analysis timepoints include Day 1, Day 7 (i.e., steady state) 
and Day 14.   
After the first 20 subjects  have been treated for at least 7 days, an interim PK evaluation will 
be conducted to ensure that there are no clinically relevant effects of the co-administration of 
SCY-078 and voriconazole on the PK exposure (predicted AUC and Cmax based on updated 
population PK model) of both drugs. The data from this analysis will inform, and if necessary 
adjust, the doses of the study drug for subjects subsequently randomized. The overall goal, 
considering that IPA is a life-threatening condition, is to ensure that >80% of subjects achieve 
an exposure that is at least equal to that reported as efficacious in the mice models of invasive 
aspergillosis (15.6 μg•mL/hr). 
The results from the PK analyses will be presented in a separate report. 
 
 

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7.0 
Schematic of Study Design 
 
 
 
Figure 1 
Schematic of Study Design 
 
 
 
 
End of Treatment 
Screening 
(Days -4 to -1) 
Baseline 
(Day 1) 
Randomization 1:1 
IV or Oral Voriconazole 
+  
Oral SCY-078 
(min. 6 and max. 13 weeks of 
treatment) 
IV or Oral Voriconazole 
+  
Oral Matching Placebo 
(min. 6 and max. 13 weeks of 
treatment) 

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8.0 
Background Information and Scientific Rationale 
8.1 
Background Information 
 Introduction and rationale  
SCY-078 represents the first compound of the triterpene class of β-(1,3)-D-glucan synthesis 
inhibitors in development for the treatment of fungal infections. It is structurally distinct and 
retains activity in vitro against both azole-resistant and, importantly, the majority of clinical 
Candida isolates containing FKS gene mutations, which confer echinocandin resistance. Unlike 
echinocandins, SCY-078 is orally bioavailable, with in vitro and in vivo activity against Candida 
and Aspergillus species and, as such, it would represent the first oral non-azole treatment 
alternative for these infections. 
Aspergillus species are ubiquitous in nature, and inhalation of infectious conidia from the 
environment is a frequent event. Tissue invasion is uncommon and invasive pulmonary 
aspergillosis (IPA) occurs most frequently in the setting of neutropenia and immunosuppression 
associated with therapy for hematologic malignancies, hematopoietic cell transplantation, or 
solid organ transplantation. 
Histopathologically, invasive aspergillosis is characterized by progression of the infection across 
tissue planes. One hallmark of infection is vascular invasion with subsequent infarction and 
tissue necrosis. Most invasive infections are caused by members of the A. fumigatus species 
complex followed by A. flavus, A. niger, and A. terreus.  
 
Treatment options for Invasive Aspergillosis 
Voriconazole and isavuconazole are recommended for first-line (or “primary”) therapy for IPA 
and lipid formulations of amphotericin B (LFABs) as well as echinocandins are alternative 
treatments.1,2 However, diagnosis and treatment are still sub-optimal, and outcomes remain poor, 
especially in hematopoietic stem cell transplant (HSCT) recipients, with studies demonstrating 
unfavorable responses in >40% of such patients.3 This is reflected by increased efforts in 
prophylactic and diagnostic strategies to either prevent the disease or start treatment as early as 
possible.  Polyenes, azoles and SCY-078 target different cellular sites, impacting the fungal cell 
membrane and the cell wall, respectively. Voriconazole and isavuconazole are azole drugs that 
block the synthesis of ergosterol. The mechanism of action of polyenes, such as amphotericin B 
(AMB), has been proposed to be an interaction with cell membrane sterol resulting in the 
production of aqueous pores. Echinocandins such as caspofungin block the synthesis of (1-3)-β-
D glucan, an essential component of the fungal cell.  
Development of resistance of Aspergillus spp. against currently used antifungal agents has been 
reported and is particularly concerning for azoles.  The widespread use of triazole antifungals in 
agricultural industry is suspected as the cause for the increasing numbers of “azole-resistant 
invasive aspergillosis”. Lipid formulations of amphotericin B are often the recommended 
alternative treatment for invasive aspergillosis in patients who fail or have infections that are 

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resistant to mold-active azoles.2,4 However, their use is often constrained by renal toxicity. 
Caspofungin is also approved for therapy in patients with invasive aspergillosis who experience 
failure with other antifungal drugs (i.e., approved for “salvage” therapy). It should be noted that 
neither echinocandins nor amphotericin B formulations are available for oral administration, 
posing a considerable limitation in terms of optimal patient care for fungal infections, which 
typically require several weeks of therapy. 
 
Combination therapy 
Although monotherapy with a single antifungal agent is in general recommended for most cases 
of IPA, combination therapy with 2 agents with different mechanisms of action has been 
explored in multiple trials and is recommended in some circumstances in recognized guidelines, 
particularly when there is a high risk of azole resistance.2,5,6 
The largest randomized controlled study evaluating antifungal combination therapy for patients 
with IPA was reported by Marr K et al. in 2015.7 This study assessed the safety and efficacy of 
voriconazole and anidulafungin compared with voriconazole monotherapy for the treatment of 
IPA. The study included 454 patients with hematological malignancies or hematopoietic stem 
cell transplantation and suspected or documented IPA and the primary analysis was done in 277 
patients with documented IPA. Although the study failed to demonstrate statistically significant 
improvement in all-cause mortality with the combination therapy when compared with 
monotherapy, there was a clear trend towards improved survival in the group receiving 
combination therapy. Overall mortality rates at 6 weeks were 19.3% (26 of 135) for combination 
therapy and 27.5% (39 of 142) for monotherapy (difference,  - 8.2 percentage points [95% CI, - 
19.0 to 1.5]; P = 0.087).  
Most patients (218 of 277 [78.7%]) had a diagnosis of IPA established by radiographic findings 
and mycological evidence in the form of galactomannan positivity. In a post hoc analysis of this 
dominant subgroup, 6-week mortality was lower in combination therapy than in monotherapy 
(15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; 
P= 0.037).  A limitation of this study was that anidulafungin is only available intravenously (IV), 
thus limiting its use for long-term administration as often needed in IPA patients, resulting in a 
median duration of the combination therapy of 14 days. 
 
SCY-078 antifungal activity 
The spectrum and potency of activity of SCY-078 has been evaluated by numerous independent 
laboratories against an extensive panel of clinically relevant yeast and mold isolates using the 
Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial 
Susceptibility Testing (EUCAST) methods. Overall, the epidemiological studies have 
demonstrated that SCY-078 has potent, broad-spectrum activity against the majority of the 
clinical isolates tested. These studies have laid the foundation in support of the use of SCY-078 
for the treatment of invasive fungal infections. 
 

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In vitro activity against Candida spp. 
SCY-078 has been evaluated against >2000 Candida isolates, including all clinically relevant 
species, more than 400 C. glabrata isolates and >100 C. auris isolates. These in vitro studies 
have demonstrated the broad range of anti-Candida spectrum of activity of SCY-078. 
Additionally, SCY-078 demonstrated in vitro activity against pre-formed biofilms, which is a 
relevant feature when addressing catheter-related Candida infections. Studies conducted with 
azole- and echinocandin-resistant strains have shown that SCY-078 retains activity (i.e., no 
significant change in minimum inhibitory concentration when compared to wild type) against 
>90% of azole-resistant strains and >70% of Candida strains with FKS mutations commonly 
associated with echinocandin resistance. Interestingly, although SCY-078 and the echinocandins 
share a similar mechanism of action (β-[1,3]-D-glucan synthesis inhibition), their clearly 
different molecular structure provides them with some differentiating characteristics in terms of 
microbiological activity. 
 
In vitro activity against Aspergillus spp. 
The in vitro activity of SCY-078 has been evaluated against >450 clinical Aspergillus isolates, 
including most clinically relevant species and azole-resistant strains, both with mutational 
resistance as well as a wide range of so-called cryptic Aspergillus species with reduced 
antifungal susceptibility.  
A recent study including more than 300 clinical Aspergillus spp. isolates illustrates the potent 
activity of SCY-078 against Aspergillus species.8 
 
Table 1    
In vitro Activity of SCY-078 against Aspergillus species 
 
MEC (µg/ml) 
Species 
Range 
50% 
90% 
A. flavus (n=54) 
<0.06 to 0.25 
<0.06 
<0.06 
A. fumigatus (n=134) 
<0.06 to 4 
<0.06 
0.125 
A. niger (n=27) 
<0.06 to 0.5 
<0.06 
<0.06 
A. terreus (n=72) 
<0.06 to 0.125 
<0.06 
0.125 
Other Aspergillus spp (n=24) 
<0.06 to 0.25 
<0.06 
<0.06 
A. glaucus (n=5) 
<0.06 to 0.125 
NDa 
ND 
A. nidulans (n=9) 
<0.06 to 0.125 
ND 
ND 
A. ustus (n=1) 
<0.06 
ND 
ND 
A. versicolor (n=8) 
<0.06 to 0.25 
ND 
ND 
A. westerdijkiae (n=1) 
<0.06 
ND 
ND 
All isolates (n=311) 
<0.06 to 4 
<0.06 
0.125 
a: ND, not determined (MEC50s and MEC90s  were not determined to the low number of 
isolates. 
 
 

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In vitro synergistic activity of SCY-078 with other antifungals against Aspergillus spp.  
The combination of SCY-078 with azoles and polyenes has demonstrated synergistic or additive 
anti-fungal activity in vitro. This is consistent with findings for combinations with established 
glucan-synthase inhibitors (GSIs). No antagonistic effects were observed.  
As illustrated in the table below, combination testing of SCY-078 with isavuconazole, 
voriconazole or amphotericin B demonstrated synergistic activity against most of the strains 
tested.8 
 
Table 2 
In vitro activity of SCY-078 plus VOR in combination against A. fumigatus 
strains (each test performed in duplicate) 
 
 
 
Efficacy in animal models 
The antifungal efficacy of SCY-078 has been evaluated in several murine models of 
disseminated candidiasis and aspergillosis. In a disseminated candidiasis murine model, the most 
relevant pharmacokinetic/pharmacodynamics (PK/PD) parameter associated with efficacy was 
AUC/MIC and SCY-078 area under the curve (AUC) in plasma necessary to achieve target 
efficacy in these models was estimated to be 11.2 μg•mL•hr. This exposure target has guided 
subsequent steps of the development.9 
The in vivo activity of SCY-078 was assessed against wild type (WT) and azole-resistant (TR34, 
L98H) A. fumigatus strains in neutropenic ICR mice.  Mice were infected IV into the lateral tail 
 
MIC (µg/ml) 
 
 
 
Drug tested alone 
Drug in combination 
 
 
Aspergillus 
fumigatus 
MRL strain 
SCY-078 
VOR 
SCY-078 
VOR 
FICI 
Interpretationa 
20438 
8 
1 
0.125 
0.25 
0.27 
S 
4 
1 
0.25 
0.25 
0.31 
S 
28378 
8 
0.5 
0.5 
0.125 
0.31 
S 
4 
0.25 
0.5 
0.016 
0.19 
S 
28382 
8 
0.5 
0.5 
0.125 
0.31 
S 
8 
0.5 
0.016 
0.25 
0.5 
S 
28401 
8 
2 
0.25 
0.5 
0.28 
S 
8 
2 
0.125 
0.5 
0.27 
S 
28383b 
8 
>16 
0.031 
>16 
1 
NI 
8 
>16 
0.031 
>16 
1 
NI 
28500b 
4 
>16 
1 
>16 
1.25 
NI 
8 
>16 
1 
>16 
1.13 
NI 
Abbreviations: FICI = fractional inhibitory concentration index? 
a: S, synergistic interaction (FICI ≤ 0.5); NI, no interaction (0.5 < FICI ≤ 4.0). 
b: Azole-resistant strains. 
 

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vein and SCY-078 was administered orally as a loading dose followed by twice daily (BID) 
maintenance doses. Intraperitoneal caspofungin (CSP) and AMB were used as comparator.   
Oral SCY-078 was well tolerated at all doses. Treatment with SCY-078 at 7.5 mg/kg/day or 
10 mg/kg/day BID significantly increased mean survival in all strains (P ≤ 0.003). SCY-078 
exposure resulting in significant reductions in fungal kidney burden (p<0.05) and serum GM 
levels (p<0.005) in all Aspergillus strains was 15.6 μg•mL/hr. 
Evidence for efficacy of combination treatment from animal models 
Combinations, in particular of azoles and echinocandins have been reported in several animal 
models, consistently showing evidence of improved outcomes when azoles and echinocandins 
are given in combination when compared with agent alone.10,11,12 
The combination of SCY-078 with isavuconazole (ISA) was investigated for the 
pharmacokinetics, pharmacodynamics, and antifungal efficacy against experimental pulmonary 
aspergillosis in a neutropenic rabbit model. Galactomannan antigen expression (GMI) and 
(1→3)-β-D-glucan concentrations in serum were incorporated as surrogate molecular and 
biochemical markers of invasive aspergillosis.  
The combination of SCY-078 and isavuconazole at the selected doses was more active than 
either agent alone, as measured by increased survival, reduced organism-mediated pulmonary 
injury, as well as decreased serum galactomannan and (1→3)-β-D-glucan levels in treatment of 
experimental IPA in persistently neutropenic rabbits.  

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Figure 2 
Cumulative survival probability in neutropenic rabbit model of experimental 
pulmonary aspergillosis (n=6 each group) 
 
 
The significantly greater survival was likely related to the synergistic antifungal activity and 
reduction of organism-mediated pulmonary injury, as reflected by lung weights and pulmonary 
hemorrhage score. This reduction was also paralleled by similar declines in serum 
galactomannan and (1→3)-β-D-glucan.    
 

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Figure 3 
Galactomannan antigenemia in neutropenic rabbit model of experimental 
pulmonary aspergillosis (n=6 each group) 
 
 
*p < 0.05; lower GMI in rabbits treated with combination therapy in comparison to that 
of single drug therapy. 
The usefulness of serial GMI sampling in reflecting the therapeutic response was confirmed in 
this study and also in clinical practice as outlined in our study rationale further below. 
 
Clinical experience  
As of April 2020, approximately 1244 (376 healthy subjects and 868 patients) have been 
exposed to SCY-078 in 29 clinical trials. 
In Phase 1 studies, oral SCY-078 has been generally safe and well tolerated following single oral 
doses of up to 1600 mg and multiple oral doses of up to 800 mg for 28 consecutive days. In 
Phase 2 and 3 studies, SCY-078 was also generally safe and well tolerated. The dose regimens 
have included a loading dose of up to 1500 mg (750 mg BID) on Days 1 and 2 followed by 
maintenance doses of 750 mg once daily (QD) for up to 90 days in patients with refractory 
fungal infections.  
Adverse events (AEs) with oral SCY-078 were generally transient and mild to moderate in 
intensity. The most frequently reported treatment-related AEs were mild to moderate 

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gastrointestinal (GI) events (diarrhea, nausea, abdominal pain, and vomiting). There appears to 
be a dose relationship with the frequency and severity of GI AEs. With the exception of transient 
increases in liver function tests (LFTs) in a few subjects (not clinically significant but notable), 
no clinically important abnormalities have been noted in routine blood and urine chemistry 
panels, electrocardiograms (ECGs), and physical examinations including vital signs.  
Peak plasma concentrations after oral administration of SCY-078 occur within approximately 4 
to 6 hours post-dose. Plasma concentrations decline from Cmax in an approximately monophasic 
decline, with a harmonic mean terminal half-life of ~20 hours. Dosing with a high-fat meal 
increased AUC and Cmax by ~60%, within the intersubject variability. The mean AUC0-∞ and 
Cmax appeared, in general, to be dose proportional for doses from 10 mg to 1600 mg. Plasma 
exposures of SCY-078 were not altered in subjects who were older than 65 years compared to 
younger subjects or in healthy female subjects compared to healthy male subjects after single 
oral dose administration. 
Additional pre-clinical and clinical information can be found in the Investigator’s Brochure (IB). 
 
Drug-Drug Interactions Potential 
In vitro evaluation of the potential of SCY-078 to cause drug-drug interactions indicated that 
SCY-078 was a potential reversible inhibitor of CYP2C8 (IC50, 1.5 μM), a moderate reversible 
inhibitor of CYP3A4/5 (IC50, 7.2 μM), but not an inhibitor of other enzymes investigated 
(CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, IC50 all >10 μM). The potential of SCY-
078 to induce human CYP3A4/5 at clinically efficacious concentrations based on in vitro 
evaluations is low. SCY-078 metabolism was predominantly oxidative, with cytochrome P450 
(CYP) 3A being the primary enzyme involved in its oxidative metabolism and strong inhibitors 
of CYP3A would be expected to increase plasma levels of SCY-078.   
Multiple doses of ketoconazole, a potent CYP3A4 inhibitor, increased SCY-078 area under the 
concentration-time curve (0 to infinity) (AUC0–∞) by approximately 5.8-fold. Multiple doses of 
diltiazem, a moderate CYP3A4 inhibitor, increased SCY-078 area under the concentration-time 
curve (0 to 24 hours) (AUC0–24) by 2.5-fold. The coadministration of SCY-078 with multiple doses 
of a proton-pump inhibitor (pantoprazole) decreased SCY-078 AUC0–∞ by ~30%.  
In a subsequent clinical trial, SCY-078 showed not to be a CYP2C8 inhibitor at clinically 
relevant plasma concentrations, based on the absence of effect of the coadministration of SCY-
078 with rosiglitazone.13 SCY-078 showed only mild potential for interaction with tacrolimus, as 
the relative tacrolimus exposure (AUC0-∞) was 1.42-fold greater when SCY-078 was 
coadministered with tacrolimus.14 
To further evaluate the potential for drug-drug interaction of SCY-078 with mold-active azoles 
(voriconazole), a Physiologically Based Pharmacokinetic (PBPK) model was developed. 
This PBPK model was developed using GastroPlus® software (v9.0, Simulations Plus, Inc.). The 
model parameters for SCY-078 and voriconazole were obtained from previously conducted 

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experiments and/or collected from the literature. ADMET Predictor was used to supplement 
physiochemical parameters as necessary. 
 
The results indicated that SCY-078 would not be expected to have any clinically meaningful 
effect on the PK profile of voriconazole, as illustrated below in the graph showing observed 
voriconazole levels (dots) and simulated voriconazole levels with the addition of SCY-078 (solid 
line). Physicians will be advised to follow voriconazole label guidelines and local clinical 
practice for therapeutic drug monitoring.  
 
 
 
The impact of the co-administration of voriconazole on SCY-078 was also evaluated in this 
model using the proposed dosing regimen of each drug for this indication. The results indicate 
that co-administration of SCY-078 with voriconazole may result in an increase of SCY-078 
exposure (both AUC and Cmax) in the range of 20%-30%.  The estimated overall exposure with 
the dosing regimen currently being used in other invasive fungal disease studies where SCY-078 
is administered as monotherapy (i.e., Study SCY-078-301 dose regimen of 750 mg BID for 
2 days followed by 750 mg QD), after considering a potential 30% increase, is within the safe 
exposure range established to date for SCY-078. As a precautionary measure, the SCY-078 dose 
administered in this study where SCY-078 is co-administered with voriconazole, will be reduced 
by 30% until the results of the model are confirmed in an interim PK analysis that will include 
the first 20 randomized subjects.  
Additionally, as further expanded in the IB, the results of the non-clinical toxicology studies 
conducted with SCY-078 thus far do not suggest overlapping toxicities with voriconazole. Most 
commonly reported toxicology findings for SCY-078 have been limited to phospholipidosis, 
which is regarded as an adaptive response and of no consequence to human safety, and mucosal 
degeneration of the glandular stomach, observed primarily in rats, and regarded to be irrelevant 
for human risk assessment. 
 
