Clinical trial NCT03583164
Conditions: Invasive Fungal Infections
Keywords: Anti fungal Invasive aspergillosis Rare moulds Coccidioidomycosis
Sponsor: F2G Biotech GmbH
Start date: 2018-06-06; Completion date: 2023-02-10
Enrollment: 203 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A study to evaluate olorofim (F901318) for the treatment of invasive fungal infections in participants lacking suitable alternative treatment options.

Detailed description:
An open label, single arm Phase IIb study of olorofim (F901318) in participants with invasive fungal infections with limited treatment options. Participants received study treatment for up to 12 weeks in the main phase of the study. At the Investigator's request and after discussion with the medical monitor, open-label treatment with F901318 could be continued in patients judged by the Investigator to need therapy beyond 84 days and considered likely to continue to benefit from extended treatment.

Arms: arm 1: Olorofim (F901318) was given orally for up to 90 days in the Main Study Phase and could be continued for those participants entering the Extended Treatment Phase.

Patients received fixed doses comprising of a 1-day loading dose of 150 mg of olorofim twice a day followed by a maintenance dose of 90 mg of olorofim twice a day.

Up until Protocol Amendment 06, 58 patients received a weight-based olorofim dosing consisting of a 1-day loading dose of 4 mg/kg/day on Day 1, then a maintenance dose of 2.5 mg/kg/day (divided into 2 or 3 doses). The dose was then adjusted based on plasma levels of olorofim with the maximum total daily dose of 300 mg.
Interventions: intervention 1: Olorofim
Intervention descriptions: intervention 1: 30mg oral tablets

Protocol documents:
Prot_000.pdf: 
Clinical trial protocol 
 
Clinical trial protocol number: F901318/0032 
 
Protocol Title: An open-label single-arm Phase IIb study of F901318 as treatment of 
invasive fungal infections due to Lomentospora prolificans, Scedosporium spp., 
Aspergillus spp., and other resistant fungi in patients lacking suitable alternative 
treatment options 
 
NCT number: NCT03583164 
 
Document date: 28 February 2020 


Sponsor Name: F2G 
 
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Drug Name: F901318 
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Clinical Study Protocol 
Protocol Title:  
An open-label single-arm Phase IIb study of F901318 as 
treatment of invasive fungal infections due to 
Lomentospora prolificans, Scedosporium spp., Aspergillus 
spp., and other resistant fungi in patients lacking suitable 
alternative treatment options. 
Working title: 
FORMULA-OLS: F901318, the first orotomide for 
invasive fungal diseases - an open-label single-arm study. 
Protocol Number: 
F901318/0032 
Date of Original Protocol: 
 
19 December 2017 
Date of Protocol Amendment 01 
24 January 2018 
Date of Protocol Amendment 01-01  
07 March 2018 
Date of Protocol Amendment 02 
02 May 2018 
Date of Protocol Amendment 03 
28 November 2018 
Date of Protocol Amendment 04 
03 May 2019 
Date of Protocol Amendment 05 
30 October 2019 (not implemented) 
Date of Protocol Amendment 06 
28 February 2020 (updated from Amendment 04) 
Product: 
F901318 
Product INN: 
Olorofim 
IND No.: 
 
EudraCT No.: 
2017-001290-17  
Study Phase: 
IIb 
Sponsor: 
F2G Biotech GmbH (FN 483749 x) 
Seilerstätte 17/13 
1010 Vienna 
Austria 
 
 




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Sponsor Signature 
PROTOCOL TITLE: 
An open-label single-arm Phase IIb study of F901318 as 
treatment of invasive fungal infections due to Lomentospora 
prolificans, Scedosporium spp., Aspergillus spp., and other 
resistant fungi in patients lacking suitable alternative treatment 
options. 
 
PROTOCOL NO: 
 
F901318/0032 
PROTOCOL VERSION: 
Amendment 06 
 
 
 
 


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Protocol Amendment Summary of Changes 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 06a 
28 February 2020 
Yes 
Global  
Amendment 05b 
(not implemented) 
30 October 2019 
Yes 
Global  
Amendment 04 
03 May 2019 
Yes 
Global 
Amendment 03 
28 November 2018 
Yes 
Global 
Amendment 02 
02 May 2018 
Yes 
Global 
Amendment 01-01 
07 March 2018 
Yes 
Local (Belgium) 
Amendment 01 
24 January 2018 
Yes 
Global 
Original Protocol 
19 December 2017 
- 
- 
a: Changes introduced to Amendment 05 which are relevant to Amendment 06 are included in the Summary of Changes for 
Amendment 06. 
b: Amendment 05 was signed by the Sponsor and by the Principal Investigator but was not implemented. Amendment 05 was 
not submitted to any Regulatory Authorities or Ethics Commitees, nor was it circulated to any study centres. 
Amendment 06 
28 February 2020 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for Amendment 06 
The number of patients and number of centres have been increased; the intent is to continue 
Study 32 in parallel with a Phase III study, such that patients who have no suitable treatment 
options for their invasive fungal disease and are ineligible for the Phase III study will be able 
to enrol into Study 32 and receive treatment with F901318.  
An initial analysis was been added after 100 patient; F901318 has been granted Breakthrough 
Therapy Designation based on preliminary clinical evidence that demonstrates F901318 may 
provide substantial improvement over available therapy. As this designation is intended to 
expedite the development and review of important products, an initial analysis of data will be 
performed when the first 100 patients have completed treatment, to enable the Sponsor to 
formally consider the possibility that initial approval might be achievable based on the data for 
the population of patients with limited or no treatment options for life-threatening fungal 
infections.  
Body-weight adjustment of the F901318 dose has been removed; Population pharmacokinetic 
(PK) modelling has predicted that use of body weight-adjusted dosing increases the between-
patient variability in systemic exposure (as the effect of body weight on F901318 PK is 
relatively small, dose adjustment by body weight tends to overcompensate). As a 


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consequence, all patients will start treatment on F901318 with a fixed dosing regimen, unless 
the use of concomitant medications requires dose adjustment.  
Therapeutic drug monitoring (TDM) is being removed 
 
 
 
 
 
 
 
The inclusion of 16 year old and 17 year old patients who weigh at least 40 kg has been 
introduced following requests from study investigators to allow enrolment of patients who are 
less than 18 years old. 
 
 
  
 
 
  
 
 
 
 
 
 
Description of Changes in Amendment 06 












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Probable invasive aspergillosis (IA) will be enrolled in the study and receive treatment with F901318. For 
patients who have non-LTRD IA (Tracheobronchitis, Sinonasal infection, Central Nervous System 
infection), only patients with Proven non-LRTD IA can be enrolled. 
Patients will be treated until they reach a defined treatment endpoint, up to a maximum of 90 days. Patients 
should receive treatment for at least 14 days. Patients who are considered by the Investigator to have 
experienced a successful overall outcome will continue treatment for at least 7 days after resolution of all 
clinical symptoms and physical signs. Patients judged to have a successful overall outcome on Days 78 to 
83 of treatment (and hence requiring 85 to 90 days of total treatment) are eligible to receive up to 90 days of 
treatment in the main study phase (90 days is the maximum duration of the nonclinical safety toxicology 
studies). In addition, at the Investigator’s request and after discussion with the Medical Monitor (MM), 
open-label treatment with F901318 may be continued beyond Days 84 to 90 in patients who are judged by 
the Investigator to need therapy beyond 84 days and who are considered likely to continue to benefit from 
extended treatment (ET). The Investigator’s request to extend treatment with F901318 must be approved by 
the MM. For patients who are to receive ET with F901318, the End of Treatment (EOT) and End of Study 
(EOS) for the main study phase are taken as the day on which therapy is completed under the main study 
phase (Days 1 to 84-90) of this protocol. 
The recommended regimen for adults who are not being treated with medications that either inhibit or 
induce CYP enzymes will be a 1 day oral loading dose regimen of 150 mg F901318 twice daily (bid), dosed 
12±1 hours apart, followed by an oral maintenance dose regimen of 90 mg bid, dosed 12±1 hours apart, for 
Day 2 onwards. Based upon emerging data from both this study and from studies in healthy volunteers, the 
recommended maintenance dose regimen for oral dosing may be revised to total daily dosages of up to 
300 mg divided into two doses. Current guidance will be given by the MM at study initiation and may be 
updated during study execution.  
Efficacy and safety endpoints will be formally assessed at Day 7, Day 14, Day 28, Day 42, Day 84/EOT 
main study phase and 4 weeks after EOT in the main study phase (4-week follow-up [FU]). Patients are to 
attend these core study visits, even if treatment has been discontinued before these visits due to a successful 
outcome. For patients who will receive ET beyond Day 84-90, the Day 84 visit, the EOS visit, and the main 
study phase EOT visit will be combined into a single Day 84/EOS/EOT visit during the window Day 84-90. 
An ET-EOT visit will occur on the day that ET dosing stops and will be followed by an ET-EOS follow-up 
visit that will occur 4 weeks after dosing stops under the ET phase of this protocol. 
The efficacy and safety of treatment with F901318 will be assessed 
 after the Day 84/Day 90 
visit in patients who receive ET, and 4 weeks after the end of ET.  
Quality of life will be assessed 
 
Patients will either have Proven IFD known or predicted to be susceptible to F901318, or will have 
Probable LRTD IA. Proven IFD or Probable LRTD IA will be based on 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) criteria.  
Patients will initially be assigned by the Investigator to one of the following categories, based on the nature 
of the IFD:  
1. Lomentospora (Scedosporium) prolificans (LoPro), 
2. Scedosporium spp., 
3. Aspergillus spp., 
4. Other F901318-susceptible fungi (as described in the Investigator’s brochure [IB]) 
5. Probable LRTD IA. 
Patients with Probable LRTD IA must meet the EORTC/MSG requirements for high risk host factor, 
clinical features and mycological criteria. Patients with Probable LRTD IA may be re-assigned to the 
Proven category if the infection is subsequently proven.  
Patients will also have limited treatment options based on meeting one or more of the following criteria: 
a) Known or predicted resistance of the infecting isolate to all licensed agents. LoPro automatically 
meets this criterion. 
b) Failure of available therapy. Failure to improve based on clinical or radiologic grounds despite 
receiving ≥7 days of standard antifungal treatment AND alternative licensed agents are either predicted 
to be ineffective or are contraindicated. 
c) Intolerance to available therapy. Current therapy cannot be continued due to therapy-related adverse 
events (AEs) (e.g., increase in serum creatinine above upper limit of normal [ULN] with an 