Conclusion  
Co-administration of SCY-078 with a mold-active azole such as voriconazole has the potential to 
improve clinical outcomes in patients with life-threatening IPA.  

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Non-clinical data do not indicate a potential for antagonistic antifungal activity when SCY-078 is 
combined with other mold-active agents and actually strongly suggest the potential for synergistic 
effect. 
The risk for overlapping toxicities or clinically meaningful drug-drug interaction when SCY-078 
is co-administered with voriconazole is low.  
All patients in the proposed study will receive an effective approved therapy (i.e., voriconazole) 
with the potential advantage of receiving a combination regimen that may result in improved 
outcomes.  
For additional information on SCY-078, please refer to the IB. 
 
8.2 
Rationale for the Study 
Despite the introduction of new antifungal agents, the morbidity and mortality associated with 
invasive aspergillosis is very high; therefore, the evaluation of novel treatment strategies such as 
combination therapy, which may improve the outcomes for this condition, is warranted.  
Combination therapy studies typically evaluate the combination regimen with each one of its 
individual components and with placebo, if feasible. In the case of IPA, considering the high 
mortality associated with this disease, placebo-controlled trials are not ethical. The two 
components of the combination therapy proposed in this protocol are voriconazole, an approved 
mold-active azole coadministered with SCY-078, an investigational GSI. GSIs have activity 
against Aspergillus and studies have been conducted administering echinocandins as 
monotherapy to IPA patients. However, GSI as monotherapy is only approved for salvage 
therapy and not as first-line therapy, whereas mold-active azoles are recommended as first-line 
therapy in most treatment guidelines. In line with these guidelines, the only monotherapy arm in 
this study is with a mold-active azole (voriconazole) taken with placebo, and monotherapy with 
SCY-078 is not included in this design. Regardless of this limitation in the design, the study as 
planned should be able to provide information towards defining the potential improvement in 
efficacy by adding SCY-078 to a voriconazole regimen for the treatment of IPA.  
Voriconazole was selected as the mold-active azole to use in this combination taking the 
following elements into consideration:  
• it is the first recommended choice is most treatment guidelines, 
• there is substantial information regarding its safety and efficacy for this indication and 
voriconazole has been used as comparator in most registration trials,  
• it can be administered both orally and intravenously allowing for initiation with IV and 
step-down to oral when appropriate, 
• it is widely available in the intended countries and institutions,  
• the investigators responsible for treating the intended population for this study are 
familiar with its use, and  
• there has not been any new antifungal that has demonstrated better efficacy. 
  

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Rationale for the objectives of the study 
This study will evaluate the safety of SCY-078 when coadministered with voriconazole to the 
intended population. This Phase 2 study also aims to investigate the effect of the 
coadministration of SCY-078 with voriconazole on multiple outcome endpoints including ACM 
and global response (typical endpoints for this indication) but also investigates other biological 
markers of therapeutic response such as serum galactomannan index. The information from this 
study is expected to guide the selection of clinically relevant endpoints to evaluate subsequently 
in a larger Phase 3 study.  
 
Rationale for proposed doses 
Voriconazole 
The subjects in the study will receive either intravenous or oral formulation of voriconazole, as 
indicated and per investigator’s discretion. Typical regimen for IPA includes start of therapy 
with the IV formulation of voriconazole with subsequent step-down to oral formulation. The 
doses of voriconazole will be as recommended in the label.  The drug-drug interaction simulation 
PBPK-based model does not indicate any need for a modification to the approved dose of 
voriconazole when coadministered with SCY-078.  Therapeutic drug monitoring will follow 
label recommendation and also local practices. Modifications to voriconazole dose will be 
allowed aiming to maintain recommended serum concentration target ranges above 1.5 mg/L and 
to avoid potential toxicities associated with high exposure (i.e., > 6mg/L).  
 
SCY-078 
The oral formulation of SCY-078 will be administered in this study. The oral formulation allows 
for a combination strategy for the entire duration of the antifungal treatment. At the time of 
initiation of this study, an intravenous formulation of SCY-078 is not available. The dose 
selected for study SCY-078-206 took into consideration the data from the study in invasive 
candidiasis patients (SCY-078-202) as well as the PK data available from other Phase 1 studies 
with the oral formulation of SCY-078.  
In summary:  
Population Pharmacokinetic Modeling and Simulation 
A population PK model to describe the SCY-078 concentration-time profile in healthy subjects 
and patients treated for fungal infections was developed in order to provide predictions of the 
percentage of patients that achieve daily AUC values above the efficacy target for invasive 
fungal infection (11.2 μg•mL•hr for invasive candidiasis models and 15.6 μg•mL•hr for invasive 
aspergillosis models). The population PK model for SCY-078 was based on pooled data from 
nine Phase 1 studies and two Phase 2 studies. The overall dataset consisted of a total of more 
than 5000 measurable plasma drug concentrations of SCY-078 collected from nearly 200 healthy 
subjects and over 30 patients treated for fungal infections.  A simulation was performed based on 

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the oral dosing regimen for the treatment of IPA, which consists of a two-day loading dose 
regimen of 750 mg BID administered on Days 1 and 2 followed by an oral maintenance dose of 
750 mg QD starting on Day 3. Based on this simulation, it is predicted that greater than about 
90% of patients will reach target exposure by Day 2, which is in line with antifungal agents that 
require loading doses. The target exposure is maintained during treatment. This dosing regimen 
is currently being used in other invasive fungal disease studies (SCY-078-301). 
The impact of the co-administration of voriconazole on SCY-078 was evaluated in a PBPK 
model. The results indicate that co-administration of SCY-078 with voriconazole may result in 
an increase of SCY-078 exposure (both AUC and Cmax) in the range of 20%-30%.  The estimated 
overall exposure with the dosing regimen currently being used in other invasive fungal disease 
studies (750 mg BID for 2 days followed by 750 mg QD), after considering a potential 30% 
increase, is within the safe exposure range established to date for SCY-078. As a precautionary 
measure, the SCY-078 dose administered in this study will be reduced by 30% until the results of 
the model are confirmed in an interim PK analysis that will include the first 20 randomized 
subjects.  Specifically, the first 10 subjects assigned to SCY-078 and voriconazole therapy will 
receive an oral SCY-078 loading dose of 500 mg BID on Days 1 and 2 followed by a 
maintenance dose of 500 mg QD from Day 3 onwards. Based on the data from this analysis, the 
oral SCY-078 dose may be increased up to a loading dose of 750 mg BID on Days 1 and 2 
followed by a maintenance dose of 750 mg QD from Day 3 onwards. 
9.0 
Study Objectives 
9.1 
Primary Objectives 
• To evaluate the safety and tolerability of the coadministration of SCY-078 and voriconazole 
compared with coadministration of SCY-078 placebo and voriconazole in the treatment of 
invasive pulmonary aspergillosis (IPA).  
9.2 
Secondary Objectives 
• To evaluate the efficacy of the coadministration of SCY-078 and voriconazole compared 
with that of SCY-078 placebo and voriconazole in the treatment of IPA.  
o based on Global Response  
 as determined by the DRC 
 as determined by the Principal Investigator  
o based on all-cause mortality (ACM) 
o based on serum galactomannan index (GMI) decrease 
o based on clinical response, mycological response and radiological response  
 as determined by the DRC 
 as determined by the Principal Investigator 

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• To evaluate the pharmacokinetics (PK) of SCY-078 and voriconazole. 
9.3 
Exploratory Objectives 
The exploratory objectives will be evaluated as data allow and include: 
• To evaluate the efficacy of the coadministration compared with coadministration of SCY-078 
placebo and voriconazole  
o based on other biomarkers of fungal infection (i.e., serum levels of β-D-glucan and 
plasma Aspergillus PCR) 
o based on change in the performance indicator (i.e., Karnofsky score) 
o based on the rate of recurrence of IPA at Week 6 after end of treatment (EoT) as 
determined by the DRC 
o based on the need for additional systemic antifungal treatment (other than secondary 
prophylaxis) until Week 6 after EoT 
• To evaluate the relationship between selected endpoints to ACM at Days 42 and 84. 
• To evaluate healthcare resources utilization for the patients receiving the coadministration of 
SCY-078 and voriconazole compared with coadministration of SCY-078 placebo and 
voriconazole based on overall hospital stay and intensive care unit stay.  
• To assess the effect of the coadministration of SCY-078 and voriconazole compared with 
coadministration of SCY-078 placebo and voriconazole on on-schedule administration of 
planned therapies for the underlying condition.  
10.0 Study Endpoints 
10.1 
Primary Endpoints 
• Frequency of treatment-emergent adverse events (TEAEs), drug-related adverse events 
(AEs), discontinuations due to AEs and deaths. 
10.2 
Secondary Endpoints  
Efficacy as measured by: 
• Global Response as measured by: 
o Percentage of subjects with Complete Response or Partial Response at EoT (key 
secondary endpoint), Day 42 and Day 84, as determined by the DRC 
o Percentage of subjects with Complete Response or Partial Response at EoT, Day 42 
and Day 84, as determined by the Principal Investigator 
• Overall survival, defined as the time from randomization to time of death up to Day 84 
• Percentage of subjects who died (any cause) at Days 42 and 84  

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• Absolute reduction and percent change in serum GMI from Baseline to Weeks 1, 2, 4 
and 6 
• Percentage of subjects with the following changes in serum GMI from Baseline: 
o Fifty percent reduction or greater at Weeks 1, 2, 4 and 6 
o Twenty-five percent reduction or greater at Weeks 1, 2, 4 and 6 
o Any percent reduction at Weeks 1, 2, 4 and 6 
o Reduction equal to or greater than 0.25 at Weeks 1, 2, 4 and 6 
o Reduction to < 0.5 at Weeks 1, 2, 4 and 6 
• Time to achieve the following changes in serum GMI from Baseline: 
o Fifty percent reduction  
o Twenty-five percent reduction  
o Any percent reduction  
o Reduction equal to or greater than 0.25  
o Reduction to < 0.5 in 2 consecutive samples 
• Percentage of subjects with: 
o Clinical Response at EoT, Day 42 and Day  84, as determined by the DRC 
o Mycological Response at EoT, Day 42 and Day  84, as determined by the DRC 
o Radiological Response at EoT, Day 42 and Day  84, as determined by the DRC 
• Percentage of subjects with: 
o Clinical Response at EoT, Day 42 and Day  84, as determined by the Principal 
Investigator  
o Mycological Response at EoT, Day 42 and Day  84, as determined by the Principal 
Investigator 
o Radiological Response at EoT, Day 42 and Day  84, as determined by the Principal 
Investigator 
PK as measured by: 
• SCY-078 and voriconazole plasma concentrations population PK analysis  
10.3 
Exploratory Endpoints 
Efficacy as measured by: 
• Absolute and percentage changes in serum β-D-glucan from Baseline at Weeks 1, 2, 4 
and 6 
• Percentage of subjects with the following changes in serum β-D-glucan from Baseline (if 
positive): 
o Fifty percent reduction or greater at Weeks 1, 2, 4 and 6 
o Twenty-five percent reduction or greater at Weeks 1, 2, 4 and 6 
o Any percent reduction at Weeks 1, 2, 4 and 6 
o Negative serum β-D-glucan at Weeks 1, 2, 4 and 6 
 

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• Percentage of subjects that convert from positive plasma Aspergillus PCR at Baseline to 
negative  at Weeks 1, 2, 4 and 6 
• Absolute change in Karnofsky score (unit change = 10) from Baseline to Days 42 and 84 
• Time to achieve a 10-point improvement in Karnofsky score from Baseline 
• Percentage of subjects with a recurrence of the baseline fungal infection within 42 days 
(Week 6) after EoT 
• Relationship between GMI decrease and ACM at Days 42 and 84  
• Days of hospital stay, and days of ICU stay 
• Percentage of subjects who are able to receive on schedule administration of the planned 
therapies for their underlying condition 
11.0 Study Design 
11.1 
Overall Description of the Study 
This is a multicenter, randomized, double-blind, two-arm study to evaluate the safety, 
tolerability, efficacy and PK of the coadministration of SCY-078 plus voriconazole compared to 
coadministration of SCY-078 placebo plus voriconazole in male and female subjects 18 years of 
age and older with probable or proven IPA as defined in Section 22.3 (adapted EORTC-MSG 
criteria).  
The primary objective of the study is to evaluate the safety and tolerability of the 
coadministration of SCY-078 plus voriconazole compared to the coadministration of SCY-078 
placebo plus voriconazole in the treatment of IPA. Secondary objectives include efficacy 
assessments based on Global Response, ACM and GMI decrease (GMI decrease will only be 
assessed for subjects with a serum GMI above 0 at Baseline) , and PK. Being this a Phase 2 
study, multiple secondary and exploratory endpoints are planned, which will be evaluated as data 
allow considering the limitations of the planned sample size. 
Subjects must meet all study criteria to be eligible for inclusion.  
This study is intended for subjects with an IPA episode that, in the investigator´s judgement, 
requires antifungal therapy and is reasonable to expect that be adequately treated with 
voriconazole. Subjects with breakthrough IPA while receiving antifungal prophylaxis may be 
considered for enrollment if, in the investigator´s judgement, the IPA episode is expected to be 
adequately treated with voriconazole.  
The study will be conducted at approximately 30 sites globally. Approximately 90 subjects will 
be screened to randomize a total of approximately 60 subjects (30 subjects per group) into one of 
the two treatment groups of the study (SCY-078 plus voriconazole or SCY-078 placebo plus 
voriconazole).  
Subjects will receive study treatment for the entire duration of the antifungal therapy (i.e., for a 
recommended minimum of 6 weeks and a maximum of 13 weeks). 
The study will consist of a Screening Period (Days -4 to -1) to assess subject eligibility; a 

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Baseline visit (also considered Treatment Day 1) to confirm subject eligibility and begin study 
treatment; additional scheduled treatment visits (Treatment Days 3, 7, 10, 14 and treatment visits 
every 14 days thereafter until the EoT) to perform safety, tolerability, efficacy and PK 
assessments, an EoT visit to assess efficacy outcomes, a Follow-up (FU) visit 6 weeks after EoT 
(6-Week FU) to assess recurrence and safety, and 2 survival visits/contacts to determine survival 
status and treatment outcome. The Screening Period and Baseline visit may be combined for 
certain subjects. Unscheduled visits may also be conducted as needed. 
A summary description of the study visits, treatment groups and assessments is provided below. 
A schematic of the study design is available in Section 7.0. Detailed descriptions of study 
treatments are provided in Section 13.0. A full description of each study procedure is available in 
Section 15.0 and  a detailed schedule of procedures by study visit is available in Section 16.0.  
11.1.1 Study Visits 
11.1.1.1 
Screening Period (Days -4 to -1) 
At Screening, subjects will be assessed to determine eligibility. All subjects must have a 
diagnosis of possible, probable or proven IPA. Subjects must have a current IPA episode that, in 
the Investigator´s judgement, requires antifungal therapy and may be adequately treated with 
voriconazole, and must be able to tolerate medication orally or through a nasogastric (NG) tube 
or percutaneous endoscopic gastrostomy (PEG) tube to be able to participate in the study.  
 
Subjects with Probable or Proven IPA 
Subjects with a probable or proven IPA, as defined in Section 22.3 and who meet all other inclusion and 
exclusion criteria will enter the Treatment Period and will be randomized to one of the two study treatment 
groups. 
The Screening Visit and Baseline visit (Treatment Day 1) may occur simultaneously for subjects who have 
met the criteria for probable or proven  IPA at screening, if all other criteria are met. 
 
 
Subjects with Possible IPA 
Subjects with possible IPA may enter the Screening Period of the study. During the Screening Period, 
subjects will receive voriconazole or any other mold-active agent (e.g., echinocandin, amphotericin B, or 
other azoles for mold infections) as per label instructions and local standard practice,  and samples for 
serum determination of GMI will be collected on a daily basis.  Other samples (e.g., bronchioalveolar 
lavage, cytology or histopathology) may be collected as clinically indicated to confirm the IPA diagnosis. 
Subjects may remain in the Screening Period (i.e. Screening Days -4 to -1) until the criteria of probable or 
proven IPA is met (Section 22.3), but in no case for more than 4 days of mold-active antifungal treatment 
unless approved by the medical monitor, as explained below. This 4-day mold-active antifungal treatment 
limit prior to randomization is inclusive of any days of mold-active antifungal that the subject may have 
received prior to Screening.  Once the criteria for a probable or proven IPA is met and, if all other inclusion 

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and exclusion criteria are met, the subject will enter the Treatment Period and will be randomized to one of 
the two study treatment groups. 
Subjects meeting criteria for probable or proven IPA shortly after the subject has reached the 4-day mold-
active antifungal treatment limit allowance (i.e., after 4 days but no more than 7 days of mold-active 
antifungal treatment) may be randomized into the study with the approval of the medical monitor, who 
will take into consideration the total number of days of mold-active agent administration up to that point 
as well as the subject´s response to therapy. If the criteria for probable or proven IPA is not met within 7 
days after initiation of mold-active antifungal treatment for the IPA episode, the subject will not be 
randomized and will be discontinued from the study. Only limited information will be collected for 
screened subjects who do not qualify for enrollment 
11.1.1.2 
Baseline (Treatment Day 1) 
For subjects who have a probable or proven IPA the Screening Period and Baseline visit may 
be combined. For subjects who have a possible IPA at Screening Visit AND the criteria for 
upgrading the case to probable or proven IPA is gathered during the Screening Period, the 
inclusion and exclusion criteria will be reviewed again at Baseline to confirm eligibility. Eligible 
subjects will be enrolled in the study and randomized in a 1:1 ratio to one of the two study 
treatment groups: (IV or oral voriconazole + oral SCY-078) or IV or oral voriconazole + 
matching oral SCY-078 placebo. 
Subjects will begin randomized study treatment and clinical, radiological, mycological, PK and 
safety procedures will be performed. 
11.1.1.3 
Treatment Days 3, 5, 7, 10, 14, and every 14 days thereafter 
Subjects will continue on their randomized study treatment and will undergo clinical, 
radiological and mycological procedures for the assessment of efficacy. They will also have 
blood samples drawn for PK assessment and clinical laboratory tests and AE collection for safety 
monitoring. 
Subjects will receive study treatment for a recommended minimum of 6 weeks and a maximum 
of 13 weeks.  
11.1.1.4 
End of Treatment (EoT) 
Subjects will receive study treatment for a maximum duration of 13 weeks. At EoT, subjects will 
undergo safety procedures and clinical, radiological and mycological assessments for the 
determination of efficacy outcomes. EoT procedures should also be performed for subjects who 
discontinued from study treatment before the EoT visit. 
11.1.1.5 
6-Week Follow-Up (6 Weeks After EoT) 
A FU visit will be conducted 6 weeks after the EoT visit to assess recurrence and to conduct a 
final safety assessment.  

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11.1.1.6 
Visits on Treatment Days 42 and 84 
Visits will be conducted on Days 42 and 84 to assess clinical, mycological and radiological 
outcomes as determined by an independent DRC. In addition, patient-reported outcomes 
(Karnofsky scale) will be scored. 
Survival will also be assessed at these visits. These can be conducted as in-person visits or phone 
contacts and will document subject status (alive or deceased) and relationship to the IPA. If 
subject is deceased, the date of death and the investigator´s assessed relationship to the fungal 
infection will also be recorded.  If an autopsy is conducted, key findings should be collected in 
the eCRF. 
11.1.2 Study Assessments 
The study will include safety, tolerability, efficacy and PK assessments. 
 
Safety and Tolerability 
Subjects will be evaluated for safety and tolerability throughout the study, including parameters 
such as physical exam including visual function assessment, vital signs, 12-lead ECGs, safety 
laboratory tests (hematology, blood chemistry and urinalysis), concomitant medications, AEs 
and treatment discontinuations. Electrolyte disturbances such as hypokalaemia, 
hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to 
initiation and during voriconazole therapy.   
 
Efficacy Assessments 
Efficacy will be assessed primarily in terms of Global Response (a composite assessment that 
includes clinical, radiological and mycological evaluations) at EoT, Day 42 and Day 84 as 
assessed by an independent DRC and the Principal Investigator; ACM at Days 42 and 84; and 
GMI decrease at Weeks 1, 2, 4 and 6. Clinical, mycological and radiological outcomes at EoT, 
Day 42 and Day 84 as determined by an independent DRC and by the Principal Investigator will 
also be assessed. 
The following study procedures will be performed to assess treatment outcome:  
• clinical signs and symptoms of IPA 
• radiological assessments, including chest computed tomography (CT) scans and other 
imaging procedures (e.g., X-ray, ultrasound, CT and magnetic resonance imaging [MRI]) 
• mycological testing, including fungal cultures, PCR, histopathological or 
cytopathological analysis of relevant tissues or samples (e.g., lung biopsy sample, 
bronchoalveolar lavage [BAL] fluid), and serological testing ( GMI). 
Exploratory efficacy assessments include, among others, recurrence, Karnofsky Performance 
Status outcomes and other serological biomarkers (β-D-glucan and Aspergillus PCR). 
 
Pharmacokinetics 
Voriconazole level determination as well as SCY-078 PK will be performed for all study 
subjects.  

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Therapeutic drug monitoring (TDM) for voriconazole will be conducted as per local standard 
practice and samples for voriconazole TDM will be analyzed at the local laboratory. The target 
trough plasma concentration should be above 1.5 mg/L.   
 
For the first 20 randomized subjects, blood PK samples will be collected predose on Treatment 
Days 1, 3, 7 and 14, approximately within 1 hour before dosing, and on Treatment Days 1, 7 and 
14 at 2-4 hours and 6-8 hours after dosing for SCY-078 and voriconazole central lab PK testing. 
Results for plasma concentrations of SCY-078 and voriconazole analyzed by the central 
laboratory will not be available in real time. The PK data from the first 20 subjects will be 
assessed in an interim PK analysis that will keep the study team blinded. 
For subsequent randomized subjects, blood PK samples will be collected predose on Treatment 
Days 1, 3, 7 and 14, approximately within 1 hour before dosing, and on Treatment Days 1, 7 and 
14 at 4-8 hours after dosing for SCY-078 and voriconazole central lab PK testing.  Results for 
plasma concentrations of SCY-078 and voriconazole analyzed by the central laboratory will not 
be available in real time.  
11.2 
Blinding, Randomization and Stratification 
This is a double-blind study. All site and sponsor personnel will be blinded to treatment 
assignment. Subject randomization will be performed using an Interactive Web Response System 
(IWRS).  
Approximately 60 eligible subjects (30 subjects per treatment arm) will be randomized in a 1:1 
ratio to one of the two study treatment arms: voriconazole and SCY-078 or voriconazole and 
SCY-078 placebo. For the purpose of maintaining treatment blinding, all randomized subjects 
will receive SCY-078 or SCY-078 matching placebo. Subjects will be randomized at Baseline, 
after all baseline evaluations have been completed. Only one randomization number and study 
treatment arm will be assigned to each eligible subject. 
 Eligible subjects will be stratified to one of these groups at randomization: 
• Hematological malignancies and /or hematopoietic cell transplantation recipients 
• Solid organ transplant recipients 
• Other immunocompromising conditions  
11.3 
Study Duration/End of Study 
Each subject is expected to complete the study, including all FU and Survival visits, within 
approximately 132 days. The end of study is when the last visit of the last subject occurs. 
11.4 
Number of Subjects and Centers 
The study will be conducted at approximately 30 sites globally. Approximately 90 subjects are 
planned to be screened to randomize a total of approximately 60 subjects (30 subjects per group) 

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into one of the two treatment groups of the study (voriconazole and SCY-078 or voriconazole 
and SCY-078 placebo). 
12.0 Study Population 
12.1 
Inclusion Criteria 
Subjects must fulfill all of the following criteria to be eligible for study admission:  
1. Subject is a male or female adult ≥18 years of age on the day the study informed consent 
form (ICF) is signed. 
2. Subject has a probable or proven IPA based on the protocol-specified criteria (Section 22.3) that 
requires antifungal treatment. 
Note: Subjects with possible IPA may enter the screening phase of the study but will only be 
randomized after meeting criteria for probable or proven IPA 
3. Subject has a result of a serum GMI from a sample obtained within the 96 hours preceding 
enrollment into the study (Baseline/Treatment Day 1). 
4. Subject has one of the following: 
a. has a diagnosis of a hematological malignancy or a myelodysplastic syndrome or 
aplastic anemia or has undergone a hematopoietic cell transplantation OR 
b. who either recently resolved or ongoing neutropenia (neutropenia defined as 
absolute neutrophil count < 0.5 x 109/L [< 500/mm3] for > 10 days), temporally 
related to the onset of fungal disease OR 
c. who received treatment with other recognized T-cell immunosuppressants (such 
as cyclosporine, tacrolimus, monoclonal antibodies or nucleoside analogs) during 
the past 90 days including solid organ transplant patients OR 
d. with inherited severe immunodeficiency (e.g. chronic granulomatous disease, 
severe combined immunodeficiency). 
5. Subject has not received more than 4 days (96 hours) of prior mold-active antifungal therapy 
for the treatment of the IPA episode in the 7 days preceding enrollment into the study 
(Baseline/Treatment Day 1). However, subjects who have received more than 4 days but less 
than 7 days of prior mold-active antifungal therapy for the treatment of the IPA episode in 
the 7 days preceding enrollment into the study may be enrolled but will require approval 
from the study medical monitor, who will evaluate each subject on a case-by-case basis. 
6. For subjects who were receiving antifungal prophylaxis, the  IPA episode would, in the 
investigator´s judgement, be adequately treated with voriconazole .  
7. Subject is able to tolerate medication orally or through a nasogastric (NG) tube or 
percutaneous endoscopic gastrostomy (PEG) tube.  
8. Subject is not pregnant and is highly unlikely to become pregnant or to impregnate a partner 
since he/she meets at least one of the following criteria:  

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a. Subject is a female subject who is not of reproductive potential and is eligible 
without requiring the use of contraception. A female subject who is not of 
reproductive potential is defined as one who: (1) has reached natural menopause 
(defined as 6 months of spontaneous amenorrhea with serum follicle-stimulating 
hormone levels in the postmenopausal range as determined by the local 
laboratory, or 12 months of spontaneous amenorrhea); (2) is 6 weeks´ post-
surgical bilateral oophorectomy or hysterectomy; or (3) has undergone bilateral 
tubal ligation. Spontaneous amenorrhea does not include cases for which there is 
an underlying disease that causes amenorrhea (i.e., anorexia nervosa). 
b. Subject is a male subject who is not of reproductive potential and is eligible 
without requiring the use of contraception. A male subject who is not of 
reproductive potential is defined as one whom has undergone a successful 
vasectomy. A successful vasectomy is defined as (1) microscopic documentation 
of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant 
pregnancy despite sexual activity post vasectomy. 
c. Subject is a male or female subject who is of reproductive potential, is not 
pregnant or nursing, and agrees to remain abstinent or use (or have his/her partner 
use) 2 acceptable methods of contraception starting from the time of consent 
through 28 days after the completion of study therapy. Acceptable methods of 
birth control are intrauterine device, condom and highly effective hormonal 
contraceptives. 
Note: Participating females of childbearing potential must have a negative urine or serum 
pregnancy test (β-human chorionic gonadotropin [β-hCG]) at Screening and prior to 
enrollment (Baseline/Treatment Day 1) (performed by the site’s local laboratory). 
9. Subject and/or legal representative is/are able to understand and sign a written ICF, which 
must be obtained prior to treatment and any study-related procedures. 
10. Subject and/or legal representative is able to understand and sign a consent or authorization 
form, which shall permit the use, disclosure and transfer of the subject’s personal health 
information (e.g., in the US, a Health Information Portability and Accountability Act 
Authorization form).  
11. Subject and/or legal representative is able to understand and follow all study-related 
procedures including study drug administration. 
12. Subject is willing and able to comply with the study restrictions and participate for the full 
length of the study. 
12.2 
Exclusion Criteria 
A subject will be excluded from participation in the study if he or she meets any of the following 
exclusion criteria:  
1. Subject has a fungal disease with central nervous system involvement suspected at 
Screening. 

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2. Subject is receiving, has received or anticipates to be receiving concomitant medications that 
are listed in the prohibited medication list (Section 22.1) within the specified washout 
periods. 
3. Subject has a Karnofsky score <20. 
4. Subject is expected to die from a non-infectious cause within 30 days from  the day the study 
ICF is signed. 
5. Subject is under mechanical ventilation. 
6. Subject has abnormal liver test parameters: AST or ALT ≥5 x ULN and/or total bilirubin 
>2.5 x ULN.  
Note: Subjects with unconjugated hyperbilirubinemia (< 7mg/dL) with a diagnosis of 
Gilbert’s disease are not excluded. 
7. Subject has a grade II-IV acute or extensive chronic graft-versus-host disease (GvHD). 
8. Subject has renal failure requiring dialysis. 
9. Subject has a prolonged QTcF interval (Fridericia’s correction: QTc= QT/(RR)0.33) >480 ms 
for females and prolonged QTcF interval (Fridericia’s correction: QTc= QT/(RR)0.33) 
>450 ms for males, on the baseline ECG or other abnormalities deemed clinically significant 
by the investigator that would put the subject at unacceptable risk for participation in the 
study. 
10. Subject has any other condition including history of conditions or medications that may 
increase the risk for QTc prolongation, or laboratory abnormality that, in the judgment of the 
investigator, would put the subject at unacceptable risk for participation in the study or may 
interfere with the assessments included in the study. 
11. Subject has a known hypersensitivity to SCY-078 and/or voriconazole or any of the 
components of the formulations. 
12. Subject has participated in any other investigational study (except open-label studies 
including approved chemotherapy agents) within at least 28 days or 5.5 half-lives of the 
investigational product (whichever is longer) before signing the ICF.  
13. Subject has received prior treatment with SCY-078 in a previous trial. 
14. Subject is an employee of SCYNEXIS, Inc., the investigator or the Contract Research 
Organization (CRO) involved in the study, or is an immediate family member (partner, 
offspring, parent, sibling, or sibling’s offspring) of an employee involved in the study. 
15. Subject is unlikely to comply with protocol requirements. 
12.3 
Discontinuation Criteria  
A subject may be discontinued from the study or study drug for any of the following reasons: 
• Withdrawal of consent; 
• Investigator or Sponsor decision that withdrawal is in the subject’s best interest; 
• Lack of efficacy, defined as deterioration of the clinical condition or delayed response 
requiring, in the opinion of the investigator, alternative antifungal therapy; 

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• Occurrence of an AE that, in the opinion of the investigator, warrants discontinuation of 
the subject from the study drug; 
• Pregnancy; 
• Lost to follow up (every attempt should be made to contact the subject). 
The reason for a subject’s discontinuation of treatment or withdrawal from the study will be 
clearly documented in the source documents and on the electronic case report form (eCRF). All 
EoT procedures should be performed for subjects who discontinue from study treatment before 
the EoT visit.  
12.4 
Replacement of Dropouts 
Subjects who discontinue early from treatment will not be replaced. 
13.0 Study Treatments 
13.1 
Study Treatment Groups 
13.1.1 Description of Study Groups 
All eligible subjects will be randomized in a 1:1 ratio to one of the two study treatment groups 
and will receive treatment for a recommended minimum of 6 weeks and a maximum of 13 
weeks.  
Once randomized, the subjects will receive either voriconazole plus SCY-078 or voriconazole 
plus matching SCY-078 placebo for the entire duration of the antifungal treatment, until they 
reach EoT or a discontinuation occurs.  
 
Voriconazole + SCY-078 
• Either IV voriconazole (loading dose of 6 mg/kg BID on Day 1 followed by maintenance 
dose of 4 mg/kg BID from Day 2 onwards) OR oral voriconazole (loading dose of 
400 mg BID on Day 1 followed by maintenance dose of 200 mg BID from Day 2 
onwards). For subjects weighing <40 kg, the loading and maintenance dose of oral 
voriconazole will be determined per label instructions.  
PLUS 
• Oral SCY-078 (loading dose of 500 mg [2 tablets of 250 mg] BID on Days 1 and 2 
followed by maintenance dose of 500 mg [2 tablets of 250 mg] QD from Day 3 onwards). 
After the first 10 randomized subjects have been treated with the coadministration 
therapy for at least 7 days, an interim PK analysis will be conducted. Based on the data 
from this analysis, the oral SCY-078 dose for subjects subsequently randomized may be 
increased up to a loading dose of 750 mg (3 tablets of 250 mg) BID on Days 1 and 2 

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13.1.3 Renal Insufficiency 
In patients with moderate or severe renal insufficiency (creatinine clearance <50 mL/min), 
accumulation of the IV voriconazole vehicle, SBECD, occurs. Oral voriconazole should be 
administered to these patients, unless an assessment of the benefit/risk balance for the patient 
justifies the use of IV voriconazole. Serum creatinine levels should be closely monitored in these 
patients, and, if increases occur, consideration should be given to changing to oral voriconazole 
therapy. 
13.1.4 Voriconazole Dosing and Dose Adjustment 
Voriconazole will be administered as per voriconazole label instructions.  
Important recommendations for voriconazole treatment 
• Voriconazole therapy should be initiated using the IV formulation administered for at 
least 3 days unless there is a contraindication or lack of vascular access. The IV 
formulation should be followed by maintenance oral voriconazole. 
• Initiation of voriconazole therapy (i.e.,  loading dose) with an oral formulation rather than 
an IV is recommended in subjects who cannot tolerate IV voriconazole (see 
Section 13.1.3 [Renal Insufficiency]). 
• IV voriconazole should be infused over 1 to 2 hours (rate is not to exceed 3 mg/kg/h). 
IV voriconazole should not be administered as an IV bolus injection.  
• Oral treatment may be given on an inpatient or outpatient basis, as needed.  
• The loading dose of voriconazole should be administered only once, at the beginning of 
voriconazole therapy. 
Dose adjustment 
Adjustment of voriconazole doses will be allowed, at the investigator’s discretion and per local 
standard practice, with the objective of maintaining voriconazole trough levels above 1.5 mg/L 
and  to avoid potential toxicities associated with high exposure (i.e., > 6 mg/L). 
13.1.5 Oral Treatment via NG or PEG Tube 
For subjects who are unable to take oral tablets but are able to tolerate medications through an 
NG or PEG tube, SCY-078 (or matching placebo) tablets may be crushed and administered with 
approximately 8 oz./240 mL of water via an NG or PEG tube. The tube should be flushed with 
water before and after drug administration.  
13.2 
Dietary Requirements 
Oral SCY-078 should be taken with meals or immediately after a meal and with approximately 
8 oz./240 mL of water.  Oral voriconazole should be administered 1 hour before or 1 hour after a 
meal. 

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13.3 
Study Drug  
Study drug, SCY-078 250-mg and SCY-078 250-mg matching placebo tablets will be provided 
by the Sponsor.  Standard of care (SOC) voriconazole (IV and oral) will be provided by the study 
site’s pharmacy. In extenuating circumstances when the site’s pharmacy is not able to provide 
the SOC voriconazole, the Sponsor will assist in obtaining it. 
13.3.1 SCY-078 Description 
Study Drug Identifier: 
SCY-078 
Empirical Formula: 
C50H75N5O11 (citrate salt) 
Molecular Weight: 
922.18 (citrate salt) 
Physical Description: 
White to off-white solid 
Chemical Name: 
(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-
2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-
pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-
dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-
phenanthro[1,2-c]pyran-7-carboxylic acid, citrate salt] 
 
Figure 4 
Chemical Structure of SCY-078 Citrate 
 
13.3.2 Formulation, Packaging and Labelling 
SCY-078 citrate drug product for oral administration will be supplied as a tablet containing 
250 mg of SCY-078 active ingredient on a free-base basis. In addition to the active ingredient, 
the tablet formulation also contains silicified microcrystalline cellulose, crospovidone, mannitol, 
colloidal silicon dioxide, magnesium stearate (non-bovine) and butylated hydroxyanisole.  
IV voriconazole will be supplied in a single-use vial as a sterile lyophilized powder equivalent to 
200 mg of voriconazole. Oral voriconazole will be supplied as a 200-mg tablet. 
SCY-078 drug supplies (SCY-078 citrate and matching placebo tablets) will be packaged in high 
density polyethylene (HDPE) bottles fitted with induction seals and child-resistant 
polypropylene plastic closures.  

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Labels on the bottles containing SCY-078 and matching placebo tablets will include the 
following information and any other information required by applicable regulations: 
• Sponsor information 
• Protocol number 
• Protocol visit number 
• Place to write the subject number 
• Route of administration 
• Lot number  
• Product name and potency 
• Contents, e.g. number of tablet count per bottle  
• Storage conditions 
• Name of manufacturer and date of manufacture 
• Caution statement: "Caution: New Drug – Limited by Federal (United States) Law to 
Investigational Use Only” 
13.3.3 Storage and Stability 
The pharmacist or appropriate designee at each clinical research site will be responsible for the 
study drug. For long-term storage at the site, SCY-078 drug supplies (SCY-078 citrate and 
matching placebo tablets) provided in bottles must be kept in a secure area (e.g., locked cabinet) 
and stored at room temperature, between 15°C and 30°C.  
IV and oral voriconazole supplies should be stored following voriconazole prescribing 
information. 
The site will be required to keep a temperature log to establish a record of compliance with these 
storage conditions. All study drugs will be kept in a secure cabinet or room with access restricted 
to necessary clinic personnel. 
13.4 
Drug Accountability 
The investigator or designee will inventory and acknowledge receipt of all shipments of the 
study drug. Drug accountability logs will be used to maintain accurate records of receipt, 
dispensing, administration to each subject and return of drug. A study monitor will periodically 
check the supplies of investigational products held by the site to verify accountability of all study 
drugs. At the conclusion of the study, after final drug accountability has been completed by the 
monitor, all unused study drug and all medication containers will be returned to the Sponsor or 
destroyed on-site if the site has procedures in place for study drug destruction. 
Drug supplies will be maintained in a secure, limited-access storage area under the recommended 
storage conditions (see Section 13.3.3). 