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5) Male patients with female partners of childbearing potential must either totally 
abstain from sexual intercourse or use a highly effective means of 
contraception throughout study participation and agree to continue its use for 
30 days after stopping study drug. 
6) Patients with confirmed Proven IFD (based on EORTC/MSG criteria) in the 
following categories*:  
a)  Lomentospora (Scedosporium) prolificans (LoPro), 
b)  Scedosporium spp., 
c)  Aspergillus spp.,  
d)  Other F901318-susceptible fungi (as described in the IB or based on 
information provided by the MM, and in either case requiring approval of 
the MM).  
OR with 
e)  Probable LRTD IA who meet the EORTC/MSG requirement for high risk 
host factor, clinical features and mycological criteria. 
*Enrolment is based on presumed F901318 susceptibility for categories a-c 
and selected other species as described in the IB. For IFD due to isolates from 
species of uncertain susceptibility, enrolment may occur with the approval of 
the MM before isolate susceptibility is confirmed. If an isolate is not available 
for shipping to the appropriate central lab for susceptibility testing, 
susceptibility will be predicted from species identification determined locally. 
If the isolate is subsequently found to be resistant, study therapy may be 
continued or discontinued based on clinical response at the discretion of the 
Investigator. Patients with infections due to multiple fungi can be enrolled 
provided at least one fungus is known or predicted to be F901318-susceptible 
AND the patient has limited alternative treatment options for that fungus as 
defined in Inclusion Criterion 7. As a specific example, a patient with 
simultaneous IA due to an azole-resistant strain and also invasive 
mucormycosis could be enrolled and treated with the combination of F901318 
and isavuconazole. The choice of additional agents to treat other fungi should 
also consider the limitations applied to allowed medications. Cases of 
polyfungal infection should be discussed with the MM. 
7) Patients will ALSO have limited alternative treatment options based on meeting 
one or more of the following criteria: 
a) Known or predicted resistance of the infecting isolate to all licensed 
agents. LoPro automatically meets this criterion. 
b) Failure of available therapy. Failure to improve based on clinical or 
radiologic grounds despite receiving at least 7 days of standard antifungal 
treatment AND alternative licensed agents are either predicted to be 
ineffective or are contraindicated, 
c) Intolerance to available therapy. Current therapy cannot be continued 
due to therapy-related adverse reactions (e.g., increase in serum creatinine 
above ULN with an amphotericin, persistent visual disturbances with 
voriconazole, allergic reaction with any compound, or other recognized 
drug-related AE) AND alternative licensed agents are either predicted to 
be ineffective or are contraindicated,  
d) Inability to manage DDIs. Inability to continue current therapy due to 
DDIs that cannot be managed AND alternative licensed agents are either 
predicted to be ineffective or are contraindicated, 
e) Inability to produce therapeutic drug levels. Inability to produce or 
maintain therapeutic blood levels with current therapy AND alternative 
licensed agents are either predicted to be ineffective or are contraindicated 
f) 
An IV-only option (e.g., an amphotericin) has produced a clinical 
response AND it is standard practice to switch to an oral azole for 
completion of therapy AND one of the following is true: 


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i) 
Azole-resistance is known based on susceptibility testing of the 
infecting isolate, 
ii) Azole-resistance is predicted by PCR or similar molecular diagnostic 
tool, 
iii) Azole-resistance is suspected based on epidemiological or clinical 
grounds (e.g., development of aspergillosis while on mould-active 
azole prophylaxis; history of lack of response to a mould-active azole 
at an early point in the therapeutic course), 
iv) An azole would be acceptable therapy but it is known or predicted 
that unmanageable DDIs will occur 
g) Other MM agreed inclusion. Patient does not meet any of criteria a) to 
f), but treatment with F901318 is judged appropriate by the Investigator. 
Inclusion of patients based on this category must be agreed with the MM 
and the rationale must be documented.  
Exclusion Criteria: 
1) Women who are pregnant or breastfeeding. 
2) Known history of allergy, hypersensitivity, or any serious reaction to any 
component of the study drug. 
3) Patients with chronic aspergillosis, aspergilloma or allergic bronchopulmonary 
aspergillosis.  
4) Suspected zygomycosis (mucormycosis) as the IFD used to qualify for the 
study. Evidence for the presence of F901318 non-susceptible filamentous 
fungi such as Mucorales should be urgently followed up. Increased vigilance 
for the possibility of zygomycosis is required for suspected IA with negative 
baseline GM. 
5) Microbiological findings (e.g., bacterial, virological) or other potential 
conditions that are temporally related and suggest a different aetiology for the 
clinical features. 
6) HIV infection but not currently receiving antiretroviral therapy. In cases where 
HIV infection is first diagnosed at the same time as the invasive fungal 
infection, if antiretroviral therapy is commenced at the time of enrolment, then 
such patients are eligible for enrolment. 
7) Any known or suspected condition of the patient that may jeopardize 
adherence to the protocol requirements or impede the accurate measurement of 
efficacy (e.g. neutropenia not expected to resolve, patients with uncontrolled 
malignancy who are treatment refractory and receiving only palliative 
therapy). 
8) Patients with a concomitant medical condition that, in the opinion of the 
Investigator, may be an unacceptable additional risk to the patient should he / 
she participate in the study. 
9) Patients previously enrolled in a study with F901318.  
10) Treatment with any investigational drug in any clinical trial within the 30 days 
prior to the first administration of study drug except for unblinded protocols 
(e.g. open-label oncological regimen variations or biologic studies). Prior to 
enrolling patients that are on other open-label studies it is the site’s 
responsibility to ensure that the study criteria for that study allow for 
enrolment into this study. 
11) Patients receiving treatment limited to supportive care due to predicted short 
survival time. 
12) Patients with a baseline prolongation of QTcF ≥500 msec, or at high risk for 
QT/QTc prolongation, e.g. 
a) a family history of long QT syndrome  
b) other known pro-arrhythmic conditions 
c) risk factors for Torsade de Pointes (e.g. uncompensated heart failure, 
abnormal plasma potassium or magnesium levels that cannot be corrected, 
an unstable cardiac condition during the last 30 days) 


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13) Evidence of hepatic dysfunction with any of the following abnormal 
laboratory parameters at Screening: 
a) Total bilirubin ≥2 x ULN  
b) Alanine transaminase or aspartate transaminase ≥3 x ULN. 
c) Patients with known cirrhosis or chronic hepatic failure. 
14) Prohibited concomitant medications. Concomitant administration of inhibitors 
of human DHODH (teriflunomide and leflunomide) is prohibited. There are 
currently no other absolutely prohibited concomitant medications but there are 
medications with potentially significant DDIs and the management of potential 
interactions should be considered before study enrolment. 
15) Additional exclusion criteria required by local regulatory authorities. 
Duration of 
Treatment: 
Duration of treatment in the main study phase of this study is limited to 90 days 
and will be at the discretion of the Investigator based on the site and severity of the 
IFD, the patient’s underlying disease, and the rate of clinical response. All patients 
should receive treatment for at least 14 days.  
Treatment with F901318 beyond 90 days in an ET phase of the study may be 
approved by the MM if requested by the Investigator for those patients who are 
considered likely to continue to benefit from extended treatment. 
Test Product, Dose 
and Mode of 
Administration: 
F901318 will be provided as an oral formulation. 
This is a Phase IIb protocol and the dosing regimen for F901318 may be updated 
during the study. The dosing regimen for adults who are not being treated with 
medications that either inhibit or induce CYP enzymes will be a 1-day oral loading 
dose regimen of 150 mg F901318 bid, dosed 12±1 hours apart, followed by a 
maintenance dose regimen of 90 mg bid, dosed 12±1 hours apart, for Day 2 
onwards. As this is the first study in which F901318 has been administered to 
patients, the target dosing regimen may need to be revised based upon emerging 
data, to ensure that the majority of patients achieve target plasma levels from the 
start of treatment. The revision to target doses will be captured in the Dose 
Guidance Manual. The dosage regimen will be determined from the Dose 
Guidance Manual (and following discussion with the MM if necessary). 
• 
An adjustment to loading and/or maintenance doses of F901318 may be 
required for patients who are being treated with drugs that either inhibit or 
induce CYP enzymes (or if such drugs are started or stopped); treatment of 
these patients must be discussed with the MM. 
• 
An adjustment to the maintenance dose of F901318 may be required if patients 
develop abnormal liver enzymes; treatment of these patients must be discussed 
with the MM.  
• 
Based upon clinical evaluation of efficacy by the Investigator, stepwise 
increases of maintenance doses of F901318 (to 120 mg bid then 150 mg bid) 
may be permitted, following discussion with the MM. 
No dietary restrictions around time of dosing will be applied, although timing of 
meals or enteral feedings prior to each trough PK sample, and prior to and during 
Intensive PK sampling will be documented.  
Reference Therapy, 
Dose, and Mode of 
Administration: 
This is an open-label study and results will be compared with historical data. 
Concomitant 
medication: 
Concomitant administration of teriflunomide and leflunomide is prohibited. There 
are no other absolutely prohibited or contraindicated medications. However, there 
are potential DDIs with F901318 and the choice of concomitant medications 
should take this into consideration. The impact of F901318 upon cytochrome P450 
(CYP) 3A4 has been shown to be mild; transplant drugs and other medications 
which are sensitive CYP3A4 substrates and with potential DDI liability will, where 
possible, be monitored, and changes in drug treatment will be recorded. Use of 
concomitant medications that may affect the PK profile of F901318 must be 


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discussed and approved by the MM. An extra visit for Unscheduled Trough PK 
sampling (for rapid PK analysis of F901318) will occur 3 to 5 days after starting or 
stopping such concomitant medication, to support evaluation of potential DDIs.  
Concomitant treatment with cytostatic anti-cancer agents (initiation or continuation 
of treatment) is acceptable, provided assessment of study endpoints is expected to 
be feasible based on the Investigators clinical judgement, potential impact on 
adherence to study procedures and endpoints, and the lack of treatment 
alternatives. Concomitant treatment with cytostatic anti-cancer agents must be 
discussed with and approved by the MM. 
Data to date suggest that F901318 does not prolong the QTc interval, and 
concomitant agents with known potential to prolong the QTc interval may be used 
with caution. Ongoing therapy with an agent known to have a risk of QT 
prolongation is not a contraindication for enrolment provided the patient meets the 
requirements of Exclusion Criterion 12. After enrolment, initiation of new 
concomitant treatment with known QTc-prolonging agents must be discussed with 
and approved by the MM. 
Concomitant 
Antifungal 
Therapy: 
In order to meaningfully analyse the efficacy of F901318, it is important to avoid 
concomitant use of other systemic antifungal agents with known or potential 
activity against the primary fungal infection. The constraints on the choice of 
additional agents may be complex and thus use of any other systemic concomitant 
antifungal or combination treatment (such as addition of terbinafine for confirmed 
Lomentospora prolificans infections or an echinocandin to manage infection due to 
Candida) is permitted but is discouraged. 
Antifungal combinations should be based on the Investigator’s clinical judgement 
and must be discussed with the MM. 
Depending on the treatment given, an extra visit for Unscheduled Trough PK 
sampling (for rapid PK analysis of F901318) may be required 3 to 5 days after 
starting or stopping such concomitant medication, to support evaluation of 
potential DDIs.  
Criteria for Evaluation: 
Efficacy Endpoints: 
Primary Endpoint: 
• 
DRC-adjudicated overall response rate by pathogen at Day 42. 
Secondary Endpoints (all by pathogen and also in aggregate) 
• 
DRC-adjudicated overall response at Day 7, Day 14, Day 28, main study phase EOT, Day 84 and 
4-week FU. 
• 
Clinical response at Day 7, Day 14, Day 28, Day 42, main study phase EOT, Day 84 and 4-week 
FU. 
• 
Where appropriate for the IFD, radiological response at Day 7, Day 14, Day 28, Day 42, main 
study phase EOT, Day 84 and 4-week FU. 
• 
Mycological response by pathogen and by susceptibility category at Day 7, Day 14, Day 28, Day 
42, main study phase EOT, Day 84 and 4-week FU. 
• 
Investigator-assessed overall response (integration of clinical, radiological, and mycological 
response) at Day 7, Day 14, Day 28, Day 42, main study phase EOT, Day 84 and 4-week FU. 
• 
All-cause mortality at Day 42, main study phase EOT, Day 84 and 4-week FU. 
• 
Quality of life (patient-reported outcome) 
, based on the EQ-5D-5L 
questionnaire. 
Note: For patients who will receive ET beyond Day 90, the Day 84 visit and the main study phase EOT 
visit will be combined into a single Day 84/EOS/EOT visit on approximately Day 90. Subsequent visits 
 to assess the safety of continued treatment and to assess the need for further 
treatment, and there will be a FU visit 4 weeks after ET is completed. 
Safety: 




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Data collected in the main study phase up to Day 84/Day 90 and the subsequent 4-week follow-up visit will 
be included in the data analyses and presented in the clinical study report (CSR). Data collected during ET 
will not be included in the data analyses or in the CSR, and will be presented in the report addendum. 
Analyses will be made using the overall study population and within the DRC-adjudicated baseline disease 
categories, and will be descriptive in nature. Data will be presented using appropriate summary statistics. 
Categorical data will be described using absolute and relative frequencies (n and %). Continuous data will 
be presented using descriptive statistics (n, mean, standard deviation, minimum, median, and maximum). 
All variables will be listed in individual patient listings, sorted by DRC-adjudicated baseline disease 
category and patient number. 
Given the various patient sub-groups included in this study data may be summarised in the following 
groupings: 
a) Efficacy for all patients. 
b) Efficacy by baseline DRC-adjudicated infection category (the 5 categories of Inclusion 
Criterion 6). 
c) Efficacy by disease location (CNS, bone, lung/sinus, skin/subcutaneous, other, disseminated). 
d) Efficacy by underlying condition (haematological malignancy, allogeneic haematopoietic stem cell 
transplant, solid organ transplant, diabetes, active malignant disease, neutropenia at diagnosis, 
glucocorticoid use, T-cell immunosuppressant use, renal dysfunction). 
e) Efficacy by baseline infection status (no prior therapy; progression or lack of response to prior 
therapy; partial response to prior therapy but alternative continued therapy is needed; complete 
clinical response to prior therapy but alternative continued therapy is needed). 
f) 
Efficacy by baseline objective measure of infection activity (objective marker of active disease 
status such as radiological finding, physical examination finding). 
. Details on sub-group 
analyses will be provided in the Statistical Analysis Plan. 
Patients with complete clinical response to study drug treatment will also be evaluated for relapse of the 
treated IFD and for newly emergent IFD at selected study visits up to the main study phase EOT visit (Day 
84 to Day 90). 
In the event that a patient is judged to have active disease that merits treatment but where a baseline 
objective marker of active infection does not exist, said patient will be evaluated only for safety. Any 
efficacy data from such patients will be listed only. 
All other patients will be evaluated for response. 
Efficacy Analyses: 
Based on the DRC-adjudicated overall response categorized as Success/Failure a response rate will be 
calculated based on all patients included in the mITT population. In addition, a 95% confidence interval 
(CI) for the single binomial proportion will be calculated. This 95% CI will be compared with an estimated 
historical response rate (and 95% CI) both overall and by DRC-adjudicated disease category. 
Secondary efficacy analyses will be presented in a similar manner as described for the primary efficacy 
analysis. 
All-cause mortality will be estimated using the Kaplan-Meier method summarizing median time to death, 
stratified by DRC-adjudicated disease category. 
Patient-reported outcomes as measured by the EQ-5D-5L questionnaire will be summarised as the number 
of patients with each category of response for each of the 5 quality of life questions. In addition, the overall 
score will be summarised using the number of patients, mean, standard deviation, minimum, median and 
maximum values. 
Safety Analyses: 
Frequency tables will be used to present the safety outcomes including incidences of treatment-emergent 
AEs (TEAE), SAEs (including deaths), TEAEs leading to death, treatment-emergent AESIs, liver-related 
TEAEs, TEAEs leading to premature treatment discontinuation, TEAEs leading to premature study 
withdrawal, TEAEs by relationship and TEAEs by severity. 


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Change from baseline and incidence of pre-defined treatment-emergent abnormalities in vital signs, clinical 
laboratory test results and ECG results will be summarised. Graphical presentations will also be used to 
help describe vital signs, selected laboratory test values and ECG parameters. 
Pharmacokinetics: 
All PK sample collection times and concentrations will be listed and summarised by visit. 
For the Intensive PK set, PK parameters will be listed and summarised.  
PK of F901318 will be characterised by nonlinear mixed-effects modelling. From this analysis, the 
influence of various demographic covariates (e.g., body weight, gender) and other patient-specific factors 
on F901318 trough levels and drug exposure may be assessed. Intensive PK analysis will be performed on 
data generated in this study in accordance with a separate modelling data analysis plan and reported outside 
of the CSR. 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE ....................................................................................................... 3 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................ 28 
2.0 
INTRODUCTION ..................................................................................................... 31 
2.1 
Background Information .............................................................................. 31 
2.1.1 
Unmet need in Invasive Fungal Infections........................................ 31 
2.1.2 
F901318 has potential to address that unmet need............................ 32 
2.1.3 
Clinical pharmacology: Potentially efficacious and well 
tolerated exposures can be achieved after oral and IV 
dosing ................................................................................................ 33 
2.2 
Rationale ......................................................................................................... 36 
2.3 
Hypothesis ...................................................................................................... 36 
2.4 
Risk Assessment ............................................................................................. 37 
3.0 
STUDY OBJECTIVES ............................................................................................. 39 
3.1 
Primary Objective ......................................................................................... 39 
3.2 
Secondary Objectives .................................................................................... 39 
3.3 
Exploratory Objectives ................................................................................. 39 
3.4 
Extended Treatment Exploratory Objective .............................................. 39 
4.0 
INVESTIGATIONAL PLAN ................................................................................... 40 
4.1 
Summary of Study Design ............................................................................ 40 
4.1.1 
Extended Treatment .......................................................................... 48 
4.2 
Discussion of Study Design ........................................................................... 50 
4.3 
Selection of Study Population ....................................................................... 52 
4.3.1 
Inclusion Criteria for Main Study Phase ........................................... 52 
4.3.1.1 
Inclusion Criteria for Extended Treatment 
Phase ............................................................................... 54 
4.3.2 
Exclusion Criteria for Main Study Phase .......................................... 54 
4.3.2.1 
Exclusion Criteria for Extended Treatment 
Phase ............................................................................... 56 
4.3.3 
Patient Restrictions............................................................................ 56 
4.3.4 
Patient Withdrawal ............................................................................ 57 
4.3.5 
Study Termination ............................................................................. 58 
5.0 
STUDY TREATMENTS ........................................................................................... 60 
5.1 
Treatments Administered ............................................................................. 60 
5.2 
Identity of Investigational Products ............................................................. 62 
5.3 
Packaging and Labelling ............................................................................... 63 
5.4 
Method of Assigning Patients to Treatment Group ................................... 63 
5.5 
Selection of Doses in the Study ..................................................................... 63 
5.6 
Selection and Timing of Dose for Each Patient .......................................... 63 


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5.7 
Trough PK Sample Analysis ......................................................................... 63 
5.8 
Blinding .......................................................................................................... 64 
5.9 
Prior and Concomitant Treatments ............................................................. 64 
5.9.1 
Excluded Medications ....................................................................... 65 
5.9.1.1 
Agents with a potential effect on the QT 
interval ............................................................................. 65 
5.9.1.2 
Interaction of F901318 with Concomitant 
Medication ....................................................................... 66 
5.9.1.3 
Co-Dosing with Strong CYP Inducers ............................ 66 
5.9.1.4 
Co-Dosing with CYP Inhibitors ...................................... 67 
5.9.1.5 
Co-Dosing F901318 with Sensitive and 
Moderately Sensitive CYP3A4 Substrates...................... 68 
5.9.2 
Allowed Medications ........................................................................ 69 
5.9.2.1 
Candida Prophylaxis and Concomitant 
Antifungal Therapy ......................................................... 69 
5.10 
Medical Care of Patients after End of Study .............................................. 69 
5.11 
Treatment Compliance ................................................................................. 70 
5.12 
Study drug Accountability ............................................................................ 70 
6.0 
ASSESSMENTS AND PROCEDURES .................................................................. 72 
6.1 
General Considerations ................................................................................. 72 
6.1.1 
Schedule of Assessments .................................................................. 72 
6.1.2 
Informed Consent .............................................................................. 72 
6.2 
Procedures ...................................................................................................... 73 
6.2.1 
Demography ...................................................................................... 73 
6.2.2 
Pregnancy Test .................................................................................. 73 
6.2.3 
Underlying Disease or Condition ...................................................... 73 
6.2.4 
Infectious Disease History and Microbiological 
Assessments ...................................................................................... 73 
6.2.5 
Medical History ................................................................................. 74 
6.2.6 
Prior and Concomitant Medication ................................................... 74 
6.2.7 
Non-medication Procedures .............................................................. 74 
6.2.8 
Hospitalization Status........................................................................ 75 
6.3 
Efficacy Assessments ..................................................................................... 75 
6.3.1 
Investigator’s Assessment of Overall Response ............................... 75 
6.3.1.1 
Clinical Response ............................................................ 76 
6.3.1.2 
Radiological Response .................................................... 78 
6.3.1.3 
Bronchoscopic Assessment ............................................. 79 
6.3.1.4 
Mycological Assessments and Responses ...................... 79 
6.3.1.5 
Investigator’s Assessment of Overall Response ............. 83 
6.3.2 
Survival ............................................................................................. 84 
6.3.3 
Data Review Committee Assessment of Overall Response .............. 85 
6.3.4 
Patient-Reported Outcomes .............................................................. 85 
6.4 
Safety .............................................................................................................. 85 
6.4.1 
Adverse Events .................................................................................. 85 
6.4.1.1 
Reporting of Adverse Events .......................................... 90 


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6.4.1.2 
Reporting of Serious Adverse Events to 
Regulatory Authorities and Investigators........................ 92 
6.4.1.3 
Follow-up of Adverse Events .......................................... 93 
6.4.1.4 
Procedures for Documenting Pregnancy During 
Study ............................................................................... 93 
6.4.2 
Clinical Laboratory Evaluations ....................................................... 94 
6.4.2.1 
Creatinine Clearance ....................................................... 96 
6.4.2.2 
Neutropenic Status .......................................................... 96 
6.4.2.3 
Liver enzymes and bilirubin............................................ 96 
6.4.3 
Vital Signs, Physical Findings and Other Safety 
Assessments ...................................................................................... 97 
6.4.3.1 
Vital Signs ....................................................................... 97 
6.4.3.2 
Physical Examination ...................................................... 97 
6.4.3.3 
Electrocardiogram ........................................................... 98 
6.4.3.4 
 ........................................................ 98 
6.4.4 
Safety Monitoring ............................................................................. 98 
6.4.4.1 
Independent Data and Safety Monitoring Board ............ 98 
6.4.4.2 
Data Review Committee ................................................. 99 
6.4.4.3 
Hepatic Safety Review .................................................... 99 
6.5 
Pharmacokinetics (PK) and Rapid Trough Sample Analysis ................... 99 
6.6 
 ...................................................................................... 101 
6.7 
Appropriateness of Measurements ............................................................ 101 
7.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 102 
7.1.1 
Monitoring....................................................................................... 103 
7.1.2 
Data Management/Coding .............................................................. 103 
7.1.3 
Quality Assurance Audit ................................................................. 105 
8.0 
STATISTICS ............................................................................................................ 106 
8.1 
Determination of Sample Size .................................................................... 106 
8.2 
Statistical Methods ...................................................................................... 107 
8.2.1 
General Considerations ................................................................... 107 
8.2.2 
Primary Efficacy Endpoint .............................................................. 107 
8.2.3 
Secondary Efficacy Endpoints ........................................................ 108 
8.2.4 
Safety Endpoints ............................................................................. 109 
8.2.5 
Pharmacokinetic Analyses .............................................................. 110 
8.2.6 
Data to be Analysed ........................................................................ 110 
8.2.7 
Analysis Sets ................................................................................... 111 
8.2.8 
Missing Data ................................................................................... 111 
8.3 
Patient Disposition ....................................................................................... 111 
8.4 
Patient Characteristics ................................................................................ 112 
8.5 
Disease Characteristics................................................................................ 112 
8.6 
Medical History ........................................................................................... 112 
8.7 
Medications and Procedures ...................................................................... 112 
8.8 
Efficacy Analyses ......................................................................................... 113 
8.8.1 
Primary Efficacy Analysis .............................................................. 113 