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The study drug supplied for this study is only for use in subjects properly consented and enrolled 
under this protocol. 
This is a double-blind study. A study site designee (e.g. pharmacist, study nurse/coordinator) 
will: 
• Record the treatment in the appropriate drug accountability log 
• Count the number of tablets per bottle before dispensing to the subject 
• Report and document any study medication issues such as crushed or broken tablets  
o All product quality complaints should be reported to the Sponsor 
• Collect and count the number of tablets remaining at the EoT visit 
• Review subject diary and tablet count, record any unused or remaining drug in the drug 
accountability log and eCRF, and note any discrepancies and reason for discrepancies 
13.5 
Subject Compliance with Study Drug Dosing 
Subjects who are not hospitalized and subjects who are discharged from the hospital will be 
instructed to have the study medication (including empty bottles/units) with them at each visit.  
Compliance will be assessed based on remaining study drug as compared to what should have 
been taken and the subject diary where the subject will enter the details of dosing. Details of 
treatment including any missing dose will be recorded in the eCRF. Sites are encouraged to 
contact the medical monitor or Sponsor for concerns of compliance with the treatment regimen, 
especially for subjects who miss doses due to problems with tolerability. 
14.0 Non-Study Treatments 
14.1 
Prior and Concomitant Medications 
All medications (including prescription and OTC medications, supplements, and herbal products) 
taken from 28 days before Screening through the EoT will be recorded on the eCRF. Only the 
use of antifungal medications, antibiotics for any reason or medications to treat an AE will be 
recorded after EoT and through the 6-Week FU visit. Start and stop times of concomitant 
medications taken during antifungal therapy will be recorded on the eCRF. Subjects will also 
record any new concomitant medications taken between visits in the subject diary. 
Certain concomitant medications must be administered with caution or close monitoring as 
described in Section 14.2 and Section 14.3. 
14.2 
Prohibited Medications 
Medications specifically not permitted prior to the study and during treatment or through the 6-
Week FU visit include the following: 
• Other investigational drug(s).  
• Other antifungals except randomized study drug. 

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• Mold-active antifungal therapy for the treatment of the IPA episode for more than 4 days 
(96 hours) in the 7 days preceding enrollment into the study (Baseline/Treatment Day 1), 
except for those subjects who have received more than 4 days but less than 7 days of 
prior mold-active antifungal therapy for the treatment of the IPA episode in the 7 days 
preceding enrollment into the study and were granted approval for randomization by the 
medical monitor. 
• Select strong CYP3A4/5 inhibitors, CYP3A4/5 inducers, and select P-gp substrates. 
A detailed list of prohibited medications and timeframes is provided in Section 22.1 
(Appendix A). 
14.3 
Medications to be Administered with Caution and Monitored as 
Appropriate 
The following medications must be administered with caution and must be monitored as 
appropriate: 
• Select CYP3A4 substrates, including but not limited to sirolimus, tacrolimus, warfarin, 
cyclosporine and amiodarone 
• Organic anion-transporting polypeptide 1B3 (OATP1B3) substrates 
A detailed list of medications to be administered with caution is provided in Section 22.1 
(Appendix A).  
 
14.4 
Voriconazole Drug Interactions 
The systemic exposure to voriconazole is expected to be reduced by the concomitant 
administration of the following agents and their use is contraindicated: 
• Rifampin (potent CYP450 inducer) 
• Rifabutin (potent CYP450 inducer) 
• Ritonavir (potent CYP450 inducer) 
• St. John’s Wort (CYP450 inducer; P-gp inducer) 
• Carbamazepine and long-acting barbiturates (potent CYP450 inducers) 
 
The systemic exposure of the following drugs is expected to be significantly increased by 
coadministration of voriconazole and their use is contraindicated: 
• Sirolimus (CYP3A4 substrate) 
• Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates) 
• Ergot alkaloids 
Coadministration of voriconazole with the following agents could result in significant drug 

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interactions that may require dosage adjustment, frequent monitoring of drug levels and/or 
frequent monitoring of drug-related adverse events/toxicity: 
• Alfentanil (CYP3A4 substrate) 
• Fentanyl (CYP3A4 substrate) 
• Oxycodone (CYP3A4 substrate) 
• Cyclosporine (CYP3A4 substrate) 
• Methadone (CYP3A4, CYP2C19, CYP2C9 substrate) 
• Tacrolimus (CYP3A4 substrate) 
• Warfarin (CYP2C9 substrate) 
• Oral Coumarin Anticoagulants (CYP2C9, CYP3A4 substrates) 
• Statins (CYP3A4 substrates) 
• Benzodiazepines (CYP3A4 substrates) 
• Calcium Channel Blockers (CYP3A4 substrates) 
• Sulfonylureas (CYP2C9 substrates) 
• Vinca Alkaloids (CYP3A4 substrates) 
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates) 
• Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; 
CYP3A4 inhibitor and substrate) 
• Phenytoin (CYP2C9 substrate and potent CYP450 inducer) 
• Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate) 
• Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor) 
• Other HIV Protease Inhibitors (CYP3A4 substrates and inhibitors) 
• Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates, 
inhibitors or CYP450 inducers) 
 
Additional information regarding medications that are contraindicated or require specific 
precautions when coadministered with voriconazole can be found in Section 22.2 (Appendix B: 
Voriconazole Label). 
14.5 
Study Restrictions 
There are no additional study restrictions other than those described in Sections 12.2 (Exclusion 
Criteria), Section 13.2 (Dietary Requirements) and Section 14.2 (Prohibited Medications). 

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15.0 Study Procedures 
The following sections provide a description of the individual study procedures to be performed 
during the conduct of the study. Detailed schedules of study assessments are provided in the 
Schedule of Visits and Procedures in Table 4. 
15.1 
Informed Consent 
Every study subject (or the subject´s legal representative) must provide written informed consent 
at Screening, prior to participating in any screening evaluations or any other study activities (see 
Section 20.3). 
15.2 
Inclusion and Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed at Screening and at Baseline (Treatment 
Day 1) prior to randomization to study drug treatment to ensure that the subject qualifies for the 
trial. 
15.3 
Subject Enrollment and Assignment of Subject Number 
At Baseline/Treatment Day 1, all subjects who have signed an ICF will receive an 8-digit subject 
identification (ID) number that will be composed of a 3-digit study number (206) and a 2-digit 
site number followed by a 3-digit sequentially assigned subject number starting at 001. Subject 
numbers will be sequentially assigned by the database upon entry by the site. For instance, if site 
01 enters the first subject in the database, the subject ID will be 206-01-001. The second subject 
entered in the database will get the subject number 002 as entered by any site, so that if site 02 
enters the second subject, the subject ID will be 206-02-002. This number will be unique to each 
subject and will be used to identify the subject throughout the study.  
Subjects who are screen failures or who are not eligible for enrolment will be recorded as such in 
the subject screening log. The subject numbers assigned to eligible subjects will be recorded in 
the eCRF. Only one subject number will be assigned to each eligible subject.  
For subjects who signed an ICF (i.e., are assigned a subject number) but were NOT randomized 
because they did not meet all of the inclusion/exclusion criteria or other reason, selected 
Screening visit pages of the eCRF will be completed. The criteria that were not met for 
enrolment will also be documented in the eCRF.  
All eligible subjects must be approved by the Sponsor for enrollment. When available, the 
antifungal therapy administered and Survival status at Days 42 and 84 will be collected for 
subjects who signed the ICF but were NOT randomized.  
15.4 
Randomization  
At Baseline (Treatment Day 1), subjects who meet all of the inclusion and none of the exclusion 
criteria will be randomized to one of the two study treatment groups.  Subject randomization will 
be performed using an IWRS, which will assign a unique randomization number for each 

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randomized subject corresponding to a study treatment. Only one randomization number and 
study drug treatment will be assigned to each eligible subject. 
15.5 
Medical History and Demographics 
At Screening, a complete medical history for the prior 5 years will be recorded for each subject. 
The medical history will include previous and current medical diagnoses, as well as major 
surgical procedures. Subject demographics such as age, sex, race and ethnicity will also be 
collected. 
15.6 
General Physical Examination, Including Visual Function Assessment  
A general physical exam will be conducted at Screening and Baseline (Treatment Day 1), at EoT 
and at the 6-Week FU visit. The physical examination will include an abbreviated assessment of 
general appearance, skin, eyes, heart, chest and abdomen. 
An overall assessment and questions to investigate visual acuity, visual field and color 
perception should be conducted by the Principal Investigator or designee during Screening or at 
Baseline and again at approximately Treatment Day 28 (if voriconazole treatment continues 
beyond 28 days). An ophthalmologist exam is recommended if there are clinically significant 
visual function abnormalities identified during the general physical exams at or after Baseline. 
An ophthalmologist exam is not required for the enrollment of patients into the study but should 
be conducted as early as possible, if clinically significant visual function abnormalities are 
identified.  Additional evaluations of visual function may be conducted as needed, at the 
investigator’s discretion.  Any visual disturbance identified should be documented either as part 
of the subject’s medical history and/or as an AE, accordingly. 
15.7 
Vital Signs 
Vital signs, including blood pressure (systolic and diastolic), heart rate, respiratory rate and body 
temperature will be measured at Screening and Baseline (Treatment Day 1), at EoT and at 
unscheduled visits, if applicable. 
15.8 
Twelve-Lead Electrocardiogram  
A 12-lead ECG will be obtained and evaluated locally by a physician for the presence of 
abnormalities at Screening and Baseline (Treatment Day 1), once between days 7 and 21, at EoT 
and at unscheduled visits, if applicable. 
Heart rate, PR interval, QRS, QT and QTcF values will be recorded in the eCRF. Any clinically 
relevant abnormality will be recorded as AE accordingly and will be followed up to 
resolution/satisfaction. 

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15.9 
Pregnancy Test  
A urine or serum pregnancy test will be performed at Screening, Baseline (Treatment Day 1), 
and at EoT, as well as once a month while on study treatment, by the local laboratory for all 
female subjects of childbearing potential.  
15.10 Karnofsky Performance Status Scale 
Karnofsky scores will be determined using the Karnofsky Performance at Screening and 
Baseline (Treatment Day 1), every 14 days during treatment up to EoT, at EoT, and on Day 42 
and Day 84 (42 and 84 days after Baseline [Treatment Day 1] [first dose of study drug]). 
15.11 Targeted Physical Examination, Including Clinical Evaluation of Signs 
and Symptoms of Infection 
A targeted examination of the fungal infection site, including the signs and symptoms of the 
fungal disease, will be conducted at Screening and Baseline (Treatment Day 1), on Treatment 
Days 3, 5, 7 and 14, and then every 14 days up to EoT, at EoT and at the 6-Week FU visit. 
The signs and symptoms of the fungal disease include, but are not limited to, the following: 
o Fever, defined as oral temperature ≥38.3°C (≥101°F) on one occasion or >37.8°C 
(>100°F) on two measurements at least 4 hours apart  
o Hypothermia <36°C (<96.8°F) 
o Hypertension 
o Tachycardia 
o Hemoptysis 
o Cough 
o Respiratory distress 
o Thoracic pain 
o Pleural rub 
Subjects who are not hospitalized or who are discharged from the hospital during study treatment 
will record selected signs and symptoms on subject diaries and the signs and symptoms will also 
be assessed by the site staff at the study visits. The site will assess whether the signs and 
symptoms recorded on the subject diary are related to the Aspergillus infection. 
15.12 Chest CT Scan 
A chest CT scan obtained within 5 days prior to enrollment must be available at Baseline 
(Treatment Day 1). In line with current aspergillosis treatment guidelines, follow-up chest CT 
scans will be performed to evaluate response to treatment, ideally within 3 days prior to or after 
EoT. Additional chest CT scans may be performed at other visits including the 6-Week FU visit, 
if applicable. 
The results of all chest CT scans should be documented on the eCRF. A digital copy of the CT 
scan images will be uploaded to a designated central imaging system. 

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Special attention should be given to evaluate, and document radiological signs often associated 
with invasive pulmonary aspergillosis: 
i. 
Dense well-circumscribed lesion(s) (nodules) with or without halo sign 
ii. 
Hypodense sign  
iii. 
Air crescent sign 
iv. 
Cavity 
A detailed description of EORTC/MSG criteria is available in Section 22.3 (Appendix C). 
15.13 Other Imaging  
If images other than the chest CT scan are available at Baseline (Treatment Day 1) to support the 
diagnosis of IPA (e.g., X-ray, ultrasound, magnetic resonance imaging), these other images will 
be collected, if available, to evaluate response.   
The results of these studies should be documented on the eCRF. 
15.14 Mycological Testing Other than Serum GMI, Serum β-D Glucan and 
Plasma Aspergillus PCR 
Other mycological tests include fungal cultures (e.g., BAL culture, culture from biopsy), 
histopathological or cytopathological analysis of relevant tissues or samples (e.g., lung biopsy 
sample, BAL fluid.), and other tests (BAL GMI). Primary testing of these samples, including 
culture, histopathology and cytopathology, should be conducted at the site. All available results 
from these tests must be collected in the eCRF, including those available at Screening and those 
collected subsequently, until the FU visit.  
BAL and relevant tissue samples should be submitted to the central laboratory for additional 
diagnostic tests including histopathology and Aspergillus PCR, if sufficient material is available.  
The site’s local microbiology laboratory will be primarily responsible for the fungal cultures of 
relevant clinical samples and should perform species identification as per local standards. A 
sample of all mold isolates, including Aspergillus, should be sent to the central laboratory for 
species identification confirmation and antifungal susceptibility testing that will include 
voriconazole and SCY-078, at a minimum.  The central laboratory will process these samples in 
batches and the results will not be available in real time to the sites.  
Details for the procedures to collect, store and ship biological samples and mold isolates, 
including Aspergillus, will be described in the laboratory manual.  
15.15 Galactomannan Index Assessment 
Serum GMI will be determined at all study visits. At Screening, at least one sample collected 
within 96 hours before enrollment must be available for all subjects. For subjects with a possible 
IPA, serum samples will be collected daily for a maximum Screening Period of 4 days (Days -4 
to -1) or until one positive GMI result (≥ 0.5) is reported.  BAL samples, if collected per local 
practices,  should be sent for  GMI determination.   

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GMI samples during the Screening Period for evaluation of enrollment qualification will be 
processed locally (either the site laboratory or a designated regional laboratory). These results 
will be available in real time to make enrollment decisions. Results from GMI tests processed  
locally should be entered into the eCRF. 
At Baseline, a serum sample will be collected for all randomized subjects within 2 hours before 
the first dose of SCY-078 or matching placebo for the determination of GMI. Serum GMI will 
also be assessed at all subsequent study visits, including all treatment visits, EoT, 6-Week FU 
visit and unscheduled visits. For randomized subjects, serum GMI samples collected after 
randomization will be analyzed at a central laboratory and results will not be available in real-
time.  If, at investigator’s discretion, serum GMI results are needed during the study for adequate 
subject’s care, additional GMI samples should be processed locally, and results should also be 
entered in the eCRF. 
An immunoenzymatic sandwich microplate assay method will be generally used to determine 
serum GMI. Other methods such as lateral flow devices, which have received CE mark and/or 
FDA approval for galactomannan determination in serum and BAL, may be used during the 
Screening Period for evaluation of enrollment qualification. In these cases, enrollment 
qualification will be based on the device label recommendation for considering a serum test as 
positive.  
15.16 Serum β-D-Glucan and Plasma Aspergillus PCR Test 
Blood samples will be collected to perform serum β-D-glucan and plasma Aspergillus PCR 
testing throughout the study at all scheduled visits. Testing may also be conducted at 
unscheduled visits, if applicable. Serum β-D-Glucan and plasma Aspergillus PCR tests will be 
processed by a central laboratory. Procedures for collecting, storing, and shipping samples to the 
central laboratory are described in the study laboratory manual. It is anticipated that some sites 
may not have the central laboratory data on time, therefore if the sites happen to perform these 
tests locally, the results from the local laboratory should be recorded in the eCRF. 
15.17 Safety Laboratory Tests  
Safety laboratory tests (hematology, blood chemistry and urinalysis) will be performed at 
Screening and Baseline (Treatment Day 1), and on Treatment Days 7 and 14, at EoT and 6-Week 
FU. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia 
should be monitored and corrected, if necessary, prior to initiation and during voriconazole 
therapy.  If clinically indicated, safety tests will be repeated every 14 days following Treatment 
Day 14 up to EoT, and at unscheduled visits. These may also be done more frequently as follow-
up to a laboratory abnormality. If the subject is still receiving study drug by Day 42 (i.e., EoT 
has not occurred), a safety lab assessment should be conducted on Day 42 or on Day 56.  
Safety laboratory tests will be processed at a central laboratory. Procedures for collecting, 
storing, and shipping samples to the central laboratory are described in the study laboratory 
manual. 

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Results from safety laboratory test by the central lab will be made available to the sites on an 
ongoing basis; however, the site should not relay on timely availability of these result to make 
medical decisions for subjects’ care.   
Additional laboratory tests should be collected and analyzed by the local laboratory, as needed, 
to make real-time medical decisions. Specifically, in line with voriconazole label 
recommendations, serum transaminase levels,  bilirubin levels, serum electrolytes (potassium, 
magnesium and calcium) and amylase and lipase should be monitored at initiation of 
voriconazole therapy (Day 1) and then weekly during the first month of treatment (Day 7, Day 
14, Day 21 and Day 28). Monitoring frequency of these laboratory parameters may be reduced to 
monthly intervals during continued use of voriconazole if no clinically significant changes are 
noted. 
The following laboratory parameters will be determined for all samples sent to the central 
laboratory: 
Hematology  
 White blood cell (WBC) count  
 Hemoglobin 
 Red blood cell (RBC) count  
 Hematocrit 
 Platelet count 
 
 Differential WBC count will include percentages for segmented neutrophils, lymphocytes, 
monocytes, eosinophils and basophils, and absolute counts for neutrophils, lymphocytes, 
atypical lymphocytes, monocytes, eosinophils and basophils. 
 
Blood Chemistry 
 Sodium 
 Glucose 
 Potassium 
 Albumin 
 Magnesium 
 Amylase 
 Calcium 
 Lipase 
 Alkaline Phosphatase 
 Chloride  
 Blood urea nitrogen (BUN) 
 Creatinine 
 Total creatine phosphokinase (CPK) 
 Aspartate aminotransferase (AST/SGOT) 
 Alanine aminotransferase (ALT/SGPT) 
 Gamma glutamyl transferase (GGT) 
 Lactate dehydrogenase (LDH) 
 Bilirubin (total, direct) 
 Total protein  
 

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Urinalysis 
 Appearance (clarity, color) 
 Glucose  
 Specific gravity 
 Ketones  
 pH 
 Protein  
 Blood 
 Leukocytes  
 Bilirubin  
 Urobilinogen  
15.18 Voriconazole Therapeutic Drug Monitoring  
TDM for voriconazole will be conducted as per local standard practice. Samples for voriconazole 
TDM will be processed at a local laboratory. All results available from locally conducted tests of 
voriconazole plasma concentrations, including those prior to randomization, will be documented 
on the eCRF. The target trough plasma concentration should be above 1.5 mg/ L. 
15.19 Voriconazole Level Determination  
Voriconazole plasma level determinations will be conducted for all subjects at a central 
laboratory. For the first 20 randomized subjects, blood samples for the determination of 
voriconazole levels will be collected predose on Treatment Days 1, 3, 7 and 14, approximately 
within 1 hour before dosing, and on Treatment Days 1, 7 and 14 at 2-4 hours and 6-8 hours after 
dosing. The PK data from the first 20 subjects will be assessed in an interim PK analysis. For 
subjects subsequently randomized, blood PK samples will be collected predose on Treatment 
Days 1, 3, 7 and 14, approximately within 1 hour before dosing, and on Treatment Days 1, 7 and 
14 at 4-8 hours after dosing. The time of dosing and sample collection must be recorded in the 
eCRF. Procedures for collecting, storing, and shipping samples to the central laboratory are 
described in the study laboratory manual. 
The results from voriconazole plasma concentration analyses performed at the central laboratory 
will not be available for making real-time decisions for voriconazole TDM.  Voriconazole TDM 
will be conducted as per local standard practice and samples for voriconazole TDM will be 
processed at a local laboratory, as indicated in Section 15.17, Voriconazole Therapeutic Drug 
Monitoring. 
15.20 SCY-078 Pharmacokinetic Sample Collection  
PK testing for the determination of SCY-078 will be conducted for all subjects by a central 
laboratory. For the first 20 randomized subjects, blood samples for SCY-078 PK testing will be 
collected predose on Treatment Days 1, 3, 7 and 14, approximately within 1 hour before dosing, 
and on Treatment Days 1, 7 and 14 at 2-4 hours and 6-8 hours after dosing.  The PK data from 
the first 20 subjects will be assessed in an interim PK analysis. For subjects subsequently 
randomized, blood PK samples will be collected predose on Treatment Days 1, 3, 7 and 14 
approximately within 1 hour before dosing, and on Treatment Days 1, 7 and 14 at 4-8 hours after 
dosing. 