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8.8.2 
Secondary Efficacy Analyses .......................................................... 113 
8.8.3 
Patient-Reported Outcomes ............................................................ 114 
8.9 
Safety ............................................................................................................ 115 
8.9.1 
Exposure .......................................................................................... 115 
8.9.2 
Adverse Events ................................................................................ 115 
8.9.3 
Clinical Laboratory Evaluations ..................................................... 116 
8.9.4 
Vital Signs Measurements, ECG, Physical Findings and 
Other Safety Evaluations ................................................................. 117 
8.9.4.1 
Vital Signs ..................................................................... 117 
8.9.4.2 
ECG ............................................................................... 117 
8.9.4.3 
Other Safety Evaluations ............................................... 118 
8.10 
Hospitalisation Status .................................................................................. 118 
8.11 
Pharmacokinetic Analyses .......................................................................... 118 
8.11.1 
Trough Sampling Data Analysis ..................................................... 119 
8.11.2 
Intensive PK Data Analysis ............................................................ 119 
8.12 
 ....................................................................... 119 
8.13 
Interim Analyses .......................................................................................... 119 
9.0 
ETHICS .................................................................................................................... 121 
9.1 
Institutional Review Board or Independent Ethics Committee .............. 121 
9.2 
Ethical Conduct of the Study ...................................................................... 121 
9.3 
Patient Information and Informed Consent ............................................. 122 
9.4 
Patient Data Protection ............................................................................... 122 
10.0 
STUDY ADMINISTRATION ................................................................................ 124 
10.1 
Administrative Structure ............................................................................ 124 
10.2 
Data Handling and Record Keeping .......................................................... 124 
10.3 
Direct Access to Source Data/Documents .................................................. 124 
10.4 
Investigator Information ............................................................................. 125 
10.4.1 
Investigator Obligations .................................................................. 125 
10.4.2 
Protocol Signatures ......................................................................... 125 
10.4.3 
Publication Policy ........................................................................... 125 
10.5 
Financing and Insurance ............................................................................ 125 


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11.0 
REFERENCES ........................................................................................................ 126 
12.0 
APPENDICES .......................................................................................................... 129 
APPENDIX 1: 
SIGNATURE OF INVESTIGATOR .......................................... 130 
APPENDIX 2: 
DEFINITIONS OF INVASIVE FUNGAL DISEASE 
(IFD) AND DIAGNOSTIC CRITERIA IN REFERENCE TO EORTC 
MSG (DE PAUW 2008) ........................................................................................... 131 
APPENDIX 3: 
LIVER BIOCHEMISTRY MANAGEMENT 
ALGORITHM 135 
APPENDIX 4: 
PROTOCOL AMENDMENT HISTORY .................................. 138 
 


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LIST OF TABLES 
Table 1  
Schedule of Events (Assessments and Procedures): Main Study 
Phase ................................................................................................................ 44 
Table 2 
Schedule of Blood Sampling for Intensive PK Analysis  ................................ 48 
Table 3 
Schedule of Events: Extended Treatment (Assessments and 
Procedures) ...................................................................................................... 49 
Table 4 
Investigational Products .................................................................................. 62 
Table 5 
Criteria for Assessment of Overall Response .................................................. 84 
Table 6  
CTCAE Grading for Study AESIs .................................................................. 89 
Table 7 
List of Clinical Laboratory Tests ..................................................................... 95 
 


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LIST OF FIGURES 
Figure 1: Study flow diagram; main study phase .................................................................... 40 
Figure 2: Study flow diagram; extended treatment phase ....................................................... 41 
 


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1.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS  
 
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC0-tau 
Area under the curve over the 12 hour dosing interval 
BMI 
Body mass index 
CI 
Confidence interval 
CL/F 
Clearance (oral administration) 
Cmax 
Maximum plasma concentration 
Cmin 
Minimum plasma concentration (taken within 15 minutes prior to 
next study drug dose) 
CNS 
Central nervous system 
CRO 
Contract research organisation 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
DHODH 
Dihydro-orotate dehydrogenase 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDC 
Electronic data capture 
EORTC MSG 
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 
EOS 
End of study 


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EOT 
End of Treatment 
EQ-5D-5L 
The EuroQol Group health-related quality of life questionnaire 
ET 
Extended treatment 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GM 
Galactomannan 
h 
Hour 
HAC 
Hepatic Advisory Committee 
HIV 
Human immunodeficiency virus 
HRCT 
High resolution computed tomography 
IA 
Invasive aspergillosis 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDSMB 
Independent data and safety monitoring board 
IEC 
Independent Ethics Committee 
IFD 
Invasive fungal disease 
IRB 
Institutional Review Board 
IS 
Invasive scedosporiosis 
ITT 
Intent-to-treat 
IV 
Intravenous 
LoPro 
Lomentospora prolificans 
LRTD 
Lower respiratory tract disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum inhibitory concentration 
mITT 
Modified intent-to-treat 
MM 
Medical monitor 
MRI 
Magnetic resonance imaging 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic(s) 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 


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SOP 
Standard operating procedures 
SUSAR 
Suspected unexpected serious adverse reaction 
TDM 
Therapeutic drug monitoring 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
Vz/F 
Steady state volume of distribution (Oral administration) 
WBC 
White blood cell 


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2.0 INTRODUCTION 
2.1 
Background Information 
2.1.1 
Unmet need in Invasive Fungal Infections  
The presence of fungal elements either as mould or yeast in deep tissues of biopsy or needle 
aspirates that is confirmed on culture and histo-pathological examination can be described as 
an invasive fungal disease (IFD) (Ascioglu 2002). Radiological evidence of lesions with 
culture positive for the presence of fungi also confirms the IFD. Clinical features of IFD are 
variable, and include febrile illness that continues even after prolonged broad-spectrum 
chemoprophylaxis. Invasive fungal infections are a growing clinical concern in many settings 
but are especially common in immunocompromised patients, can involve any part of the body, 
and are associated with high mortality rates (Xie 2008).  
Fungi with the potential to cause invasive infections include yeasts and moulds. Of these, the 
mould fungi from the genera Aspergillus and Scedosporium represent particular threats, 
especially to immunosuppressed individuals.  
Aspergillus spp. are ubiquitous filamentous fungi found in organic matter and in the 
environment. Aspergillus infection may cause a broad spectrum of disease in the human host, 
ranging from hypersensitivity reactions to direct invasion of tissue (Denning, 1998). Invasive 
aspergillosis (IA) is a rapidly progressive, often fatal infection that occurs in patients who are 
severely immunocompromised. The triazole antifungals (especially voriconazole) are often 
effective and have emerged as standard of care for IA. However, reports of genetically distinct 
but hard to identify Aspergillus species (so-called cryptic Aspergillus species) with intrinsic 
resistance mechanisms (Lamoth 2016), as well as clinical cases of Aspergillus fumigatus 
infection with mutational resistance, most likely caused by widespread agricultural use of 
azoles, have raised concern about the limited alternative current treatment options (Garcia-
Rubio 2017). This is especially problematic as the triazole antifungals are the only available 
oral therapies for these fungi. When the triazoles are predicted to be inactive because they 
have already been used as prophylaxis or prior treatment or when resistance to azoles is 
proven, patients are limited to prolonged and toxic therapy with an amphotericin B (polyene) 
preparation (Lamoth 2017). 
Scedosporium spp. are ubiquitously present in the environment. They cause a wide spectrum 
of infections in man ranging from classical subcutaneous infections, like mycetoma with 
spread via the lymphatic system, to disseminated infections with central nervous system 
involvement. Invasive scedosporiosis (IS) is considerably less frequent than IA, but increasing 
numbers of cases are reported (Tortorano 2014). Scedosporium spp. infections are known for 
their special neurotropic nature and their high rate of therapeutic failures and relapses. In 
particular, Scedosporium (Lomentospora) prolificans represents a pan-antifungal-resistant 


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species with mortality rates of up to 90% in immunocompromised patients (Rodriguez-Tudela 
2009, Kelly 2016). 
Other “uncommon” moulds which are typically resistant to the azole antifungals and/or 
polyenes include Rasamsonia species as well as Acremonium, Scopulariopsis, Microascus, 
and Paecilomyces species. 
Despite advances in diagnostics and therapeutics, the mortality rate in immunocompromised 
patients with IFD is approximately 50% (Nivoix 2008). Currently marketed antifungal drugs 
for the treatment of IFD target the fungal cell membrane by inhibiting ergosterol synthesis (the 
triazoles, such as voriconazole), by inhibiting the synthesis of (1,3)-β-D-glucan 
(echinocandins, such as caspofungin) or by binding to ergosterol and disrupting membrane 
integrity (the polyene Amphotericin B [AMB]) (Magill 2008). Each of these 3 classes of 
treatment has limitations including limited dosage forms, drug-drug interactions (DDI) and 
significant adverse reactions. The detection of an increasing incidence of azole-resistant 
Aspergillus spp. (ECDC 2013) is of particular concern since triazoles, including the gold 
standard treatment voriconazole, have been the agents of choice in life-threatening IA and the 
only oral agents available. Resistance to the triazoles approaches 30% in some regions 
(Verweij 2016). Treatment options for IS are even more limited with intrinsic resistance to 
polyenes and no current agent with reliable activity against Lomentospora prolificans, one of 
the causative agents of IS (Rodriguez-Tudela 2009, Kelly 2016). 
There is a critical medical need for an antifungal agent with a novel mechanism of action and 
with high efficacy against a broad spectrum of fungal species. Such an agent would have 
added value if it were effective by both intravenous (IV) and oral routes of administration, was 
well tolerated, and had a limited potential for DDIs. In addition, a predictable and reliable PK 
profile would allow well controlled therapy. 
2.1.2 
F901318 has potential to address that unmet need 
F901318, also known as 2-(1, 5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-fluoro-
pyrimidin-2-yl) piperazin-1-yl]-phenyl}-2-oxo-acetamide, is the first of a new class of 
antifungal agents. F901318 has a novel, well defined mechanism of action, inhibiting a rate 
limiting enzyme of fungal pyrimidine biosynthesis, DHODH. F901318 potently inhibits fungal 
DHODH but is a very poor inhibitor of the human enzyme. This differential activity is 
consistent with the differences in structure between the human and fungal DHODH enzymes. 
As discussed in the Nonclinical Pharmacology section of the IB, F901318 is active against a 
wide range of Aspergillus species including those most commonly associated with human 
infection. Importantly, F901318 is effective against isolates of A. fumigatus resistant to other 
antifungal agents, Scedosporium spp. and Lomentospora prolificans; the latter is frequently 
refractory to all available antifungal agents. F901318 is also active against a range of other 


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filamentous fungi with the notable exception of the zygomycetes. F901318 has no activity 
against yeasts, zygomycetes, and some Fusarium species. 
Within F901318’s spectrum of activity is an evolving panel of other “uncommon” moulds 
which are typically resistant to the azole antifungals and/or polyenes, including Rasamsonia 
species as well as Acremonium, Scopulariopsis, Microascus, and Paecilomyces species. 
Treatment with F901318 may be of benefit in these IFDs, particularly in patients unable to 
tolerate alternative treatment options.  
Sustained exposure to F901318 is lethal to fungi. Vacuolation, cell wall thinning, and cell wall 
rupture are seen. Loss of cell membrane integrity can be shown by viable dye exclusion 
studies.  
Nonclinical in vivo studies, including pharmacological, toxicological and animal models of 
human invasive fungal infections, have shown F901318 has a good efficacy, safety and 
tolerability profile with in vitro studies showing that it lacks phototoxicity potential. The 
CYP-based metabolic profile of F901318 and its weak CYP inhibition potential means that 
DDIs can be predicted and managed. F901318 is active by both oral and IV routes of 
administration in nonclinical efficacy studies. Fungal burden can be reduced in lung and brain. 
Extensive nonclinical PK/pharmacodynamic studies of IA (two in vivo animal models, 
multiple strains and species of Aspergillus) have defined sustained exposure with a Cmin of 0.1 
to 0.3 µg /mL as the plasma concentration predicted to be effective in the treatment of invasive 
fungal infections in man. In addition, 
 in vivo data from a Coccidioides immitis brain 
model showed improvements in animal survival and clearance of infected brain tissue that 
could not be achieved with a control azole antifungal. 
2.1.3 
Clinical pharmacology: Potentially efficacious and well tolerated 
exposures can be achieved after oral and IV dosing 
The safety profile of F901318 in humans has been characterized in 294 healthy individuals 
given F901318 by both the oral and the IV route. 
 
 
 
 
 
  
 
 
 
 


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No embryotoxicity or teratogenicity has been detected in the rat or rabbit. Nonetheless, as a 
new molecular entity, F901318 should not be given to pregnant women unless the benefit 
clearly outweighs the risk. 
In vitro studies have shown that F901318 is a substrate for CYP1A2, CYP2D6, CYP2C19, 
CYP3A4, CYP2C9, and CYP2C8, with metabolism being more significant for CYPs 3A4, 
2C9, and 2C8. F901318 is not an inducer of any CYP enzyme. In man, hepatic metabolism 
produces a single major metabolite, 
, that circulates at concentrations approximately 
40% of the concentration of F901318. This metabolite has MICs for Aspergillus spp. that are 
16- to 32-fold higher than F901318 and hence is considered to contribute little or no 
meaningful microbiological activity. 
The specific combination of fluconazole (CYP3A4 and CYP2C9 inhibitor) and F901318 has 
been studied in man and exposure to fluconazole has been shown to increase mean AUC0-12 
and Cmax of F901318 by 2.0 and 1.7-fold, respectively. In vitro and in vivo studies have shown 
that F901318 is a weak inhibitor of CYP3A4; in a clinical study treatment with F901318 
resulted in an approximately 1.6-fold elevation of midazolam exposure. F901318 also shows 
potential for inhibition of the P-gp, BCRP, and BSEP transporters in in vitro studies, and 
whilst the potential for drug interactions is thought to be low, careful monitoring may be 
needed for sensitive substrates of these transporters which have narrow therapeutic windows. 
Based on these findings, caution should be exercised when F901318 is dosed together with 
any CYP inducer (this may reduce F901318 levels) or inhibitor (this may increase F901318 
levels). In addition, F901318 could increase the exposures of compounds metabolized by 
CYP3A4. 
The Investigator is advised to consult with the MM on concomitant medications that either are 
metabolized by the liver or that influence hepatic metabolism. Concomitant administration of 
inhibitors of human DHODH (teriflunomide and leflunomide) is prohibited. Co-dosing with 
moderate or strong CYP3A4 or 2C9 inhibitors will require a dose reduction for F901318 and 
guidance on dose adjustment must be sought from the MM. It is anticipated that co-dosing 
with strong CYP inducers (e.g., phenytoin and rifampicin) will significantly reduce F901318 
exposures and is discouraged. It is anticipated that co-dosing with immunosuppressive agents 


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that are sensitive CYP3A4 substrates (e.g., cyclosporine, sirolimus, or tacrolimus) will be 
possible, 
. 
2.2 
Rationale 
In nonclinical studies, F901318 exhibits a highly promising antifungal profile which can 
potentially address the critical treatment requirements for IFD in a changing clinical 
environment. In clinical pharmacology studies, F901318 has been well tolerated when 
administered at dosages which provide sustained systemic exposure within the predicted 
therapeutically effective range. 
The present study is designed to evaluate the safety, tolerability and efficacy of F901318 in 
patients with IFDs caused by Aspergillus spp, Scedosporium spp. and other fungal species for 
which there are limited treatment options available. Based on the nonclinical efficacy profile, 
F901318 may offer an effective treatment in patients with a diverse selection of fungal 
infections.  
This study will also assess the PK profile of F901318 in a patient population, some of whom 
will be receiving concomitant medications. All previous F901318 PK and DDI studies have 
been conducted in healthy volunteers. The results of this study will provide insight into 
possible differences between the PK profiles of F901318 in healthy volunteers and in patients, 
and also on potential F901318 DDIs. 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP), and applicable regulatory requirements. 
2.3 
Hypothesis 
This is a single-arm, open-label, Phase IIb study. The efficacy, safety and tolerability of 
treatment with F901318 will generally be presented in a descriptive manner. In addition, the 
response rates will be compared with estimated historical response rates in the respective 
DRC-adjudicated disease categories. The PK profile of F901318 will be compared with data 
from previous studies of F901318 in healthy volunteers. 
Invasive fungal infections due to resistant fungi cause substantial morbidity and mortality 
when either not treated or when available therapy lacks activity, especially in patients with 
reduced immune function: 
1. Invasive aspergillosis in immunocompromised patients is a devastating illness with a 
mortality that approaches 100% without effective therapy (Verweij 1994; Denning 1996; 
van der Linden 2011; Dixon 2015; Steinmann 2015). Timely treatment of IA with an 
effective modern drug may reduce mortality to approximately 20% at 6 weeks (Herbrecht 
2002; Maertens 2016). 












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regimen of 90 mg F901318 bid (dosed 12 ± 1 hour apart) for Day 2 onwards. Based upon 
Investigator assessment of clinical efficacy, the dose regimen may be increased to 150 mg bid 
(with stepwise increases from 90 mg bid to 120 mg bid to 150 mg as discussed with the MM). 
There are no dietary restrictions around the time of dosing, but timing of meals or enteral 
feedings prior to and during Intensive PK sampling and prior to scheduled or unscheduled 
trough sampling will be documented. 
Patients will be treated until they reach a defined treatment endpoint. All patients should 
receive treatment for at least 14 days. Patients who are considered by the Investigator to have 
experienced a successful overall outcome will continue treatment with F901318 for at least 
7 days after resolution of all clinical signs and symptoms. The maximum duration of treatment 
in the main study phase will be 90 days. Patients judged to be a success on Days 78-83 (and 
hence requiring 85-90 days of total treatment) are eligible to receive up to 90 days of treatment 
in the main study phase (90 days is the maximum duration of nonclinical safety toxicology 
studies). In addition, at the Investigator’s request and after discussion with the Medical 
Monitor (MM), open-label treatment with F901318 may be continued beyond Day 90 in 
patients who are considered likely to continue to benefit from ET. The Investigator’s request 
to extend treatment with F901318 must be approved by the MM. In the case of patients 
proceeding to the ET phase, the end of treatment (EOT) and end of study (EOS) are taken as 
the day therapy is completed in the main study phase. Extended treatment may continue as 
required, but will stop if the study drug becomes commercially available or if development of 
the study drug is terminated for any reason. 
If, at any point during the study period, cultures yield F901318-resistant isolates, patients may 
remain in the study in the presence of clinical improvement, otherwise they will be considered 
as treatment failures, treatment with F901318 will be stopped, and the patient will be 
withdrawn from the study. 
To assess efficacy and disease progression during treatment the diagnostic test used to enrol 
the patient will be repeated. It is essential that the same test is used throughout the study, to 
provide a robust assessment of change. 
 
 
 
 
 
Assessment of efficacy at other study visits will be in accordance with local practice and as 
clinically indicated. In patients with IA, GM testing will be conducted more frequently.  
Visits and assessments are scheduled as shown in Table 1 for visits up to Day 84/Day 90 and 
the post-treatment FU in the main study phase, and in Table 3 for ET visits and the post-ET 
FU in the extended treatment phase. 


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Safety assessments will be conducted at every study visit, including the ET visits, by recording 
AEs. Clinical chemistry and haematology assessments, physical examination 
 
, vital signs and ECG will be conducted as shown in Table 1 and in Table 3. 
Clinical chemistry and haematology analysis will be conducted by the local laboratory to 
facilitate patient management, and a second sample will be taken at the same time for analysis 
by the appropriate central laboratory for visits up to Day 84/Day 90 and the post-treatment FU. 
All samples taken during ET and at the post-ET FU will be analysed only by the local 
laboratory.  
As an additional safety measure, 
 
 
 
 Blood sampling for evaluation of 
liver function must always be consistent with the Liver Biochemistry Management Algorithm 
as described in Appendix 3. Analysis of these samples will be conducted by the local 
laboratory, and a second sample will also be taken for analysis by the appropriate central 
laboratory for visits up to Day 84/Day 90 and the post-treatment FU. 
Trough PK samples will be taken 15 minutes prior to an observed dose on 
 
 For 
patients proceeding to ET, the Day 84 and main study phase EOT trough PK samples will be 
combined into a single trough sample at the time of the final visit for the main study phase; 
thereafter, trough PK samples will be taken at each visit during ET. 
 
 
. The schedule of blood sampling for Intensive PK analysis is presented in Table 2. 
Unscheduled Trough PK samples may be taken, at the request of the Investigator, MM and/or 
PK Consultant. 
The EOS for each patient is defined as the last assessment (scheduled or unscheduled) 
assigned to the study which that patient completes. For patients receiving ET with F901318, 
EOS and EOT for the main study phase will be the same visit and occur at approximately Day 
90. The EOS overall is defined as the last Day 84/Day 90 visit attended by the last patient in 
the main study phase of the study (Days 1 to 84-90). 
 
 
 
  