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On PK sampling days, the investigator must record the dosing times and sample collection times 
in the eCRF and on the subject’s medical record. Results for plasma concentrations of SCY-078 
analyzed by the central laboratory will not be available in real time 
Procedures for collecting, storing, and shipping plasma samples to the central laboratory for PK 
are described in the study PK Manual.   
In addition to blood, other biological samples such as pleural effusion and tissue biopsies may 
also analyzed for SCY-078 PK determination, when available.  
15.21 Assessment of Treatment Outcome  
Efficacy will be assessed primarily in terms of Global Response (a composite assessment that 
includes clinical, radiological and mycological evaluations) as determined by an independent 
DRC and the Principal Investigator at EoT, Day 42 and Day 84, ACM at Days 42 and 84, as well 
as by GMI decrease from Baseline. Clinical, mycological and radiological outcomes at EoT, 
Day 42 and Day  84 as determined by the DRC and by the Principal Investigator will also be 
assessed.   
The following study procedures will be performed to assess treatment outcome: 
• Clinical signs and symptoms of IPA (Section 15.11) 
• Radiological assessments 
o Chest CT scans (Section 15.12) 
o Other imaging procedures, as applicable (e.g., X-ray, ultrasound, CT and MRI) 
(Section 15.13). 
• Mycological testing 
o Serum GMI (Section 15.15) 
o Serum  β-D glucan and plasma Aspergillus PCR (Section 15.16) 
o Other mycological tests, including fungal cultures, histopathological and cytological 
analyses, and other serological tests (including BAL GMI) (Section 15.14) 
15.22 Recurrence  
Recurrence (after EoT) will be assessed by measuring recurrence of the baseline fungal infection 
within 42 days after EoT (6-Week FU). The DRC will be responsible for determining recurrence. 
15.23 Survival  
Survival will be determined on Day 42 and Day 84 (42 and 84 days after Baseline [Treatment 
Day 1] [first dose of study drug] for randomized subjects and 42 and 84 days after the ICF is 
signed for screen failures). This can be an in-person visit or a phone contact, and will document 
subject status (alive or deceased). If subject is deceased, the date of death and the investigator’s 
assessed relationship to the fungal infection will also be recorded. If autopsy is conducted, key 
findings should be collected in the eCRF. 
See Section 19.7 for a detailed description of efficacy outcomes. 

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15.24 Study Drug Dispensing 
The study drug will be dispensed at Baseline (Treatment Day 1), and approximately every 14 
days thereafter until EoT. Subjects who are hospitalized and are later discharged from hospital 
will be dispensed their study drug at the time they are discharged.  
See Section 13.3.2 for information on study drug supplies. 
15.25 Study Drug Dosing  
Study drug doses (oral SCY-078 or oral SCY-078 matching placebo) will be administered daily 
to subjects from Baseline (Treatment Day 1) through EoT. The study drugs will be administered 
in a blinded fashion.  Treatment may be given on an inpatient or outpatient basis, as needed, and 
for as long as is clinically indicated, at the investigator´s discretion, but in no event for more than 
a total of 13 weeks (i.e. 91 days) of study drug treatment.  
For subjects who are unable to take oral medications, SCY-078 tablets may be crushed and 
administered with approximately 8 oz./240 mL of water via an NG or PEG tube. The tube should 
be flushed with water before and after drug administration. 
Oral SCY-078 will be administered preferably with meal. 
Loading dose:  
• The first 4 doses of oral SCY-078 500 mg will be administered BID, approximately every 12 
hr (total dose of 1000 mg per day for 2 days) 
Maintenance dose:  
• Starting with the 5th dose of oral SCY-078 500 mg the subsequent doses will be administered 
QD (total dose of 500 mg per day). The 5th dose may be administered within 12 to 24 hrs of 
the 4th dose, to allow for adjustment to a QD dose regimen that is the most convenient for the 
patient (either AM or PM). Subsequent doses should be administered approximately 24 hr 
apart.   
The dose of SCY-078 may be adjusted for subjects who are randomized after the interim PK 
analysis.  Until a decision to adjust the dose is made based on data from this analysis, subjects 
will continue receiving SCY-078 500 mg doses as described above.  
If after interim PK analysis the daily dose is changed from 500 mg to 750 mg the dosing 
instructions will be the same but 500mg dose will be substituted by 750 mg dose. Specifically, 
the loading dose will be oral SCY-078 750 mg BID for 4 doses, followed by maintenance dose 
of 750 mg QD subsequently.  
For subjects who are intolerant of SCY-078 due to gastrointestinal (GI) related conditions such 
as clinically significant nausea or diarrhea, the following dose administration adjustments are 
allowed: 
• Each tablet of SCY-078 may be administered every 10-20 min rather than all at once. 
• The daily dose during the maintaining phase (after the first 4 loading doses) can be changed 
from QD to BID, administering 250 mg of SCY-078 (one tablet) approximately every 12 hr, 
preferably with a meal  (total dose of 500 mg per day).  

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• If, after the interim PK analysis the daily dose is increased to 750 mg of SCY078 per 
day, the daily dose during the maintaining phase (after 2 days of loading dose) can be 
changed from QD to BID, administering 375 mg of SCY-078 (one tablet and ½) 
approximately every 12 hr, preferably with a meal  (total dose of 750 mg per day).  
• Interruption of administration of SCY-078 tablets for up to 2 days (after loading dose has 
been completed) is also allowed, if GI side effects are persistent.  
• At the investigator’s discretion, concomitant medication(s) to potentially decrease GI events 
may be given to the subject. 
Further details of the study treatment and dietary requirements for treatment administration are 
provided in Section 13.1 and Section 13.2, respectively. 
15.26 Study Drug Collection and Treatment Compliance Evaluation 
Study drug use will be recorded for treatment compliance evaluation daily from Baseline 
(Treatment Day 1) through EoT (see Section 13.5 for further details).   
15.27 Subject Diary Dispensing, Collection and Review 
Non-hospitalized subjects will complete a subject diary up to their EoT visit. The subjects will 
record the date/time of study medication dosing, selected signs and symptoms, medical concerns 
or complaints and concomitant medications.   
Subject diaries will be dispensed at Screening and will be reviewed at clinic visits after 
Treatment Day 14 up to EoT. Subject diaries will be collected at EoT.  
15.28 Prior and Concomitant Medication Review 
All medications (including prescription and OTC medications, supplements, and herbal products) 
taken from 28 days before Screening through the EoT will be recorded on the eCRF. Only the 
use of antifungal medications, antibiotics for any reason or medications to treat an AE will be 
recorded after EoT and through the 6-Week FU visit.  Prior and concomitant medications will 
also be reviewed at unscheduled visits. See Section  22.1 (Appendix A) for prohibited 
medications, medications to be administered with caution and further details for non-study 
treatments. 
15.29 Adverse Event Monitoring 
AEs will be collected and evaluated from Baseline (Treatment Day 1), after the first dose of 
study drug SCY-078, and SOC voriconazole and through the end of the study. AEs will also be 
collected at any unscheduled visits.  
The effect of voriconazole on visual function is not known if treatment continues beyond 28 
days. There have been post-marketing reports of prolonged visual adverse events, including optic 
neuritis and papilledema. If voriconazole treatment continues beyond 28 days, as recommended 
in the label as part of standard of care, visual function including visual acuity, visual field and 

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color perception should be monitored to identify potential visual disturbances. Any visual 
disturbance identified should be reported as an adverse event. 
See Section  17.0 for details regarding safety assessment and monitoring. 

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17.0 Safety Assessments and Monitoring 
17.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the use of a study drug/study intervention, whether or not 
related to the study drug/study intervention. 
Any laboratory abnormality that is deemed to be clinically significant in the opinion of 
the investigator will be considered an AE and should be recorded in the eCRF, whether or 
not it is related to the study drug. 
Stable chronic conditions that are present prior to clinical trial enrollment and do not 
worsen are not considered AEs and will be accounted for in the subject’s medical history. 
The following can be considered AEs: 
• An exacerbation of a pre-existing illness 
• An increase in frequency or intensity of a pre-existing episodic event or condition 
• A condition detected or diagnosed after the initiation of treatment with study 
medication, even though it may have been present prior to the start of the study 
• Continuous persistent disease or symptoms present at Baseline that worsen after 
signing the informed consent or following the initiation of treatment with study 
medication 
The following are not considered AEs: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction or 
transfusion); the condition that leads to the procedure is an AE 
• Pre-existing disease or conditions present or detected at the start of the study that 
do not worsen 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalizations for cosmetic surgery or elective surgery or social/convenience 
admissions) 
• The disease being studied, or signs or symptoms associated with the disease, 
unless more severe than expected for the subject’s condition or a worsening of the 
disease being studied 
17.2 
Definition of a Serious Adverse Event 
A SAE is defined as an AE meeting one of the following outcomes: 
• Death 
• Life-threatening event 

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• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Congenital anomaly or birth defect 
Any other important medical event that may not result in one of the above outcomes may 
be considered a SAE when, based upon appropriate medical judgment, the event may 
jeopardize the participant and may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
A life-threatening AE is any AE that places the subject, in the view of the investigator, at 
immediate risk of death from the AE as it occurred.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
17.3 
Events of Clinical Interest 
The following are considered events of clinical interest (ECIs), and must be recorded as 
such on the AE eCRF when the PI becomes aware of the ECI: 
• QTc >500 ms or a >60-ms change from Baseline, confirmed by repeat testing 
• ALT or AST >8 x ULN, if new compared to Baseline, confirmed by repeat testing 
• ALT or AST >5 x ULN for more than 2 weeks and if new compared to Baseline, 
confirmed by repeat testing 
• ALT or AST >3 x ULN and either total bilirubin >2 x ULN or INR >1.5 and if 
new compared to Baseline, confirmed by repeat testing 
• ALT or AST >3 x ULN, confirmed by repeat testing, with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%)] 
17.4 
Overdose 
This refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively, which is above the maximum recommended dose 
according to the authorized product information.  
An overdose can occur if a subject has taken, accidentally or intentionally, a drug 
administered in a dose exceeding the protocol-specified dose.  An overdose must be 
reported within 24 hours of the site becoming aware of the overdose if such overdose 
occurs with an associated SAE. If an overdose occurs without an associated SAE, the 
overdose must be reported within 5 working days and documented in the subject medical 
record. 

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17.5 
Pregnancy 
Female subjects who become pregnant should be immediately discontinued from the 
study and followed up to determine the outcome of the pregnancy. The pregnancy must 
be reported to the Sponsor within 24 hours of the site becoming aware of the pregnancy.  
If the pregnancy ends for any reason before the anticipated date, the investigator should 
notify the Sponsor. At the completion of the pregnancy, the investigator will document 
the outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., postpartum complication, spontaneous abortion, 
stillbirth, neonatal death or congenital anomaly), the investigator should follow the 
procedures for reporting an SAE. 
17.6 
Unexpected Adverse Event 
An AE is considered “unexpected” if it is not listed in the IB or is of greater specificity or 
severity than those that have been observed with the particular study drug being tested. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the IB referred only to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the IB listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to AEs that are mentioned in the IB 
as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug but are not specifically mentioned as occurring with the particular drug under 
investigation. 
17.7 
Grading of Adverse Events 
The severity (or intensity) of an AE refers to the extent to which it affects the subject’s 
daily activities and will be classified by the investigator as mild, moderate or severe using 
the following criteria: 
• Mild: Awareness of sign or symptom, but easily tolerated. Not likely to require 
medical attention. 
• Moderate: Discomfort enough to cause some interference with daily activity. May 
require medical intervention. 
• Severe: Intense enough to disrupt daily activities. Likely requires medical 
intervention. 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious”, which is based on the outcome or action criteria usually associated with events 
that pose a threat to life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 

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17.8 
Causality Assessment 
The investigator will assess causality (i.e., whether there is a reasonable possibility that 
the study drug caused the event) for all AEs and SAEs. The relationship will be 
characterized using the following classification: 
• Related: The temporal relationship of the AE with the study drug makes causality 
possible and cannot be due to another cause such as other drugs, a surgical 
intervention or an underlying disease. 
• Not related: The temporal relationship of the AE with the study drug makes 
causality improbable and can be due to another cause such as other drugs, a 
surgical intervention or an underlying disease. 
17.9 
Adverse Event Collection Timeframe 
AEs will be collected and evaluated from Baseline (Treatment Day 1), after the first dose 
of SCY-078 study drug, and SOC voriconazole and through the end of the study. 
All AEs reported by the subject or observed by members of the clinical staff will be 
evaluated by the principal investigator (PI) or qualified designee. The PI will attempt, if 
possible, to establish a diagnosis based on presenting signs and symptoms. The nature of 
the AE, time of onset relative to study drug administration, duration, severity, and 
relationship to treatment should be determined. Details of any corrective treatment must 
be recorded in the eCRF. The PI will determine whether any changes have occurred in 
baseline signs and symptoms. All AEs and SAEs will be collected in the eCRF. 
17.10 Serious Adverse Event Reporting Requirements 
All SAEs must be reported within 24 hours of the site becoming aware of the SAE. Any 
event that is serious, study drug-related, and unexpected as assessed by the medical 
monitor or the Sponsor will be submitted to the regulatory authorities in accordance with 
national regulatory laws and regulations. The PI will be responsible for reporting all 
SAEs that require reporting to the local Institutional Review Board/Ethics Committee 
(IRB/EC) in accordance with its regulations and guidelines. 
17.11 Adverse Event and Serious Adverse Event Follow-up 
All AEs and SAEs will be followed up to resolution (the subject’s health has returned to 
her baseline status or all variables have returned to normal) or until an outcome is 
reached, stabilization occurs (the investigator does not expect any further improvement or 
worsening of the event) or the event is otherwise explained, regardless of whether the 
subject is still participating in the study. All appropriate therapeutic measures should be 
undertaken and recorded. Where appropriate, medical tests and examinations will be 
performed to document resolution of the event(s). 

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17.12 Serious Adverse Event Reporting – Procedures for Investigators 
Initial Reports and Follow-Up SAE Reports:  
To report an SAE, the SAE eCRF form within the Electronic Data Capture (EDC) system 
must be completed. All SAEs, whether or not deemed drug-related or expected, must be 
reported by the investigator or qualified designee within 24 hours of first becoming aware 
of the event. The investigator/qualified designee will enter the required information 
regarding the SAE into the appropriate form, which will automatically result in 
distribution of the information to the appropriate Sponsor contact. 
17.13 Procedures for Emergency Unblinding 
This is a double-blind study. The investigator should only be unblinded if this 
information is necessary to determine treatment of an emergency. The Interactive Web 
Response Systems (IWRS) can provide the information necessary to unblind the 
investigator, in case of an emergency. In the event that the web-based IWRS system is 
not available, emergency unblinding can occur by contacting the 
 help-desk as 
follows: 
/
.
.
/
-
 If the investigator is unblinded, the 
reason for unblinding should be documented in the comment page of the eCRF. 
18.0 Data Collection, Study Monitoring and Record 
Management 
18.1 
Data Collection and Reporting 
Data for this study will be collected using eCRFs. The investigator and study site staff 
will receive training regarding the completion of the eCRF. Visit-specific data should be 
entered into the eCRF and be ready for review as soon as possible, but no later than 5 
days after each visit/time point. 
All protocol-required information collected during the study must be entered by the 
investigator or designated representative in the source documents and eCRF. All data 
entry, modification or deletion will be recorded indicating the individual subject, original 
value, the new value, the reason for change, who made the change, and when the change 
was made.  All data changes will be clearly indicated with a means to locate prior values. 
The investigator will maintain a list of individuals who are authorized to enter or correct 
data on the eCRFs. 
The investigator or designated sub-investigator, following review of the data in the eCRF, 
will confirm the validity of each subject’s data by signing the eCRF. 
18.2 
Study Monitoring 
Study progress will be monitored by the Sponsor or its representative as frequently as 
necessary to ensure adequate and accurate data collection, protocol compliance, and 

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study conduct in accordance with accepted regulatory requirements. The PI must make 
all the subject data available to the monitor for review during the planned site monitoring 
visits. Arrangements for monitoring visits will be made in advance, except in emergency 
cases. 
18.3 
Investigator Study Files 
The PI is responsible for maintaining all study-related documents in study files. The 
Sponsor will notify the PI when retention of study files is no longer necessary. The 
following documents will be kept in the study files or be readily accessible: 
• original protocol and all amendments; 
• signed agreement or protocol; 
• signed and dated study staff roles and responsibilities log; 
• copy of the current curriculum vitae of the PI and of all sub-investigators; 
• IRB/EC membership list and all IRB/EC approvals for the protocol and amendments, 
informed consent documentation and all updates, advertisements, and written 
information provided to subjects; all IRB/EC correspondence; documentation that 
the IB and subsequent revisions have been submitted to the IRB/EC; documentation 
that all SAEs and any periodic safety reports have been submitted to the IRB/EC; 
and annual IRB/EC renewals (as required); 
• updated laboratory certification and the laboratory’s normal values (covering the 
entire time interval of the study for all laboratory tests conducted during the study); 
• all confirmations of investigational drug receipt, drug accountability logs and drug 
return records; 
• a CD or DVD containing final subject eCRF data; 
• all correspondence to or from the Sponsor or its designees; 
• blank informed consent form; 
• Investigator’s Brochure; 
• subject screening log; 
• subject list (contains subject initials and/or protocol-specific subject number); 
• all subjects’ original signed informed consents; and, 
• monitoring visit log. 
18.4 
Retention of Records 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing 
applications, or at least 2 years have elapsed since the formal discontinuation of the 
clinical development of the investigational product.  These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirements or by 
an agreement with the Sponsor. 

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The Sponsor will inform the PI/institution in writing of the need for record retention and 
will notify the PI/institution in writing when the trial-related records are no longer 
needed. 
An investigator who withdraws from the responsibility of maintaining study records or 
wishes to move them to a new location has the obligation to place them in safekeeping 
and to inform the Sponsor of their location. 
19.0 Analytical Plan 
All statistical processing will be performed using SAS® version 9.3 or later, unless 
otherwise stated.  
Descriptive statistics (i.e., number of subjects, mean, standard deviation, median, 
minimum, maximum) will be presented for all continuous variables; number and 
percentage of subjects will be presented for categorical variables. For parameters 
measured over time, observed data and changes from baseline will be described for each 
time point.  
When feasible, based on adequate sample size sub-group analyses including by gender 
and by underlying condition will be conducted. 
A Statistical Analysis Plan (SAP) describing all statistical analyses in detail will be 
provided as a separate document.  
19.1 
Sample Size Determination 
This is an exploratory study with safety as a primary objective.  As a result, no formal 
sample size calculations are defined and the data from this study will provide safety data 
for SCY-078 in patients along with a preliminary view of efficacy data, which can be 
used to design future studies. Given that this is early Phase 2 trial, it would be difficult to 
try to estimate a sample size that would be required to achieve some evidence of 
statistical superiority of the efficacy endpoints being evaluated.  The sample size needed 
to achieve statistical superiority on all-cause mortality is much larger than is feasible for 
this early stage study. In addition there is insufficient information on effect size for the 
other endpoints such as global response and kinetics of galactomannan as a marker of 
efficacy. The main goal of this study is to obtain preliminary estimates of the effect size 
expected for all of the efficacy endpoints. 
19.2 
Analysis Populations 
The study populations used for the analyses are as follows: 
Intent-to-Treat (ITT)/Safety Population: The ITT Population will include all 
randomized subjects who receive at least one dose of randomized study medication. The 
Safety Population will be the same as the ITT population. 