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four visits. Patients withdrawn from study drug or with an unsuccessful overall outcome are required to return for the main study phase EOT visit and FU visit but will not be 
asked to return for the Day 42 and Day 84 visits; however, survival status will be obtained at these timepoints. 
c. 
If the main study phase EOT occurs within 1 week of a scheduled visit, the assessments completed at that visit do not need to be repeated; however, the Investigator must 
ensure that all assessments required for main study phase EOT have been completed. As an example, Day 84 and main study phase EOT would be the same for a patient who 
completes 12 weeks of therapy and stops drug. For patients who will receive ET beyond Day 90, the Day 84 visit and the main study phase EOT visit will be combined into 
a single Day 84/EOS/EOT visit on approximately Day 90 Subsequent visits will be every 4 weeks to assess the safety of continued treatment and to assess the need for further 
treatment, and there will be a FU visit 4 weeks after ET is completed. 
d. 
Only for women of childbearing potential. At screening and on the visits indicated in the schedule of event, only if patient is not hospitalized. 
e. 
During 6 months prior to treatment start. If the qualifying infection was diagnosed before baseline, data regarding the prior symptoms and prior evaluation(s) of the invasive 
fungal infection should be noted here. 
f. 
All major illnesses or medical history should be captured with particular attention to the 3 months prior to treatment start. 
g. 
Enrolment may occur up to and including Day 1, prior to first dosing 
h. 
Prior and concomitant medication to be reported during 4 weeks prior to treatment start and up to the 4-week FU visit; for chemotherapy a summary of regimens during 12 
weeks prior to treatment start should be provided. For T-cell immunosuppressive medications (e.g. cyclosporine, tacrolimus, monoclonal antibodies or nucleoside analogues) 
given within 90 days prior to screening or any dosing prior to study entry that support the host factor criteria “Treatment with other recognized T-cell immunosuppressants” at 
the time of the initial diagnosis of the fungal infection.. All other medications given within 4 weeks prior to screening or any dosing prior to study entry that support the host 
factor criteria “Prolonged use of Corticosteroids”. All medications taken during the treatment period. All medications taken during the 4-week post-treatment period. 
i. 
All non-medication procedures (e.g. radiation therapy, blood transfusions, dialysis) including all treatment for IFD (e.g. surgery) associated with the patient’s underlying 
disease received within 2 weeks prior to the first dose of study drug, during the treatment period or during the 4 weeks post-treatment period follow-up period will be recorded 
in the appropriate section of the eCRF. 
j. 
Reason for hospitalization, date of admission and discharge and type(s) of ward, must be recorded in the eCRF. 
k. 
Diagnostic assessments include mycological culture, histology/cytology, GM, PCR and radiology tests used to confirm enrolment of the patient. It is essential that the same 
methods are used for both diagnosis and assessment of overall response. Screening assessments and assessments that support the EORTC criteria at the time of the initial 
diagnosis of the study-qualifying infection (time of the original IFD diagnosis or probable IA assessment) should be reported. 
l. 
As clinically indicated.  
m. Baseline (if available) and different (species level) isolates identified during the study will be stored and shipped to the appropriate central laboratory for species identification 
and susceptibility testing. If infection is due to multiple fungi, isolates for all infecting species should be shipped. 
n. 
Serum GM must be assessed for all patients with proven or probable IA. Serum GM assessments meeting the protocol defined requirements within 10 days prior to first dose 
of study drug are acceptable for enrolment requirements.  
o. 
Radiological assessment should be performed in accordance with local practice and as clinically indicated. Radiological examination of the site of IFD should utilize the same 
x-ray/CT/HRCT/or MRI modality as the baseline radiologic examination. 
p. 
If used as part of the enrolment criteria, radiology studies should be repeated at these time points. 
q. 
Bronchoscopic assessment should be performed in accordance with local practice and as clinically indicated. 
r. 
Within 4 weeks prior to screening. See also Section 6.4.2.2: neutropenia is defined as ANC < 0.5 × 109/L [< 500/mm3]. Neutropenia status will be recorded from the screening 
visit throughout the 4-week post treatment period. Neutropenic episodes supporting the Host Factor criteria of “Neutropenia” at the time of the initial diagnosis of the invasive 
fungal infection should also be reported. Absolute neutrophil count results from 4 weeks prior to screening through the patient’s last study visit and any values supporting the 
Host Factor Criteria Neutropenia. Local Laboratory ANCs for all neutropenic episodes (defined as ANC < 0.5 x109/L [< 500/mm3]) from 4 weeks prior to screening up to the 
end of study and those that support a Host Factor Criteria of Neutropenia at the time of the initial diagnosis (which may be greater than 4 weeks prior to Screening). ANC 
results to cover the period from onset up to and inclusive of the first 2 consecutive ANC values > 0.5 x 109/L on consecutive days confirming resolution of the episode. When 
differentials are not performed due to insufficient WBCs, the total WBC count for the day should be recorded. 
s. 
The Screening EQ-5D-5L questionnaire provides the baseline, and should be completed as close to the day prior to the start of treatment as is feasible. 
t. 
Only in patients with abnormalities observed at main study phase EOT.  








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g) 
If used as part of the enrolment criteria, radiology studies should be repeated at these time points. Radiological 
assessment should be performed in accordance with local practice and as clinically indicated. Radiological examination 
of the site of IFD should utilize the same x-ray/CT/HRCT/or MRI modality as the baseline radiologic examination. 
h) 
Bronchoscopic assessment should be performed in accordance with local practice and as clinically indicated. 
i) 
Neutropenia is defined as ANC < 0.5 × 109/L [< 500/mm3].  
j) 
Additional samples at unscheduled visits should also be taken if ALT/AST or bilirubin elevations occur (see Appendix 
3).   
k) 
Only in patients with abnormalities observed at ET-EOT  
l) 
Only if associated with an AE. 
m) 
 
 
n) 
Trough F901318 samples should be taken within 15 minutes prior to observed dose, but no earlier than 1 hour prior.  
Abbreviations: AE = adverse event; ANC = absolute neutrophil count; ECG = electrocardiogram; EOS = end of study; 
EOT = end of treatment; ET = extended treatment; GM = galactomannan; PCR = polymerase chain reaction. 
 
4.2 
Discussion of Study Design 
The overall objectives of this study are to evaluate the efficacy, safety and tolerability of 
F901318 in the treatment of IFD in patients with no alternative treatment option. These patients 
will have IFD which meets the inclusion criteria and is predicted to be susceptible to F901318. 
The diagnostic methods used to identify these patients and to confirm eligibility for the study will 
vary, and the methods used to assess efficacy or disease progression during treatment will also 
vary. To manage this variation, the Investigator is required to use the same diagnostic methods 
for each patient throughout the duration of the study to facilitate the assessment of disease 
progression. The study is designed to allow flexibility in the process used to identify patients, to 
facilitate clinical management of patients in accordance with local best practice, and at the same 
time to provide consistency in the collection of data.  
Assessment of efficacy after 42 days and 84 days of treatment has been used in other studies in 
patients with IFD. Inclusion of these 2 timepoints for assessment of efficacy will support 
comparison of the data from this study with historical and contemporary clinical data and case 
reports.  
In addition, very lengthy treatment (many months) is sometimes beneficial in treating IFD. 
 
, the main phase of this protocol is 
limited to 90 days of treatment. However, discussions with study Investigators make it clear that 
extended treatment is justified for those patients who have benefited from treatment with 
F901318 but whose IFD has not completely resolved after 84 to 90 days of treatment and who 
would continue to benefit from further treatment with F901318. No alternative treatment options 
are available for these patients, and stopping treatment with F901318 after 84 to 90 days could 
entail a risk of IFD exacerbation.
 
 
 
 


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Enrolment of patients into the study is expected to be slow, and there is no basis on which to 
predict the numbers of patients likely to be enrolled in each category. There is no limit to the 
enrolment of patients in the categories which require a positive identification of the fungal 
pathogen. This should allow unrestricted enrolment of patients in these categories. The number of 
patients with unconfirmed infection (Probable LRTD IA) will be monitored, and enrolment into 
this category may be stopped at any time by the Sponsor. This approach should facilitate the 
enrolment of patients with confirmed IFD and also limit the risk of inappropriate treatment in 
patients who do not have confirmed infection. 
This is a single-arm, open-label, Phase IIb study. There is no suitable alternative treatment for 
patients in this study, and inclusion of a comparator treatment arm would not be appropriate. In 
addition, it is unlikely that any single comparator would be appropriate for all disease categories. 
In clinical PK studies, the terminal half-life of F901318 is 24 to 30 hours. The use of a loading 
dose regimen of 150 mg bid (given at 12 ± 1 h intervals) to initiate treatment will allow a 
therapeutically effective blood concentration to be achieved rapidly. The daily maintenance dose 
of 90 mg bid (given at 12 ± 1 h intervals) has been selected to provide sustained exposure to 
blood concentrations of F901318 predicted to be clinically effective. However, should ongoing 
studies in healthy volunteers demonstrate that an alternative dosing regimen (up to three times 
daily dosing of a total daily dose of up to 300 mg) provides blood levels that fall within the target 
therapeutic range, a revised regimen may be adopted.   
Safety of patients will be monitored throughout the study. 
 
 
 
 
 
 
Enrolment of patients into this study will be based on the Investigator’s assessment of the IFD, 
and the likely susceptibility of the infection to treatment with F901318. The Sponsor will provide 
a comprehensive summary of the range of fungal species which have been tested for 
susceptibility to F901318, and will update this summary as new information becomes available. 
In addition, the MM will be available to provide advice to the Investigator. 


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4.3 
 Selection of Study Population 
4.3.1 
Inclusion Criteria for Main Study Phase 
Patients may be entered in the study only if they meet all of the following criteria: 
1. Male and female patients aged at least 18 years, or male and female patients aged 16 years or 
17 years and who weigh at least 40 kg, who have been fully informed and who have given 
voluntary written informed consent, or whose legally authorized representative(s) have been 
fully informed and have given voluntary written informed consent if applicable, and in 
compliance with local regulations 
OR: 
Patients unable to write and / or read but who fully understand the oral information given by 
the Investigator (or nominated representative) who have given oral informed consent 
witnessed in writing by an independent person and in compliance with local regulations. 
Unconscious patients may not enter the study. 
2. Ability and willingness to comply with the protocol. 
3. Patients must be able to take oral medication 
4. Female patients must be non-lactating and at no risk of pregnancy for one of the following 
reasons:  
a. Postmenopausal for at least 1 year; 
b. Post-hysterectomy and/or post-bilateral ovariectomy; 
c. Of childbearing potential, with a negative urine or serum human chorionic gonadotropin 
pregnancy test at the Screening visit and must be using a highly effective method of birth 
control throughout the course of the study period: 
i)   Established use of oral, injected, transdermal, intravaginal or implanted hormonal 
methods of contraception associated with inhibition of ovulation 
ii)  Placement of an intrauterine device or intrauterine hormone-releasing system 
iii) Male sterilisation (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate) 
iv) Bilateral tubal occlusion 
v)  Sexual abstinence (reliable sexual abstinence is acceptable but periodic abstinence 
[e.g. calendar, ovulation, symptom-thermal, or post ovulation methods] and withdrawal 
are not acceptable). 
5. Male patients with female partners of childbearing potential must either totally abstain from 
sexual intercourse or use a highly effective means of contraception throughout study 
participation and agree to continue its use for 30 days after stopping study drug. 


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6. Patients with one of these 4 forms of Proven invasive fungal infection* confirmed by culture 
or other diagnostic based on EORTC/MSG criteria (see Appendix 2) and as agreed with the 
MM:  
a) Lomentospora (Scedosporium) prolificans (LoPro), 
b) Scedosporium spp., 
c) Aspergillus spp.,  
d) Other F901318-susceptible fungi (as described in the IB or based on information provided 
by the MM, and in either case requiring approval of the MM), 
OR  
e) Probable LRTD IA based on EORTC/MSG criteria (Appendix 2) but not meeting the 
criteria for culture proven invasive fungal infection. 
*Enrolment is based on presumed F901318 susceptibility for categories a-c and selected other 
species as described in the IB. For IFD due to isolates from species of uncertain 
susceptibility, enrolment may occur with the approval of the MM before isolate susceptibility 
is confirmed. If an isolate is not available for shipping to the appropriate central lab for 
susceptibility testing, susceptibility will be predicted from species identification determined 
locally. If the isolate is subsequently found to be resistant, study therapy may be continued or 
discontinued based on clinical response at the discretion of the Investigator. Patients with 
infections due to multiple fungi can be enrolled provided at least one fungus is known or 
predicted to be F901318-susceptible AND the patient has limited alternative treatment 
options for that fungus as defined in Inclusion Criterion 7. As a specific example, a patient 
with simultaneous IA due to an azole-resistant strain and also invasive mucormycosis could 
be enrolled and treated with the combination of F901318 and isavuconazole. The choice of 
additional agents to treat other fungi should also consider the limitations applied to allowed 
medications (Section 5.9.2). Cases of polyfungal infection should be discussed with the MM. 
7. Patients will also have limited alternative treatment options based on meeting one or more of 
the following criteria: 
a) Known or predicted resistance of the infecting isolate to all licensed agents. LoPro 
automatically meets this criterion – other fungi may qualify after discussion with the MM, 
b) Failure of available therapy. Failure to improve based on clinical or radiologic grounds 
despite receiving ≥7 days of standard antifungal treatment AND alternative licensed 
agents are either predicted to be ineffective or are contraindicated, 
c) Intolerance to available therapy. Current therapy cannot be continued due to therapy-
related adverse reactions (e.g., increase in serum creatinine above upper limit of normal 


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with an amphotericin, persistent visual disturbances with voriconazole, allergic reaction 
with any compound, or other recognized drug-related AE) AND alternative licensed 
agents are either predicted to be ineffective or are contraindicated,  
d) Inability to manage DDIs. Inability to continue current therapy due to DDIs that cannot 
be managed AND alternative licensed agents are either predicted to be ineffective or are 
contraindicated, 
e) Inability to produce therapeutic drug levels. Inability to produce or maintain 
therapeutic blood levels with current therapy AND alternative licensed agents are either 
predicted to be ineffective or are contraindicated 
f) An IV-only option (e.g., an amphotericin) has produced a clinical response AND it is 
standard practice to switch to an oral azole for completion of therapy AND at least 
one of the following is true: 
i) Azole-resistance is known based on susceptibility testing of the infecting isolate, 
ii) Azole-resistance is predicted by PCR or similar molecular diagnostic tool, 
iii) Azole-resistance is suspected based on epidemiological or clinical grounds (e.g., 
development of aspergillosis while on mould-active azole prophylaxis; history of lack 
of response to a mould-active azole at an early point in the therapeutic course), 
iv) An azole would be acceptable therapy but it is known or predicted that unmanageable 
DDIs will occur 
g) Other MM agreed inclusion. Patient does not meet any of criteria a) to f), but treatment 
with F901318 is judged appropriate by the Investigator. Inclusion of patients based on this 
category must be agreed with the MM and the rationale must be documented. 
4.3.1.1 
Inclusion Criteria for Extended Treatment Phase 
1. Patient has completed 84 to 90 days of treatment with F901318 in the main study phase. 
2. In the Investigator’s opinion the patient has potential to continue to benefit from extended 
treatment with F901318. The Investigator must discuss ET with the MM, and the MM 
must approve ET for each patient. 
3. No other alternative treatment option is available. 
4. Patient is willing to give informed consent for ET. 
5. Patient is willing and able to comply with monthly visits to the clinic for assessments. 
4.3.2 
Exclusion Criteria for Main Study Phase 
Patients will not be entered in the study for any of the following reasons: 
1. Women who are pregnant or breastfeeding. 


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2. Known history of allergy, hypersensitivity, or any serious reaction to any component of the 
study drug. 
3. Patients with chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis. 
4. Suspected zygomycosis (mucormycosis) as the IFD used to qualify for the study. Evidence 
for the presence of F901318 non-susceptible filamentous fungi such as Mucorales should be 
urgently followed up. Increased vigilance for the possibility of zygomycosis is required for 
suspected IA with negative baseline GM.    
5. Microbiological findings (e.g., virological) or other potential conditions that are temporally 
related and suggest a different aetiology for the clinical features. 
6. HIV infection but not currently receiving antiretroviral therapy. In cases where HIV infection 
is first diagnosed at the same time as the invasive fungal infection, if antiretroviral therapy is 
commenced at the time of enrolment, then such patients are eligible for enrolment.  
7. Any known or suspected condition of the patient that may jeopardize adherence to the 
protocol requirements or impede the accurate measurement of efficacy (e.g. neutropenia not 
expected to resolve, patients with uncontrolled malignancy who are treatment refractory and 
receiving only palliative therapy). 
8. Patients with a concomitant medical condition that, in the opinion of the Investigator, may be 
an unacceptable additional risk to the patient should he / she participate in the study. 
9. Patients previously enrolled in a study with F901318.  
10. Treatment with any investigational drug in any clinical trial within the 30 days prior to the 
first administration of study drug except for unblinded protocols (e.g. open-label oncological 
regimen variations or biologic studies). Prior to enrolling patients that are on other open-
label studies it is the site’s responsibility to ensure that the study criteria for that study allow 
for enrolment into this study. 
11. Patients receiving treatment limited to supportive care due to predicted short survival time. 
12. Unless approved by the MM, patients with a baseline prolongation of QTcF ≥500 msec, or at 
high risk for QT/QTc prolongation, e.g. 
a) A family history of long QT syndrome  
b) Other known pro-arrhythmic conditions 
c) Risk factors for Torsade de Pointes (e.g. uncompensated heart failure, abnormal plasma 
potassium or magnesium levels that cannot be corrected, an unstable cardiac condition 
during the last 30 days). 


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13. Evidence of hepatic dysfunction with any of the following abnormal laboratory parameters at 
Screening: 
a) Total bilirubin ≥2 x ULN  
b) Alanine transaminase or aspartate transaminase ≥3 x ULN 
c) Patients with known cirrhosis or chronic hepatic failure 
14. Prohibited concomitant medications. Concomitant administration of inhibitors of human 
DHODH (teriflunomide and leflunomide) is prohibited. There are currently no other 
absolutely prohibited concomitant medications but there are medications with potentially 
significant DDIs and the management of potential interactions should be considered before 
study enrolment (Section 5.9.1). 
15. Additional exclusion criteria required by local regulatory authorities. These include, but are 
not limited to,: 
• Patients accommodated in an institution because of regulatory or legal order.  
• Prisoners or patients who are legally institutionalized. 
• Patients who are not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or patients potentially at risk of 
noncompliance to study procedures. 
• Patients who are dependent on the Sponsor or Investigator or who are deemed vulnerable 
for any reason. 
• Patients who are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
• Any specific situation during study implementation/course that may raise ethics 
consideration. 
4.3.2.1 
Exclusion Criteria for Extended Treatment Phase 
1. Patients who are not suitable for participation in the ET phase, whatever the reason, as 
judged by the Investigator, including medical or clinical conditions, or patients potentially 
at risk of noncompliance to study procedures. 
2. Patients who are unwilling or unable to continue the contraceptive measures as described 
for the main study phase. 
4.3.3 
Patient Restrictions 
The following restrictions may affect patient participation in this study: 


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• 
Concomitant medication prohibitions and restrictions as described in Section 5.9. 
• 
Female patients of childbearing potential must take adequate contraceptive precautions before 
starting study drug treatment, for the entire duration of the study and until at least 30 days 
after the last dose of study drug. Adequate contraceptive precautions include the following: 
− Established use of oral, injected, transdermal, intravaginal or implanted hormonal 
methods of contraception associated with inhibition of ovulation 
− Placement of an intrauterine device or intrauterine hormone-releasing system 
− Male sterilisation (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate) 
− Bilateral tubal occlusion 
− Sexual abstinence (reliable sexual abstinence is acceptable but periodic abstinence [e.g. 
calendar, ovulation, symptom-thermal, or post ovulation methods] and withdrawal are not 
acceptable). 
• 
Male patients with female partners of childbearing potential must either totally abstain from 
sexual intercourse or use a highly effective means of contraception throughout study 
participation, and agree to continue its use for 30 days after the last dose of study drug. 
• 
No dietary restrictions around time of dosing will be applied, although timing of meals or 
enteral feedings prior to and during Intensive PK sampling will be documented.  
4.3.4 
Patient Withdrawal 
All patients are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice to further treatment. The criteria for enrolment are 
to be followed explicitly. If a patient who does not meet enrolment criteria is inadvertently 
enrolled, that patient should be withdrawn from the study and the Sponsor or Sponsor’s designee 
must be contacted. An exception may be granted in rare circumstances where there is a 
compelling safety reason to allow the patient to continue. In these rare cases, the Investigator 
must obtain documented approval from the Sponsor or Sponsor’s designee to allow the patient to 
continue in the study. 
In addition, patients will be withdrawn from study drug and from the study in the following 
circumstances: 
• 
The Investigator decides that the patient should be withdrawn.  
• 
Intolerable AE; the study drug is to be discontinued and appropriate measures are to be taken. 
The Sponsor or Sponsor designee must be notified immediately. 


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• 
Clinically significant laboratory value; depending on the observed value, the study drug may 
need to be discontinued. Prompt consultation with the MM is required. 
• 
ALT or AST meet criteria for major enzyme elevation AND total bilirubin > 1.5x ULN (if 
baseline < ULN) OR > 1.5x baseline (if baseline > ULN) without evidence of obstruction, 
malignancy, impaired glucuronidation capacity or another explanation as detailed in 
Appendix 3. Study drug must be stopped, and patient follow-up must be conducted in 
accordance with Appendix 3. 
• 
The patient is unwilling to continue in the study (withdrawal of consent). 
• 
Lack of efficacy. 
• 
Lack of compliance with protocol. 
• 
The Sponsor, for any reason, terminates or suspends the study (see also Section 4.3.5). 
• 
Cultures performed during the treatment period yield F901318-resistant isolates judged 
clinically relevant and there is no clinical improvement in the opinion of the Investigator 
(considered as treatment failure). 
Patients who discontinue the study early will have early termination procedures performed in 
accordance with the main study phase EOT visit as shown in the Schedule of Events. 
Patients who are withdrawn from the study will not be replaced. 
The post-treatment follow-up visit (4 weeks after main study phase EOT) should be performed 
for all patients who receive at least one dose of study drug, wherever possible, except for patients 
who receive ET beyond Day 90. A post-treatment follow-up safety visit 4 weeks after the last 
dose of study drug should be performed for all patients who receive ET, but this is not considered 
to be the main study phase EOS or EOT visit. 
The reason for discontinuation of study drug and withdrawal from the study will be recorded in 
the eCRF. 
Patients who sign informed consent and are assigned a patient ID but do not meet the eligibility 
criteria will be considered Screen Failures. If the Investigator believes rescreening is warranted, a 
patient can be rescreened. There is no limit to the frequency or number of times a patient may be 
rescreened. Refer to the Schedule of Events for the list of procedures required at Screening. 
4.3.5 
Study Termination 
During the course of the study, it is possible that new risks or toxicities related to F901318 will 
be identified from this study or from other clinical or nonclinical studies conducted in parallel. If 
these result in a significant negative change in the benefit-risk, the clinical study may be put on 
hold or terminated. In addition, external medical and/or ethical insights could have an effect on 


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clinical study progress. Further, the study could be interrupted or terminated based on a decision 
by the Sponsor, based on a decision by a responsible authority, upon withdrawal of approval by 
the ethics committee, or upon advice from the IDSMB or the Hepatic Advisory Committee 
(HAC). The clinical study can also be stopped if enrolment is deemed adequate by the Sponsor. 