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Modified Intent-to-Treat (mITT): The mITT population will be a subset of the ITT 
population that will include subjects who have a probable or proven IPA at baseline, per 
DRC, with at least one positive serum GMI at baseline. 
Per-Protocol (PP) Population: The PP Population will be a subset of the ITT population 
and will include subjects who have a probable or proven IPA at baseline, per DRC, with 
at least one positive serum GMI at baseline, have completed at least 14 days of 
randomized study treatment and have at least one efficacy assessment post Baseline 
(Treatment Day 1) and no major protocol deviations. 
PK Population: The PK Population will include all enrolled subjects who provide at 
least one PK sample. 
19.3 
Subject Disposition, Discontinuation, and Baseline Data 
Subject disposition in terms of the number and percentage of subjects enrolled by site 
will be tabulated. The number of subjects enrolled, number completing the study and 
reasons for discontinuation will be summarized. Subject demographics and baseline 
characteristics such as age, race, ethnicity, sex, weight, height, body mass index, country 
and other relevant parameters will be tabulated.  
Baseline is defined as the last non-missing assessment prior to the date (and time if 
appropriate) of the first dose of study drug. Change from baseline is defined as: post-
baseline value – baseline value. 
19.4 
Handling of Missing Data, Dose Adjustments, and Early 
Withdrawals 
For the efficacy analyses, subjects who do not have an EoT assessment will be assigned 
an indeterminate outcome, so will be classed as treatment failures for the corresponding 
efficacy analyses. For subjects who withdraw from the study early, every effort will be 
made to collect EoT visit information at the point of withdrawal. 
19.5 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary terminology. The number and percentage of subjects taking each 
medication before and after the first dose of study drug will be tabulated. Medications 
taken and stopped prior to the first dose of study drug will be considered prior 
medications. Medications started on or before the FU visit date with missing stop dates or 
stop dates after the first dose of study drug will be considered concomitant medications.  

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19.6 
Safety  
19.6.1 Safety Assessments 
Subjects will be evaluated for safety and tolerability throughout the study, including 
parameters such as physical exam including visual function assessment, vital signs, 12-
lead ECGs, safety laboratory tests (hematology, blood chemistry and urinalysis), 
concomitant medications, AEs and treatment discontinuations.  Electrolyte disturbances 
such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and 
corrected, if necessary, prior to initiation and during voriconazole therapy.   
Safety procedures are described in Section 15.0 and safety assessments are described in 
Section 17.0. 
19.6.2 Safety Analyses 
All safety analyses will be conducted using the ITT/safety population; all safety variables 
will be listed. 
The incidence and severity of TEAEs and SAEs and their relationship to treatment will 
be summarized.  AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19.1 or higher and presented by system organ class and 
preferred term.   
Early discontinuation of study drug treatment will be presented and will include the 
reasons for and timing of such discontinuations.  
Prior and concomitant medications will be summarized; medications will be classified 
based on the World Health Organization´s Drug Dictionary terminology. 
Abnormal physical examinations will be listed.  Laboratory evaluations will be 
summarized as observed values and changes from Baseline; shifts with respect to the 
laboratory reference range will be summarized. Events of clinical interest will be 
summarized. 
Vital signs and ECG evaluations will be summarized as observed values and changes 
from Baseline. 
19.7 
Efficacy 
19.7.1 Efficacy Assessments 
Efficacy will be assessed primarily in terms of Global Response, ACM and GMI decrease 
(GMI decrease will only be assessed for subjects with a Serum GMI above 0 at Baseline). The 
DRC evaluation of Global Response is considered the key efficacy evaluation, 
considering the expert and independent nature of the DRC assessment. In addition to 
Global Response, clinical, mycological and radiological outcomes will also be assessed. 
Exploratory efficacy assessments include, among others, recurrence, performance 
indicators and other serological biomarkers (β-D-glucan and Aspergillus PCR). 

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19.7.1.1 
Treatment Outcome 
Global Response will be assessed based on the following definitions: 
• Global Response 
 Complete Response: Survival and resolution of all attributable symptoms 
and signs of disease; plus, successful radiological outcome; plus, 
documented mycological eradication of infected sites that are accessible to 
repeated sampling or presumed eradication of sites that are not accessible to 
repeated sampling. 
 
 Partial Response: Survival and improvement of attributable symptoms and 
signs of disease; plus at least 25% reduction in diameter of radiological 
lesion(s); plus, documented mycological eradication of infected sites that 
are accessible to repeated sampling or presumed eradication of sites that are 
not accessible to repeated sampling. In cases of radiological stabilization 
(defined as 0%-25% reduction in the diameter of the lesion), resolution of 
attributable symptoms and signs of fungal disease can be equated with a 
partial response. In cases of radiological stabilization, biopsy of an infected 
site (e.g., lung biopsy) showing no evidence of hyphae and negative culture 
results can be equated with a partial response.  
 
 Stable response: Survival and no improvement in any attributable symptoms 
and signs of disease; plus, radiological stabilization (defined as a 0%-25% 
reduction in the diameter of the lesion); or persistent isolation of mold or 
histological presence of invasive hyphae in infected sites.  
 
 Progression of disease: Worsening clinical symptoms and signs of disease; 
plus, new sites of disease or radiological worsening of preexisting lesions; 
or persistent isolation of mold species from infected sites.  
 
 Death: Death during the prespecified period of evaluation regardless of 
attribution.  
 
Clinical, mycological and radiological outcome will be assessed based on the following 
definitions:  
• Clinical response 
 Success: 
• Resolution of all attributable clinical symptoms and physical findings 
• Partial resolution of attributable clinical symptoms and physical findings 
 Failure: 

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• No resolution of any attributable clinical symptoms and physical findings 
and/or worsening 
 Not applicable: 
• No attributable signs and symptoms present at Baseline and no symptoms 
attributable to invasive fungal disease developed post Baseline 
 
• Mycological response 
 Success: 
• Eradication 
• Presumed eradication 
 Failure: 
• Persistence 
• Presumed persistence  
 Not applicable: 
• No mycological evidence available at Baseline  
 
• Radiological response 
 Day 42: 
• Success (improvement of at least 25% from Baseline) 
• Failure 
• No post Baseline radiology available for patient with baseline evidence 
of radiological disease 
• Radiology not applicable at Baseline 
 
 Day 84: 
• Success (improvement of at least 50% from Baseline) 
• Failure 
• No post Baseline radiology available for patient with baseline evidence 
of radiological disease 
• Radiology not applicable at Baseline 
 
 EoT: 
• Success (improvement of at least 25% from Baseline if EoT occurs prior 
to Day 42; if EoT occurs after Day 42, at least 50% improvement from 
Baseline) 
• Failure 
• No post Baseline radiology available for patient with baseline evidence 
of radiological disease 
• Radiology not applicable at Baseline 
 

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19.7.1.2 
All-Cause Mortality  
All-cause mortality will be defined as death during the prespecified period of evaluation, 
regardless of attribution. Survival will be determined via an in-person visit or a phone 
contact, and will document subject status (alive or deceased) as well as date of death. If 
subject is deceased, the investigator´s assessed relationship to the fungal infection will 
also be recorded. If autopsy is conducted, key findings should be collected in the eCRF. 
 
19.7.1.3 
GMI Decrease 
GMI decrease will be assessed in terms of absolute and percentage reduction relative to 
Baseline, and in terms of time to achieve the GMI absolute and percentage reductions. 
GMI decrease will be assessed in subjects with Baseline serum GMI above 0, only. 
 
19.7.1.4 
Recurrence 
Recurrence is defined as a diagnosis of probable or proven IPA based on EORTC after 
EoT in patients who have previously achieved complete response. Re-emergence of the 
Aspergillus infection is required to be with the same species (if Aspergillus isolates are 
available for both the baseline and the recurrent episode) and involving the same site that 
was initially identified at Screening. The DRC will be responsible for determining 
recurrence. 
19.7.2 Efficacy Analyses 
The secondary efficacy endpoint, the percentage of subjects with successful Global 
Response (Complete Response or Partial Response) at EoT, Day 42 and Day 84 as 
determined by the DRC and the Principal Investigator will be presented by treatment 
group along with an estimate of the difference between treatment groups.  The response 
rate will be calculated for each treatment group as the number of successes divided by the 
total number of patients (success + failure + indeterminate). The difference in response 
rates between treatments will be presented along with a 95% confidence interval (CI), 
calculated using the method of Miettinen and Nurminen. The secondary analysis of ACM 
at Day 42 and Day 84 will be presented by treatment group along with an estimate of the 
difference between treatment groups. In addition, a Kaplan Meier plot will be produced 
to summarize overall survival over time. 
The remaining secondary and exploratory endpoints will be summarized by treatment 
group. 
Provided sufficient data are available to allow meaningful presentation, results of the key 
efficacy parameters will also be presented by baseline Aspergillus species; by baseline 
minimum inhibitory concentration (MIC) and minimal effective concentration (MEC) for 
voriconazole and SCY-078, respectively; and by baseline neutropenia and persistent 
neutropenia at Week 2. 

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Considering the exploratory nature of this study, further analysis may be defined in the 
statistical analysis plan, as deemed appropriate.  For example, if the data are 
heterogeneous within this randomized study, attempts may be made to match patients 
across the treatment groups on key disease criteria, if sufficient data are available, to 
better understand the comparability of the randomized groups. 
19.8 
Pharmacokinetics  
19.8.1 Pharmacokinetic Assessments 
PK testing for the determination of SCY-078 will be conducted for all subjects.  For the 
first 20 randomized subjects, blood samples for SCY-078 PK testing will be collected 
predose on Treatment Days 1, 3, 7 and 14, approximately within 1 hour before dosing, 
and on Treatment Days 1, 7 and 14 at  2-4 hours and at 6-8 hours after dosing.   
Voriconazole level determination will also be performed for all study subjects predose on 
Treatment Days 1, 3, 7 and 14, approximately within 1 hour before dosing, and on 
Treatment Days 1, 7 and 14 at 2-4 hours and at 6-8 hours after dosing. 
The PK data from the first 20 subjects will be assessed in an interim PK analysis that will 
keep the study team blinded. 
For subsequent randomized subjects, blood PK samples will be collected predose on 
Treatment Days 1, 3, 7 and 14, approximately within 1 hour before dosing, and on 
Treatment Days 1, 7 and 14 at 4-8 hours after dosing for SCY-078 and voriconazole 
central lab PK testing.  
Results for plasma concentrations of SCY-078 and voriconazole analyzed by the central 
laboratory will not be available in real time for any subject. 
19.8.2 Pharmacokinetic Analyses 
The sparse samples collected in this study will be analyzed using Population PK (Pop 
PK) analysis methods to estimate PK parameters (Cmax, AUC, clearance/fraction 
absorbed [CL/F]) as applicable.  
Key collection and analysis timepoints include Day 1, Day 7 (i.e., steady state) and Day 
14.  After the first 20 subjects have been treated for at least 7 days, an interim PK 
evaluation will be conducted to ensure there are no clinically relevant effects of the co-
administration of SCY-078 and voriconazole on the PK exposure (predicted AUC and 
Cmax based on updated population PK model) of both drugs. The data from this analysis 
will inform, and if necessary adjust, the doses of the study drug for subjects subsequently 
randomized. The overall goal, considering that IPA is a life-threatening condition, is to 
ensure that >80% of subjects achieve an exposure that is at least equal to that reported as 
efficacious in the mice models of invasive aspergillosis (15.6 μg•mL/hr). The results 
from the PK analyses will be presented in a separate report. 
 
The interim analysis will be focused on PK parameters only. Unblinded information will 

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be provided to the independent pharmacokinetics team doing the analysis and the 
remaining of the study team will remain blinded.  The statistical team responsible for 
randomization will confirm if at least 10 subjects have been randomized to SCY-078 and 
voriconazole at the time of the planned interim analysis.  If less than 10 subjects have 
been randomized to SCY-078 and voriconazole at that point, the interim analysis will be 
postponed until 24 subjects are randomized.  
20.0 Ethics and Protection of Human Patients 
20.1 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, the ethical principles 
established by the Declaration of Helsinki (as amended in Fortaleza, Brazil, October 
2013), the International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines, the US Code of Federal Regulations (CFR) sections that address 
clinical research studies, applicable European Union regulations and/or other national and 
local ethical and legal requirements, as applicable. 
20.2 
Institutional Review Board/Ethics Committee Review 
The PI must provide the IRB/EC with all appropriate materials, including a copy of the 
subject ICF. The study will not be initiated until the PI obtains written approval of the 
protocol and the subject ICF from the appropriate IRB/EC, and copies of these 
documents are received by the Sponsor. Appropriate reports on the progress of this study 
will be made by the PI to the IRB/EC, medical monitor, and Sponsor in accordance with 
applicable government regulations and in agreement with policy established by the 
Sponsor. 
20.3 
Informed Consent  
The ICH issued guidelines to provide protection for human subjects in clinical 
investigations. The ICH Tripartite Guideline for Good Clinical Practice establishes the 
general requirements for informed consent. Each subject will be provided with oral and 
written information in a language they can understand that describes the nature and 
duration of the study. Before undergoing screening, each subject must consent in writing 
to study participation. The patient (or the subject’s legal representative) will sign and 
personally date the subject ICF. The person rendering consent will also sign and 
personally date the subject ICF as the person who obtained the consent of the subject.  
For subjects who were unable to provide consent due to incapacity and their legally 
authorized representative (LAR) provided consent on their behalf, and if during the 
course of the study, the subject regains the ability to make decisions he/she will be 
informed of the decisions made by the LAR during the time of their incapacity and any 

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effects that may have occurred as a result. The subject will then be asked to provide 
consent and decide whether to continue in the study. Alternatively, the site may choose 
not to include patients in the study, who are not able to provide consent on their own. 
The original signed subject ICF will be retained with the study center’s records. Each 
subject will receive a copy of his/her signed subject ICF. In addition, the PI, or his or her 
designee, must document in the case history that informed consent was obtained before 
study participation.  
20.4 
Future Use of Samples 
Mold isolates including Aspergillus spp. (see Section 15.14) collected in this study may 
be maintained in repositories for potential future use. Future research of isolates may 
include in vitro susceptibility testing of new or existing antifungals or analysis of 
mechanisms of resistance.  
20.5 
Subject Privacy and Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified only by a coded number to maintain subject privacy and confidentiality. 
All records will be kept in a locked file cabinet. All computer entry and networking 
programs will be performed with coded numbers only. Clinical information will not be 
released without written permission of the subject, except as necessary for monitoring by 
the medical monitor, IRB/EC, the Food and Drug Administration (FDA), the Sponsor or 
where required by law. All local privacy laws must be followed.   
20.6 
 Study Termination 
The PI, the Sponsor, the FDA, and the IRB/EC each reserve the right to terminate the 
study, due to unjustifiable risk, relevant toxicity, and/or unknown and new adverse event 
findings, in the interest of subjects’ safety and welfare. The Sponsor reserves the right to 
terminate the study at any time for administrative or any reasons. 
20.7 
Financial Disclosure 
The financial interests of all investigators from all participating clinical centers must be 
collected prior to study initiation and 1 year following the completion of the clinical trial. 

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21.0 References 
1. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht 
R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach 
WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, Bennett JE. 
Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 
Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 
15:63(4):e1-e60. Doi: 10.1093/cid/ciw326. Epub 2016 Jun 29. 
2. Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, 
Lass-Flörl C, Lewis RE, Munoz P, Verweij PE, Warris A, Ader F, Akova M, 
Arendrup MC, Barnes RA, Beigelman-Aubry C, Blot S, Bouza E, Brüggemann 
RJM, Buchheidt D, Cadranel J, Castagnola E, Chakrabarti A, Cuenca-Estrella M, 
Dimopoulos G, Fortun J, Gangneux JP, Garbino J, Heinz WJ, Herbrecht R, 
Heussel CP, Kibbler CC, Klimko N, Kullberg BJ, Lange C, Lehrnbecher T, 
Löffler J, Lortholary O, Maertens J, Marchetti O, Meis JF, Pagano L, Ribaud P, 
Richardson M, Roilides E, Ruhnke M, Sanguinetti M, Sheppard DC, Sinkó J, 
Skiada A, Vehreschild MJGT, Viscoli C, Cornely OA. Diagnosis and 
management of Aspergillus disease: executive summary of the 2017 ESCMID-
ECMM-ERS guideline. Clin Microbiol Infect. 2018 May;24 Suppl 1:e1-e38. doi: 
10.1016/j.cmi.2018.01.002. Epub 2018 Mar 12. 
3. Garcia-Vidal C, Peghin M, Cervera C, Gudiol C, Ruiz-Camps I, Moreno A, 
Royo-Cebrecos C, Roselló E, de la Bellacasa JP, Ayats J, Carratalà J. 
Causes of death in a contemporary cohort of patients with invasive aspergillosis. 
PLos One. 2015 Mar 24;10(3):e0120370. doi: 10.1371/journal.pone.0120370. 
eCollection 2015. 
4. Verweij PE, Chowdhary A, Merchers WJ, Meis JF. 
Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of 
Mold-Active Antifungal Azoles? Clin Infect Dis. 2016 Feb 1;62(3):362-8. doi: 
10.1093/cid/civ885. Epub 2015 Oct 20.  
5. Dutch Working Party on Antibiotic Policy (SWAB). SWAB Guidelines for the 
Management of Invasive Fungal Infections. December 2017. Published at 
www.swab.nl 
6. Petraitis V, Petraitiene R, Sarafandi AA, Kelaher AM, Lyman CA, Casler HE, 
Sein T, Groll AH, Bacher J, Avila NA, Walsh TJ. 2003. Combination therapy in 
treatment of experimental pulmonary aspergillosis: synergistic interaction 
between an antifungal triazole and an echinocandin. J Infect Dis 187:1834–1843. 
10.1086/375420.  
7. Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, 
Heinz WJ, Jagannatha S, Koh LP, Kontoyiannis DP, Lee DG, Nucci M, Pappas 
PG, Slavin MA, Queiroz-Telles F, Selleslag D, Walsh TJ, Wingard JR, Maertens 

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JA. Combination antifungal therapy for invasive aspergillosis: a randomized trial. 
Ann Intern Med. 2015 Jan 20;162(2):81-9. doi: 10.7326/M13-2508. 
8. Ghannoum M, Long L, Larkin EL, Isham N, Sherif R, Borroto-Esoda K, Barat S, 
Angulo D. Evaluation of the Antifungal Activity of the Novel Oral Glucan 
Synthase Inhibitor SCY-078, Singly and in Combination, for the Treatment of 
Invasive Aspergillosis. Antimicrob Agents Chemother. 2018 May 25;62(6). pii: 
e00244-18. doi: 10.1128/AAC.00244-18. Print 2018 Jun. 
9. W SA, Randolph R, Park SH, Abruzzo G, Chen Q, Flattery A, Garret G, Peel M, 
Outcalt R, Powell K, Trucksis M, Angulo D, Borroto-Esoda K. Preclinical 
Pharmacokinetics and Pharmacodynaic Target of SCY-078, a First-in-Class 
Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of 
Disseminated Candidiasis. Antimicrob Agents Chemother. 2017 Apr; 61(4): 
e02068-16.  Prepublished online 2017 Jan 30. Published online 2017 Mar 
24. doi: 10.1128/AAC.02068-16. 
10. Petraitis V, Petraitiene R, McCarthy MW, Kovanda LL, Zaw MH, Hussain K, 
Shaikh N, Maung BBW, Sekhon NK, Hope WW, Walsh TJ. 2017.Combination 
therapy with isavuconazole and micafungin for treatment of experimental 
invasive pulmonary aspergillosis. Antimicrob Agents Chemother 61:e00305-17. 
11. Petraitis V, Petraitiene R, Sarafandi AA, Kelaher AM, Lyman CA, Casler HE, 
Sein T, Groll AH, Bacher J, Avila NA, Walsh TJ. 2003. Combination therapy in 
treatment of experimental pulmonary aspergillosis: synergistic interaction 
between an antifungal triazole and an echinocandin. J Infect Dis 187:1834–1843. 
10.1086/375420. 
12. Petraitis V, Petraitiene R, Hope WW, Meletiadis J, Mickiene D, Hughes JE, 
Cotton MP, Stergiopoulou T, Kasai M, Francesconi A, Schaufele RL, Sein T, 
Avila NA, Bacher J, Walsh TJ. 2009. Combination therapy in treatment of 
experimental pulmonary aspergillosis: in vitro and in vivo correlations of the 
concentration- and dose-dependent interactions between anidulafungin and 
voriconazole by Bliss independence drug interaction analysis. Antimicrob Agents 
Chemother 53:2382–2391. 10.1128/AAC.00329-09  
13. Wring S,  Murphy G, Atiee G, Corr C, Hyman M, ,Willett M, Angulo D. Lack of 
Impact by SCY-078, a First-in-Class Oral Fungicidal Glucan Synthase Inhibitor, 
on the Pharmacokinetics of Rosiglitazone, a Substrate for CYP450 2C8, Supports 
the Low Risk for Clinically Relevant Metabolic Drug-Drug Interactions. The 
Journal of Clinical Pharmacology 2018, 00(0) 1–9. 
14. Wring S, Murphy G, Atiee G, Corr C, Hyman M, Willett M, Angulo D. Clinical 
Pharmacokinetics and Drug-Drug Interaction Potential for Coadministered SCY-
078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus. Clinical 
Pharmacology in Drug Development. 2018, 00(0) 1–10. 
15. Ben De Pauw, Thomas J. Walsh, J. Peter Donnelly, David A. Stevens, John E. 
Edwards, Thierry Calandra, Peter G. Pappas, Johan Maertens, Olivier 

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Lortholary, Carol A. Kauffman, David W. Denning, Thomas F. Patterson, Georg 
Maschmeyer, Jacques Bille, William E. Dismukes, Raoul Herbrecht, William W. 
Hope, Christopher C. Kibbler, Bart Jan Kullberg, Kieren A. Marr, Patricia 
Muñoz, Frank C. Odds, John R. Perfect, Angela Restrepo, Markus 
Ruhnke, Brahm H. Segal, Jack D. Sobel, Tania C. Sorrell, Claudio Viscoli, John 
R. Wingard, Theoklis Zaoutis, and  John E. Bennett. Revised Definitions of 
Invasive Fungal Disease from the European Organization for Research and 
Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the 
National Institute of Allergy and Infectious Diseases Mycoses Study Group 
(EORTC/MSG) Consensus Group.  Clin Infect Dis. 2008 Jan 15, 46(12):1813-21. 
 
 

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22.0 Appendices 
22.1 
Appendix A:  Prohibited Medications and Medications to be 
Administered with Caution 
Below are a few examples relevant for hematological patients. Details and flexible 
medical monitor guidance will be available, with consideration to local label, local 
standard practice and best interest of the patient.  
22.1.1 Prohibited Medications 
In addition to the prohibited medications listed below, the Voriconazole label should be 
consulted and followed for additional warnings and precautions related to concomitant 
medications. 
 
Investigational Drugs 
No other investigational drugs are allowed during the study from at least 28 days or 5.5 
half-lives of the investigational product (whichever is longer) before signing the informed 
consent through the 6-Week Follow-up visit.  
 
Antifungals 
• No antifungal treatment other than the study drug is allowed during the study.  
• Prior mold-active antifungal agents for the treatment of the IPA episode are not 
allowed for more than 4 days (96 hours) in the 7 days preceding enrollment 
(Baseline/Treatment Day 1), except for those subjects who have received more than 
4 days but less than 7 days of prior mold-active antifungal therapy for the treatment 
of the IPA episode in the 7 days preceding enrollment into the study and are 
approved for randomization by the medical monitor. 
• Prophylaxis with a mold-active azole antifungal (i.e., voriconazole, posaconazole, 
isavuconazole or itraconazole) is not allowed in the 14 days preceding enrollment 
into the study (Baseline/Treatment Day 1). 
Other Prohibited Medications 
In addition, the medications listed below are also prohibited. 
 
Strong CYP3A4/5 inhibitors and CYP3A4/5 inducers 
CYP 
Strong Inhibitorsa 
Inducersa 

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3A4/5 
 
• boceprevir 
• clarithromycin 
• conivaptan 
• indinavir 
• lopinavir  
• mibefradil 
 
• nefazodone 
• nelfinavir 
• ritonavir 
• saquinavir 
• telaprevir  
• telithromycin 
• avasimibe 
• carbamazepine 
• phenytoin 
• rifampin 
• St. John’s wort 
 
a: The CYP3A4/5 inhibitors and CYP3A4/5 inducers listed in this table are not permitted during the 
14 days prior to Baseline/Treatment Day 1 and during study treatment. 
 
P-glycoprotein (P-gp) substrates 
P-gp Drug Substratesa 
digoxin, colchicine, vinblastine and talinolol 
a. The P-gp substrates listed in this table are not permitted during the 48 hours prior to 
Baseline/Treatment Day 1  and during study treatment. 
22.1.2 Medications to be administered with Caution and Monitored as 
Appropriate 
CYP3A4 substrates 
CYP 
Substrates 
3A4 
In vitro, SCY-078 was an inhibitor of CYP3A mediated metabolism of midazolam, but 
was only a weak inhibitor of metabolism of testosterone. The clinical significance of 
this inhibition is unknown; caution should be exercised when administering SCY-078 
with drugs known to be CYP3A sensitive substrates with narrow therapeutic index, 
such as midazolam and cyclosporine. 
Subjects receiving sirolimus, tacrolimus or warfarin, cyclosporine or amiodarone are 
permitted for enrollment in the study and these medications may be administered 
concomitantly with SCY-078 with close monitoring. Dosing adjustments and 
subsequent monitoring of sirolimus and warfarin should be undertaken in accordance 
with product prescribing information for the respective agents. 
 
OATP1B3 substrates 
OATP 
Substrate 
1B3 
In vitro, SCY-078 is an inhibitor of the OATP1B3 liver uptake transporter.  The 
clinical significance of this inhibition is unknown; however, there is a potential risk 
for increased exposure of the concomitant medications (arising from lowered hepatic 
clearance) when administering SCY-078 with drugs known to be OATP1B3 selective 
substrates. Therefore, caution should be exercised when administering SCY-078 with 
drugs known to be OATP1B3 selective substrates such as telmisartan, including 
monitoring the subject for signs of overexposure associated with the concomitant 
medications as described in the product prescribing information. 

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Sources: 
• 
FDA Draft Guidance for Industry.  Drug Interaction Studies – Study Design, Data Analysis, 
and Implications for Dosing and Labeling.  2012. 
• 
Drug interactions in infectious disease by Stephen C. Piscitelli, Keith Rodvold (2007) 
• 
UCSF-FDA Transportal 
 
 

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22.2 
Appendix B: Voriconazole Label  
 
Voriconazole prescribing information in the Unites States of America: 
https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e985d908-22ca-4849-
8ac3-c081301b65f0&type=display 
  
Voriconazole prescribing information in Europe: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000387/WC500049756.pdf 
  
 
 

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22.3 
Appendix C: Definitions of Invasive Fungal Disease (IFD) 
 
Adapted from the Diagnostic Criteria published by the EORTC-MSG15 
A DRC charter will provide detailed criteria to be used for the baseline and outcome 
analysis of subjects in this study. The analysis criteria will be based on EORTC-MSG 
Consensus Criteria as outlined below. Adaptations to the EORTC-MSG criteria adopted 
by the DRC will be documented in the DRC charter.  
 
Proven Invasive Fungal Disease 
Subjects with a positive diagnostic test of either: 
• Histopathologic, cytopathologic, or wet mount examination of a needle aspiration 
or biopsy specimen showing hyphal forms with evidence of associated tissue 
damage (either microscopically or as an infiltrate or lesion by imaging); 
OR 
• Recovery of a mould by culture from a sample obtained by a sterile procedure 
from a normally sterile and clinically or radiologically abnormal site consistent 
with an infectious disease process, excluding bronchoalveolar lavage (BAL). 
Probable Invasive Fungal Disease 
At least one host factor (definitions see below) PLUS at least one clinical feature of acute 
lower respiratory tract disease (definitions see below) PLUS at least one mycological 
criterion (definitions see below). 
 
Possible Invasive Fungal Disease 
All subjects with at least one host factor who meet criteria for clinical features of lower 
respiratory tract disease (as defined below), but for which mycological criteria are absent. 
 
Definitions of Diagnostic Criteria: 
Host Factors 
a. Recently resolved (<4 weeks) or ongoing neutropenia (neutropenia defined as 
absolute neutrophil count <0.5 × 109/L [<500/mm3] for ≥10 days), associated with 
the onset of the fungal disease; or 
b. Receipt of an allogeneic haematopoietic stem cell transplant (HSCT) or BMT; or 
c. Prolonged use of corticosteroids at a mean minimum dose of 0.3 mg/kg/day of 
prednisone equivalent for > 3 weeks;  
d. Treatment with other recognized T-cell immunosuppressants, such as 
cyclosporine, TNF-α blockers, specific monoclonal antibodies (such 
as alemtuzumab), or nucleoside analogues during the past 90 days;  
e. Inherited severe immunodeficiency (such as chronic granulomatous disease or 
severe combined immunodeficiency). 

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Clinical Features of Acute Lower Respiratory Tract Disease with: 
At least one of the following imaging signs on CT: 
a. Dense well-circumscribed lesion(s) (nodules) ± halo sign 
b. Air crescent sign 
c. Cavity  
d. A “non-specific” focal infiltrate (“Tree-in-bud”, “Wedge shapes”) 
(Review of the medical history does not suggest a different etiology for the syndrome; 
syndrome onset within 2 weeks prior to the first dose of study medication. The presence 
of other clinical findings (pleural rub, pleural pain, or haemoptysis) will be recorded but 
these features are not thought sufficiently predictive to be used alone.) 
 
Note: Only subjects with lower respiratory tract disease are eligible for the study. 
Subjects with clinical features of non-lower respiratory tract disease, such as sino-nasal 
infection, tracheobronchitis as the only manifestation of invasive aspergillosis are not 
eligible. 
 
Mycological Criteria (all available GMI results from serum or BAL within 7 days 
prior to enrollment should be included in the CRF ): 
• Serum galactomannan (GM) with at least one GMI value of ≥0.5 are adequate  
mycological evidence for considering an IPA as probable in this study.  
o Subjects receiving concomitant amoxicillin/clavulanate, 
piperacillin/tazobactam or Plasma-Lyte™ (Baxter) that could potentially 
induce false positive GM should be discussed with the Medical Monitor. 
 
• BAL galactomannan (GM) with at least one GMI value of ≥1. 
 
• Cytology, direct microscopy, culture or polymerase chain reaction (PCR) from 
bronchoalveolar lavage (BAL) fluid, bronchial brush, or other lung samples 
indicating presence of Aspergillus spp. 
 
 
 

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22.5 
Appendix E: Previous Protocol Revisions 
 
 
 
Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
Clinical Trial Protocol (Title)  
Section 2 (Protocol Approvals) 
Investigator Agreement 
Statement (Title) 
• Removed “Combination Therapy” and replaced with 
“Coadministration” for clarity. 
Section 1 (Contact Information) 
Section 2 (Protocol Approvals) 
Updated Study Medical Monitor from 
 
 
 to 
 
 
 
Section 5 (Abbreviations) 
Added Amphotericin B (AMB) and Standard of Care 
(SOC). 
Synopsis (Title, Primary 
Objective, Secondary Objective, 
Exploratory Objective, Study 
Design, Study Treatment Groups) 
 
Provided clarification to the study drug and voriconazole 
coadministration by removing  “combination therapy” 
and “monotherapy” since the study treatment is 
coadministration 
of 
SCY-078 
and 
voriconazole 
compared to the coadministration of SCY-078 placebo 
and voriconazole. 
Section 8.1 (Background 
Information) 
 
In the Drug-Drug Interaction Potential section:  
• Removed “combination” and replaced with “where 
SCY-078 is coadministered with voriconazole” to 
read: 
As a precautionary measure, the SCY-078 dose 
administered in this study where SCY-078 is co-
administered with voriconazole, will be reduced by 
30% until the results of the model are confirmed in 
an interim PK analysis that will include the first 20 
randomized subjects.” 
In the Conclusion section:  
• Replaced “Combination therapy” with 
“Coadministration” to read: Co-administration of 
SCY-078 with a mold-active azole such as 
voriconazole has the potential to improve clinical 
outcomes in patients with life-threatening IPA. 

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
Section 8.2 (Rationale for the 
Study) 
In the first paragraph: 
• Replaced “in combination” with “coadministered” 
to read: 
The two components of the combination therapy 
proposed in this protocol are voriconazole, an  
approved mold-active azole coadministered with 
SCY-078, an investigational GSI. 
• Added “taken with placebo” to read: 
In line with these guidelines, the only monotherapy 
arm in this study is with a mold-active azole 
(voriconazole) taken with placebo, and monotherapy 
with SCY-078 is not included in this design. 
In the Rationale for the objectives of the study section: 
• Replaced “given in combination” with 
“coadministered” to read: 
This study will evaluate the safety of SCY-078 
when coadministered with voriconazole to the 
intended population. 
• Replaced “combination therapy” with 
“coadministation of SCY-078 with voriconazole” to 
read: 
This Phase 2 study also aims to investigate the 
effect of the coadministration of SCY-078 with 
voriconazole on multiple outcome endpoints 
including ACM and global response (typical 
endpoints for this indication) but also investigates 
other biological markers of therapeutic response 
such as serum galactomannan index. 
In the Rationale for proposed doses (Voriconazole) 
section: 
• Replaced “used in combination” with 
“coadministered” to read: 
The drug-drug interaction simulation PBPK-based 
model does not indicate any need for a modification 
to the approved dose of voriconazole when 
coadministered with SCY-078.   

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
In the Rationale for proposed doses (SCY-078) section 
(last paragraph): 
• Removed “combination” from sentence to read: 
As a precautionary measure, the SCY-078 dose 
administered in this study will be reduced by 30% 
until the results of the model are confirmed in an 
interim PK analysis that will include the first 20 
randomized subjects. 
• Replaced “combination” with “SCY-078 and 
voriconazole” to read: 
Specifically, the first 10 subjects assigned to  SCY-
078 and voriconazole therapy will receive an oral 
SCY-078 loading dose of 500 mg BID on Days 1 and 
2 followed by a maintenance dose of 500 mg QD 
from Day 3 onwards. 
Synopsis (Study Design) 
Section 11.1 (Overall Description 
of the Study)  
Section 12.1 (Inclusion Criterion 
#6) 
Addition of statement to clarify enrollment of patients 
who may have received mold active prophylaxis as 
follows: 
This study is intended for subjects with an IPA episode that, 
in the investigator´s judgement, requires antifungal therapy 
and is reasonable to expect that be adequately treated with 
voriconazole (i.e., the IPA is not due to a voriconazole-
resistant isolate or a breakthrough infection while receiving a 
mold-active azole antifungal  [voriconazole, posaconazole, 
isavuconazole or itraconazole] that requires therapy with a 
non-azole antifungal agent). Subjects with breakthrough IPA 
while receiving a mold-active azole antifungal may be 
considered for enrollment in circumstances in which the 
antifungal 
prophylaxis 
is 
considered 
not 
optimally 
administered (e.g. only few doses were given, frequent 
interruptions, subject not achieving adequate plasma 
exposures) and/or if the Aspergillus spp. isolate (when 
available) is known or expected to be susceptible to 
voriconazole.    
Section 9.1 (Primary Objectives) 
Section 9.2 (Secondary 
Objectives) 
Provided clarification to the study drug and voriconazole 
coadministration by removing  “combination therapy” 
and 
“monotherapy” 
since 
the 
treatment 
is 

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
Section 9.3 (Exploratory 
Objectives) 
Section 11.1 (Overall Description 
of the Study) 
Section 11.2 (Blinding, 
Randomization and Stratification) 
Section 16 (Study Schedule: 
footnote t) 
coadministration 
of 
SCY-078 
and 
voriconazole 
compared to the coadministration of SCY-078 placebo 
and voriconazole. 
Synopsis (Study Design and 
Target Population) 
Section 11.1 (Overall Description 
of the Study) 
Section 11.1.1.1 [Screening 
Period (Days -4 to -1)] 
 
Removal of “HM or a myelodysplastic syndrome or 
aplastic anemia or HCT” since the target subject 
population was broadened. 
Synopsis (Key Inclusion Criteria) 
Section 12.1 (Inclusion Criteria) 
Expanded Inclusion Criteria #4 and added last 3 bullets 
below to allow additional target subject population to 
enroll in the study. Added “OR” between each bulleted 
criterion below, since subjects should have one of the 4 
criteria. 
• a diagnosis of a hematological malignancy or a 
myelodysplastic syndrome or aplastic anemia or has 
undergone hematopoietic cell transplantation, OR 
• Subject who either recently resolved or ongoing 
neutropenia (neutropenia defined as absolute 
neutrophil count < 0.5 x 109/L [< 500/mm3] for > 
10 days), temporally related to the onset of fungal 
disease  OR 
• Subject who received treatment with other 
recognized T-cell immunosuppressants (such as 
cyclosporine, tacrolimus, monoclonal antibodies or 
nucleoside analogs) during the past 90 days 
including solid organ transplant patients  OR 
• Subject with inherited severe immunodeficiency 
(e.g. 
chronic 
granulomatous 
disease, 
severe 
combined immunodeficiency). 

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
Section 12.1 (Inclusion Criteria – 
criterion 8c)  
 
Added “highly effective” to hormonal contraceptive as 
the allowable form of contraception. 
Synopsis (Key Exclusion Criteria) 
Section 12.2 (Exclusion Criteria) 
For criterion 6:  
• Changed the AST or ALT value from >10 to ≥ 5 
and total bilirubin value from > 5 to > 2.5 to 
exclude subjects with Grade 3 and beyond 
elevations in LFT tests. Criterion now states: 
Subject has abnormal liver test parameters: AST or 
ALT ≥ 5 x ULN and/or total bilirubin > 2.5 x ULN.  
• For subjects with Gilbert’s disease, provided a limit 
of <7 mg/dL for unconjugated hyperbilirubinemia 
since a limit was not previously provided. 
Section 12.2 (Exclusion Criteria) 
 
• For criterion 9: added “ and prolonged QTcF 
interval (Fridericia’s correction: QTc= QT/(RR)0.33) 
>450 ms for males”. Criterion now reads: 
Subject has a prolonged QTcF interval (Fridericia’s 
correction: QTc= QT/(RR)0.33) >480 ms for females 
and prolonged QTcF interval (Fridericia’s 
correction: QTc= QT/(RR)0.33) >450 ms for males, 
on the baseline ECG or other abnormalities deemed 
clinically significant by the investigator that would  
put the subject at unacceptable risk for participation 
in the study. 
• For criterion 10: added “including history of 
conditions or medications that may increase the risk 
for QTc prolongation”.  Criterion now reads: 
Subject has any other condition including history of 
conditions or medications that may increase the risk 
for QTc prolongation, or laboratory abnormality 
that, in the judgment of the investigator, would put 
the subject at unacceptable risk for participation in 
the study or may interfere with the assessments 
included in the study. 

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
Synopsis (Study Blinding, 
Randomization and Stratification) 
Section 17.13 (Procedures for 
Emergency Unblinding) 
Added: In the event that the web-based IWRS system is 
not available, emergency unblinding can occur by 
contacting the 
 help-desk as follows: 
/
.
.
/
-
 
Synopsis (Safety Evaluations) 
Section 15.17 (Safety Laboratory 
Tests) 
• Added 6-Week FU to the timepoints when safety 
laboratory tests should be performed. 
• Added clarification to include monitoring serum 
electrolytes, amylase, lipase. 
• Added the treatment Day to correspond to the 
weekly monitoring in the first month of treatment 
and also added Day 21.  
• Added sentence as follows: Electrolyte disturbances 
such as hypokalaemia, hypomagnesaemia and 
hypocalcaemia should be monitored and corrected, 
if necessary, prior to initiation and during 
voriconazole therapy.  
Section 11.1 (Overall Description 
of the Study) 
Changed Section 22.3 to Section 12.1 since the link 
should be directed to the Inclusion Criteria. 
Section 11.1.1.1 
(Screening Period (Days -4 to -1) 
For Subjects with Possible IPA - Removed the 
following sentence:  
This 4-day mold-active antifungal treatment limit prior 
to randomization is inclusive of any days of mold-active 
antifungal that the subject may have received prior to 
Screening. 
Section 11.1.2 (Safety and 
Tolerability) 
Section 19.6.1 (Safety 
Assessments) 
Added:  Electrolyte disturbances such as hypokalaemia, 
hypomagnesaemia and hypocalcaemia should be 
monitored and corrected, if necessary, prior to initiation 
and during voriconazole therapy.   
Synopsis and Section 11.2 
(Blinding, Randomization and 
Stratification) 
Updated the stratification criterion as a result of 
broadened target population as follows: 
• Hematological malignancies and /or hematopoietic 
cell transplantation recipients  
• Solid organ transplant recipients 
• Other immunocompromising conditions 

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
Section 11.3 (Study Duration) 
• Added “End of Study” to section heading which 
now reads “Study Duration/End of Study” 
• Added definition for end of study. 
Synopsis (Study Treatment 
Groups)  
• Addition of administration of voriconazole with 
regard to meals. 
• Addition of SCY-078 frequency and administration 
with regard to meals. 
Section 13.1.1 (Description of 
Study Groups) 
• Addition of administration of voriconazole with 
regard to meals and addition of SCY-078 frequency 
and administration with regard to meals. 
• Removed row which displayed “Combination 
Therapy” and “Monotherapy” from Table 3. 
Section 13.2 (Dietary 
Requirements) 
• Addition of “oral” to SCY-078. 
• Removed dosing instruction since it should not 
belong in the dietary requirements section. 
Synopsis and Section 13.3  
(Study Drugs)  
Removal of Sponsor to provide voriconazole AND 
addition of statement that Sponsor will provide 
voriconazole in extenuating circumstances. 
Section 15.13 (Other Imaging) 
Removed “subsequent imaging studies” and changed to 
“these other”. 
Section 15.14 
(Mycological Testing Other than 
Serum GMI, Serum β-D Glucan 
and Plasma Aspergillus PCR) 
• BAL and relevant tissue samples to include 
histopathology along with Aspergillus PCR which 
should be submitted to the central laboratory for 
additional diagnostic tests. 
• Clarified by adding mold isolates including  
Aspergillus to be sent to the central laboratory 
where isolates are specified 
Section 15.16 (Serum  β-D 
Glucan and Plasma Aspergillus 
PCR Test) 
Added sentence to state that if blood samples are 
collected to perform serum β-D-glucan and plasma 
Aspergillus PCR are locally that the results from the 
local laboratory should be entered in the eCRF. 
Section 15.17  
(Safety Laboratory Tests) 
• Added magnesium, calcium, amylase and lipase and 
removed “and indirect” for bilirubin in the blood 
chemistry table.  

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
• Removed 6-Week FU since it is no longer clinically 
indicated but required. 
Section 15.20 (SCY-078 
Pharmacokinetic Sample 
Collection) 
Added “In addition to blood, other biological samples 
such as pleural effusion and tissue biopsies may also 
analyzed for SCY-078 PK determination, when 
available” to the of the paragraph. 
Section 15.24 (Study Drug 
Dispensing) 
Removed “Screening”, “Treatment Day 5”, “Treatment 
Day 14” for Study Drug Dispensing since study drug 
will now be dispensed at Baseline ( (Treatment Day 1) 
and Every 14 days during treatment. 
Section 15.25 (Study Drug 
Dosing) 
• Removed “IV and oral voriconazole” from this 
section since voriconazole (oral and IV) is standard 
of care (SOC) therapy.  
• Added SCY-078 study drug administration, 
adjustment, frequency and dosing with regard to 
meals. 
• Addition of allowable dose administration 
adjustments for subjects who are intolerant of SCY-
078 due to gastrointestinal (GI) related conditions.  
Section 15.26 (Study Drug 
Collection and Treatment 
Compliance Evaluation) 
Revised sentence to state:  Study drug use will be 
recorded for treatment compliance evaluation daily 
from Baseline (Treatment Day 1) through EoT (see 
Section 13.5 for further details).   
Section 15.27 (Study Diary 
Dispensing, Collection and 
Review) 
Removed “every 14 days” and replaced with “at clinic 
visits” for when study diaries will be reviewed. 
Synopsis (Safety Evaluations) 
Section 15.29 (Adverse Event 
Monitoring) 
Section 17.9 (Adverse Event 
Collection Timeframe 
Added clarification for when AEs should be collected 
and evaluated in the first sentence which now reads: 
“AEs will be collected and evaluated from Baseline 
(Treatment Day 1), after the first dose of study drug  
SCY-078, and SOC voriconazole and through the end 
of the study.” 
Section 15.9 (Pregnancy Test) 
Added “once a month, while on study treatment” 
regarding when pregnancy test should be performed. 

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
Section 16 (Study Schedule) 
• Added “+” to “1” for Days (allowable days) under 
Treatment Day 14.   
• Added “X” at the 6-Week follow-up visit to indicate 
Safety Laboratory Assessments to be done at that 
visit. 
• Added footnote “f” to indicate that pregnancy test 
should be done locally, once a month, while on 
study treatment.  
Added clarification to footnote “n” to include 
monitoring serum electrolytes, amylase, lipase. 
• Added the treatment Day to correspond to the 
weekly monitoring in the first month of treatment 
and also added Day 21.  
• Removed “X” at “Screening”, “Treatment Day 5”, 
“Treatment Day 14” for Study Drug Dispensing row 
since studyh will be now dispensed at Baseline ( 
(Treatment Day 1) and Every 14 days during 
treatment. 
Section 17.3 (Events of Clinical 
Interest) 
Clarified by adding that ECIs must be recorded as such 
on the AE eCRF when the PI becomes aware of the 
ECI. 
Section 19.0 (Analytical Plan) 
Added “When feasible, based on adequate sample size 
sub-group analyses including by gender and by 
underlying condition will be conducted.” 
Section 19.1  
(Sample Size Determination) 
Added text providing rationale for why no formal 
sample size is provided for the study. 
Section 20.3 (Informed Consent) 
Added instructions for subjects who had legally 
authorized representative (LAR) provide consent on 
their behalf due to incapacity. 
Section 20.4 (Future Use of 
Samples) 
Clarified and added “mold isolates including” 
Aspergillus spp. 
Section 20.6 (Study Termination) 
Added additional reasons for why the study could be 
terminated. 

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Revisions to Protocol dated 12 Nov 2018 (Protocol Version 4.0) 
Current Version and Date: Protocol Amendment 4 (Protocol Version 5.0) dated 
01 August 2019 
Protocol Sections 
Change and Rationale 
Section 22.1.1 (Prohibited 
Medications) 
• Add clarification that the voriconazole label should 
be consulted for additional warning and precautions 
related to concomitant medications. 
• Removed “long-lasting barbituates” from the 
“Strong CYP3A4/5 inhibitors and CYP3A4/5 
inducers table”. 
• Addition of vinblastine and talinolol to the “P-gp 
Drug Substrates” table. 
Miscellaneous (throughout 
protocol) 
Corrected minor typographical and grammatical errors. 
Revisions to Protocol dated 31 Oct 2018 (Protocol Version 3.0) 
Current Version and Date: Protocol Amendment 3 (Protocol Version 4.0) dated 
12 Nov 2018 
Protocol Sections 
Change and Rationale 
Synopsis 
Section 8.1 (Background 
Information) 
Section 8.2 (Rationale 
for the Study) 
Section 11.1.2 (Study 
Assessments) 
Section 13.1.1 
(Description of Study 
Groups), including 
Table 3 
Section 15.19 
(Voriconazole Level 
Determination) 
Section 15.20 (SCY-078 
PK Sample Collection) 
• Revised the number of subjects who will receive  a reduced 
SCY-078 dosing regimen consisting of a loading dose of 
500 mg BID on Days 1 and 2 followed by a maintenance 
dose of 500 mg QD from Day 3 onwards, from an overall of 
10 subjects (5 from each treatment group) to an overall of 20 
subjects (a minimum of 10 subjects randomized to the 
combination therapy group).  
 

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Revisions to Protocol dated 31 Oct 2018 (Protocol Version 3.0) 
Current Version and Date: Protocol Amendment 3 (Protocol Version 4.0) dated 
12 Nov 2018 
Protocol Sections 
Change and Rationale 
Section 16.0 (Study 
Schedule, Footnotes “p” 
and “r”) 
Section 19.8 
(Pharmacokinetics) 
Revision History 
• Corrected error in GMI value for mycological criteria in 
Section 22.3 (Appendix C: Definitions of Invasive Fungal 
Disease) 
Miscellaneous  
 
• Corrected minor typographical errors. 
Revisions to Protocol dated 04 Oct 2018 (Protocol Version 2.0) 
Current Version and Date: Protocol Amendment 2 (Protocol Version 3.0) dated 
31 Oct 2018 
Protocol Sections 
Change and Rationale 
Section 8.1 
(Background 
Information) 
Section 8.2 (Rationale 
for the Study) 
• Clarified that the efficacy SCY-078 target exposure for 
invasive candidiasis models is 11.2 μg•mL•hr and for invasive 
aspergillosis models is 15.6 μg•mL/hr. 
Section 8.1 
(Background 
Information) 
• Removed isavuconazole from the drug-drug interaction 
discussion to avoid confusion regarding azole used in this 
study.  

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Revisions to Protocol dated 04 Oct 2018 (Protocol Version 2.0) 
Current Version and Date: Protocol Amendment 2 (Protocol Version 3.0) dated 
31 Oct 2018 
Protocol Sections 
Change and Rationale 
Synopsis 
Section 12.1 (Inclusion 
Criteria) 
Section 15.15 
(Galactomannan Index 
Assessment) 
Section 16 (Study 
Schedule), including 
Table 4 
• Clarified that all subjects with IPA (possible, probable or 
proven) with a positive GMI test at Screening may be enrolled 
into the study. 
Synopsis 
Section 8.1 
(Background 
Information) 
Section 8.2 (Rationale 
for the Study) 
Section 13.1.1 
(Description of Study 
Groups), including 
Table 3 
• Added that, as a precautionary measure, the first 10 subjects 
(first 5 subjects in each treatment group) will receive a 
reduced SCY-078 dosing regimen consisting of a loading dose 
of 500 mg BID on Days 1 and 2 followed by a maintenance 
dose of 500 mg QD from Day 3 onwards, which represents a 
30% reduction relative to the prior 750 mg dose. 
• Added that an interim PK analysis will be conducted once the 
above first 10 subjects have been treated for at least 7 days 
and that, based on the results from this interim analysis, the 
SCY-078 dose may be increased for subsequent subjects up to 
a loading dose of 750 mg BID on Days 1 and 2 followed by a 
maintenance dose of 750 mg QD from Day 3 onwards  
Synopsis 
Section 13.1.1 
(Description of Study 
Groups) 
• Updated the number of SCY-078-matching placebo tablets to 
be taken before and potentially after the interim PK analysis. 
Synopsis 
Section 11.1.1.1 
(Screening Period) 
Section 11.1.1.2 
(Baseline) 
• Removed statement indicating that subjects with a possible 
IPA plus one positive GMI test result would be considered 
upgraded to probable IPA. 
Synopsis 
Section 11.1.2 (Study 
Assessments)  
Section 15.19 
(Voriconazole Level 
Determination) 
• Added blood PK sampling time points for voriconazole and 
SCY-078 for the first 10 randomized subjects and updated 
sampling time points for subsequent subjects. 
 

SCYNEXIS, Inc. 
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PROTOCOL SCY-078-206 
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CONFIDENTIAL 
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Revisions to Protocol dated 04 Oct 2018 (Protocol Version 2.0) 
Current Version and Date: Protocol Amendment 2 (Protocol Version 3.0) dated 
31 Oct 2018 
Protocol Sections 
Change and Rationale 
Section 15.20 (SCY-
078 Pharmacokinetic 
Sample Collection) 
Section 16 (Study 
Schedule), including 
Table 4 
Section 19.8.1 
(Pharmacokinetic 
Assessments) 
Synopsis 
Section 19.8.2 
(Pharmacokinetic 
Analyses) 
• Updated description of PK analyses to reflect current 
sampling time points. 
Synopsis 
Section 13.1.1 
(Description of Study 
Groups) 
• Clarified that the voriconazole dose may be adjusted for 
individual subjects based on therapeutic drug monitoring 
results but that subjects will continue to receive the 500 mg 
dose of  SCY-078 until results of the interim PK analyses are 
available. 
Section 15.10 
(Karnofsky 
Performance Status 
Scale) 
Section 16 (Study 
Schedule), including 
Table 4 and Table 5 
• Added the assessment of Karnofsky scores to the list of study 
procedures  
Section 15.17 (Safety 
Laboratory Tests) 
Section 16.0 (Study 
Schedule) 
• Added that for subjects who are still receiving study drug by 
Day 42 (i.e., EoT has not occurred), an additional safety lab 
assessment should be conducted on Day 42 or Day 56. 
Section 22.3 (Appendix 
C: Definitions of 
Invasive Fungal 
Disease) 
• Revised GMI mycological criteria to include at least one GMI 
value ≥1 OR two consecutive samples with values of ≥0.5. 
Miscellaneous  
 
• Corrected minor typographical errors. 

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PROTOCOL SCY-078-206 
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XX SEP 2020 
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Revisions to Protocol dated 20 Aug 2018 (Protocol Version 1.0) 
Current Version and Date: Protocol Amendment 1 (Protocol Version 2.0) dated 
04 Oct 2018 
Protocol Sections 
Change and Rationale 
Synopsis 
• Clarified that recurrence will be determined by the 
Data Review Committee (DRC). 
• Added a new time point (EoT) for the assessment of 
the percentage of subjects with clinical, mycological 
and radiological response as determined by the DRC 
and by the Principal Investigator. 
• Added the flexibility for each study site pharmacy to 
supply their own voriconazole (intravenous and 
oral). 
• Added the description of study treatment groups. 
• Added the performance of a visual function 
assessment as part of the general physical 
examination at Screening/Baseline and on Treatment 
Day 28 (if treatment continues beyond Treatment 
Day 28). 
• Added the need for liver function tests and bilirubin 
monitoring as per voriconazole label 
recommendations.   
• Added time points for the collection of blood 
samples at 4-8 hours after dosing for the 
determination of voriconazole and SCY-078 levels. 
Section 9.3 (Exploratory 
Objectives) 
Revised wording to clarify that recurrence will be 
determined by the DRC. 
Section 10.2 (Exploratory 
Endpoints) 
Section 11.1.2 (Study 
Assessments; Efficacy 
Assessments) 
15.20 (Assessment of Treatment 
Outcome) 
Section 16.0 (Study Schedule)  
Added a new time point (EoT) for the assessment of the 
percentage of subjects with clinical, mycological and 
radiological response as determined by the DRC and by 
the Principal Investigator. 
Section 11.1.2 (Study 
Assessments) 
Added the performance of a visual function assessment 
as part of the general physical examination at 

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PROTOCOL SCY-078-206 
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XX SEP 2020 
CONFIDENTIAL 
Page 122 
 
Revisions to Protocol dated 20 Aug 2018 (Protocol Version 1.0) 
Current Version and Date: Protocol Amendment 1 (Protocol Version 2.0) dated 
04 Oct 2018 
Protocol Sections 
Change and Rationale 
Section 15.6 (General Physical 
Examination, Including Visual 
Function Assessment) 
Section 16.0 (Study Schedule)  
Section 19.6.1 (Safety 
Assessments) 
Screening/Baseline and on Treatment Day 28 (if 
treatment continues beyond Treatment Day 28) 
Section 11.1.2 (Study 
Assessments) 
Section 15.18 (Voriconazole 
Level Determination) 
Section 15.19 (PK Collection) 
Section 16.0 (Study Schedule) 
Section 19.8.1 (Pharmacokinetic 
Assessments) 
Added time points for the collection of blood samples at 
4-8 hours after dosing for the determination of 
voriconazole and SCY-078 levels. 
Section 13.3 (Study Drugs) 
 
Added the flexibility for each study site pharmacy to 
supply their own voriconazole (intravenous and oral). 
Section 15.16 (Safety Laboratory 
Tests)  
Section 16.0 (Study Schedule)  
Added the need for liver function tests and bilirubin 
monitoring as per voriconazole label recommendations.   
Section 15.21 (Recurrence) and 
Section 19.7.1.4 (Recurrence) 
Revised the definition of recurrence and clarified that the 
DRC will be making the final determination of 
recurrence.  
Section 15.24 (Study Drug 
Dispensing) 
Revised the timepoints when study drug will be 
dispensed by removeing at “Screening”, and “Day 5 and 
14” and provided clarification by adding “approximately 
every” to 14 days thereafter until EoT. 
Section 15.28 (Adverse Event 
Monitoring) 
Added wording to reflect information from voriconazole 
label and to stress the need for the Principal Investigators 
to be aware of visual disturbances and potential adverse 
events of voriconazole.  
Miscellaneous  
 
Corrected minor typographical errors and provided 
additional clarifications. Introduced minor changes to 
Section 15.14 (Galactomannan Index Assessment), 
Section 15.3 (Subject Enrollment and Assignment of 
Subject Number), Section 15.10 (Targeted Physical 

SCYNEXIS, Inc. 
IND #107,521 
PROTOCOL SCY-078-206 
Version 5.0 
 
XX SEP 2020 
CONFIDENTIAL 
Page 123 
 
 
Revisions to Protocol dated 20 Aug 2018 (Protocol Version 1.0) 
Current Version and Date: Protocol Amendment 1 (Protocol Version 2.0) dated 
04 Oct 2018 
Protocol Sections 
Change and Rationale 
Examination, Including Clinical Evaluation of Signs 
and Symptoms of Infection), Section 15.26 (Subject 
Diary Dispensing, Collection and Review), and 
Appendix C (Definitions of Invasive Fungal Disease 
[IFD]).