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Blood sampling for evaluation of liver function must always be 
consistent with the Liver Biochemistry Management Algorithm as described in Appendix 3.   
Dose Interruptions 
Dosing interruptions are to be avoided but may be necessitated by patient care circumstances.  
• The reason for dosing interruption should be documented.  
• The approach to pausing and restarting dosing should follow the general dosing 
guidelines.  
• If the interval between the last pre-interruption dose and the first post-interruption dose 
exceeds 48 hours, redosing should begin with a loading dose regimen. 
• Guidance from the MM should be obtained. 
Patients will be treated until they reach a defined treatment endpoint, up to a maximum of 
90 days in the main study phase. Patients who are considered by the Investigator to have 
experienced a successful overall outcome will continue treatment for at least 7 days after 
resolution of all clinical symptoms and physical signs. All patients must receive at least 14 days 
of treatment, unless treatment is stopped due to one of the withdrawal criteria described in 
Section 4.3.4. Patients judged to be a success on Days 78-83 (and hence requiring 85-90 days of 
total treatment) are eligible to receive up to 90 days of treatment in the main study phase (90 days 
is the maximum duration of nonclinical safety toxicology studies); in addition, at the 
Investigator’s request and after discussion with the MM, open-label treatment with F901318 may 
be continued beyond Day 90 in patients who are considered by the Investigator to be likely to 
continue to benefit from ET. The Investigator’s request to extend treatment with F901318 must 
be discussed with the MM and approved by the MM. In the case of patients proceeding to the ET 
phase, EOT and EOS for the main study phase are defined as the day therapy is completed in the 
main study phase at approximately Day 90. 
Once enrolled, patients may remain in the study at the Investigator’s discretion based on the site 
and severity of the IFD, the patient’s underlying disease and the rate of clinical response, even if 
subsequent laboratory data suggest an alternative therapy might be possible. For example, if an 
isolate of LoPro is found to have unexpectedly low azole MICs, the patient may remain in the 
study. 
For all patients except those receiving ET, the Follow-up Visit will take place 4 weeks (±7 days) 
after the last administration of study drug, and may occur before or after Day 42 and/or Day 84 
(i.e., it is not necessarily the “end of study” visit for a given patient). For those patients receiving 
extended F901318 treatment, the main study phase EOS and EOT will be the same visit and will 


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occur at approximately Day 90, and, the follow-up safety visit will take place 4 weeks (±7 days) 
after the last administration of study drug. 
Patients with a successful overall outcome at the main study phase EOT, who subsequently 
require further treatment with F901318 before the 28-day post-treatment Follow-up Visit, may 
receive further treatment with F901318 following consultation with the MM. In this situation, 
stopping treatment with F901318 then resuming treatment will be considered to be a treatment 
interruption, and if the interval is more than 48 hours redosing should begin with a loading dose 
regimen. In addition, appropriate diagnostic tests should be undertaken to determine the cause of 
the change in clinical status and the susceptibility to F901318 of any identified IFD. 
Patients with a successful overall outcome at the main study phase EOT prior to Day 42 must 
return for Day 42 and Day 84 Visits, even if they are no longer under study treatment. If the 
administration of systemic antifungals as prophylaxis is anticipated, patients should stay on study 
treatment through Day 42. 
Patients with an unsuccessful overall outcome at the main study phase EOT and requiring 
alternative systemic antifungal therapy will not be asked to return for Day 42 and/or Day 84 
Visits; however the survival status at these timepoints will be collected at a minimum.  
5.2 
Identity of Investigational Products 
Details of the F901318 dosage form used in this study are provided in Table 4. 
Table 4 
Investigational Products 
Investigational product 
Formulation 
Dosage form and strength 
Manufacturer 
F901318 
Oral tablet 
30 mg per tablet 
 
 
F901318 
The oral formulation used in this study is a tablet containing 30 mg F901318 and standard 
pharmacopoeial excipients;
 
 
The oral product should be stored and transported refrigerated (2-8°C). 
 
 
 


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5.3 
Packaging and Labelling 
The F901318 tablet will be packed into 64 count, 50 mL high density polyethylene bottles, with 
polypropylene twist off caps containing desiccant. Each bottle will have an approved clinical 
study label that complies with local regulations. 
5.4 
Method of Assigning Patients to Treatment Group 
This is a single-arm, open-label, Phase IIb study. Patients who have provided informed consent, 
met all inclusion criteria and not met any exclusion criteria will receive treatment with F901318. 
The study centre will request the study drug assignment using the Interactive Web Response 
System (IWRS).  
All patients will be managed by IWRS. The study centre will contact IWRS and patients will be 
assigned their 8-digit patient number by the IWRS at the time of enrolment. The IWRS will 
provide the medication kit/bottle number(s) of the study drug to be dispensed. 
5.5 
Selection of Doses in the Study 
Based on data from clinical pharmacology PK studies, preliminary PK data from the ongoing 
study and Population PK modelling predictions, the dose of F901318 selected for this study is 
predicted to provide sustained and stable exposure to systemic concentrations of F901318 within 
the range expected to be effective against the target pathogens 
 
 
5.6 
Selection and Timing of Dose for Each Patient 
The recommended regimen will be as described in Section 5.1. The recommended regimen may 
change during the study and current guidance should be confirmed with the MM at study 
initiation.  
There are no dietary restrictions associated with timing of F901318 dosing. If the patient vomits 
after taking oral F901318, the patient should not repeat the dose but should wait until the next 
dose as scheduled. Any patient who vomits twice in 1 day should inform the Investigator. 
The time at which each dose is taken will be recorded in a patient dosing diary. The diary must be 
completed for hospitalized patients as well as for outpatients. 
5.7 
Trough PK Sample Analysis 
Therapeutic drug monitoring for F901318 with dose adaptations to maintain optimal trough 
levels within a pre-specified target range will no longer be used. Rapid analysis of trough levels 
of F901318 will remain to monitor the potential impact of concomitant medication upon 
F901318, to have access to systemic exposure 
 and to 
support ongoing analysis of the safety profile of F901318 across the population.  


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The Sponsor is responsible for setting up regional hubs for rapid trough PK analysis, each of 
which will have access to a suitably validated F901318 assay. Sample collection to receipt at the 
regional hub will ideally take no more than 1 working day, with analysis being completed within 
1 working day of sample receipt (i.e. 2 working days turnaround time between sample collection 
and trough PK data availability). 
Guidance for dose adjustment (for use by the MM and PK consultant) will be available prior to 
study start and will accommodate dosing regimen changes due to concomitant medication, 
clinical judgement in response or when elevations in liver function tests occur which meet or 
exceed the threshold defined as moderate in Appendix 3 of the protocol. Should any dose 
adaptations be required, the MM and/or PK consultant will advise of any additional Unscheduled 
Trough PK sampling requirements, to enable the impact of the dose adaptation to be assessed. 
5.8 
Blinding 
This is an open-label study. Study data reviewed by the DRC and Independent Data and Safety 
Monitoring Board (IDSMB) will not be blinded. 
5.9 
Prior and Concomitant Treatments 
Prior medications associated with the initial management of the study-qualifying fungal pathogen 
will be recorded in the eCRF. All other anti-fungal medication taken during the 6 months prior to 
study screening will be recorded in the eCRF. The reason for antifungal medication and the 
outcome of treatment will also be recorded. Chemotherapy regimens (summary only) taken 
during the 12 weeks prior to study screening will be recorded. All other medications taken during 
the 4 weeks prior to study screening will be recorded. Concomitant medications will be recorded 
during the main study phase and extended treatment phase of the study, and during the associated 
FU and ET FU periods. 
Prior and concomitant non-antifungal medication to be reported throughout the course of the 
study as follows: 
• All chemotherapy regimens (summary only) taken during 12 weeks prior to screening. 
• All T-cell immune-suppressants (e.g. cyclosporine, tacrolimus, monoclonal antibodies or 
nucleoside analogues) given within 90 days prior to screening or any dosing prior to study 
entry that support the host factor criteria “Treatment with other recognized T-cell 
immunosuppressants” at the time of the initial diagnosis of the fungal infection. 
• All other medications given within 4 weeks prior to screening or any dosing prior to study 
entry that support the host factor criteria “Prolonged use of Corticosteroids”. 
• All medications taken during the treatment period. 
• All medications taken during the 4-week post-treatment period. 




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5.9.1.2 
Interaction of F901318 with Concomitant Medication 
Medications with the potential for meaningful DDIs with F901318 are summarized in the IB and 
in this section. In brief, any agent that either inhibits CYP-mediated drug clearance (might reduce 
clearance of F901318) or that is cleared by CYP3A4 (levels might be increased by F901318) 
should be used with care. 
 
. All other medications with potential for DDIs 
should be approached on a case-by-case basis in consultation with the MM. 
In in vitro studies, F901318 is a substrate for CYP1A2, CYP2D6, CYP2C19, CYP3A4, CYP2C9, 
and CYP2C8, with metabolism being more significant for 3A4, 2C9, and 2C8. F901318 is not an 
inducer of any CYP enzyme. F901318 is a weak inhibitor of CYP3A4 (clinical studies have 
shown an approximate 1.6-fold elevation of midazolam exposure). F901318 also shows potential 
for inhibition of the P-gp, BCRP, and BSEP transporters in in vitro studies, and whilst the 
potential for drug interactions is thought low, careful monitoring may be needed for sensitive 
substrates of these transporters which have narrow therapeutic windows. The specific 
combination of F901318 and fluconazole (CYP3A4 and CYP2C9 inhibitor) has been studied in 
man and fluconazole has been shown to increase mean AUC0-12 and Cmax of F901318 by 2.0 and 
1.7-fold, respectively. 
 
 In 
addition, F901318 could increase the exposures of compounds metabolized by CYP3A4. 
The Investigator is advised to consult with the MM on concomitant medications that either are 
metabolized by the liver or that influence hepatic metabolism, 
 
Specific data on other drug-drug combinations is being continuously developed. 
 
 
 
 
5.9.1.3 
Co-Dosing with Strong CYP Inducers 
Due to potential DDIs with F901318 and CYP inducers, co-dosing with these agents may lead to 
CYP induction that could dramatically reduce F901318 levels. 
 
 Consultation with the MM is advised if 
the combination of F901318 with a CYP inducer cannot be avoided.  


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Strong CYP inducers include : 
• Phenytoin 
• Rifampin 
• Flucloxacillin (Kennedy 2015; Muilwijka 2017) 
• Dicloxacillin 
• Nafcillin 
• Carbamazepine 
• Ritonavir (note that ritonavir is both an inducer and an inhibitor) 
• Enzalutamide 
• Mitotane 
• St John’s wort 
See also further guidance on strong CYP inducers at the FDA website:  
(https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractions
labeling/ucm093664.htm).  
If a medication that potentially induces CYP is required, consultation with the MM is advised. An 
extra visit for Unscheduled Trough PK sampling for rapid analysis will be required after starting 
or stopping such concomitant medication, to support evaluation of the impact of the potential 
DDI.  
The Unscheduled Trough PK samples will be sent to the regional hub for rapid trough PK 
analysis of F901318 to enable assessment of potential DDIs. 
5.9.1.4 
Co-Dosing with CYP Inhibitors 
Monitoring of circulating levels of F901318 is required when co-dosing with CYP inhibitors. 
As F901318 is metabolized by CYP3A4 and CYP2C9 there is a potential for DDIs. Co-dosing 
with CYP3A4 inhibitors may increase exposure to F901318. In vitro data suggest that 
metabolism by other CYPs is limited. Consultation with the MM is advised if the combination of 
F901318 with a CYP3A4 inhibitor cannot be avoided. 
Where use of concomitant medication has been approved, an extra visit for Unscheduled Trough 
PK sampling will occur 3 to 5 days after starting or stopping such concomitant medication. This 
Unscheduled Trough PK sample will be sent for rapid trough PK analysis of F901318, to support 
evaluation of the impact of the potential DDI.  
The Unscheduled Trough PK samples will be sent to the regional hub for rapid trough PK 
analysis of F901318. 
 
 


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5.9.1.5 
Co-Dosing F901318 with Sensitive and Moderately Sensitive CYP3A4 
Substrates 
Monitoring of circulating levels of the concomitant medication is required when co-dosing 
F901318 with sensitive and moderately sensitive CYP3A4 substrates. 
F901318 is a perpetrator of potential DDIs with CYP3A4 substrates. As F901318 is a weak 
inhibitor of CYP3A4, co-dosing with sensitive and moderately sensitive CYP3A4 substrates may 
increase exposure of these substrates. Consultation with the MM and use of TDM for the 
substrate are advised if the combination cannot be avoided. 
For those concomitant medications which are sensitive and moderately sensitive CYP3A4 
substrates and which undergo routine TDM (such as transplant drugs), changes in concomitant 
drug treatment and all TDM results for the concomitant medication will be recorded. If the 
patient is receiving the concomitant medication prior to receiving F901318, a baseline TDM 
sample should be sent for analysis prior to F901318 treatment commencing. Further TDM 
sampling should be performed on a schedule based on the Investigator’s judgment regarding the 
given medication. 
Sensitive substrates: alfentanil, avanafil, budesonide, buspirone, conivaptan, cyclosporin, 
darifenacin, darunavir, dasatinib, dronedarone, ebastine, eletriptan, eplerenone, everolimus, 
felodipine, ibrutinib, indinavir, lomitapide, lovastatin, lurasidone, maraviroc, midazolam, 


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naloxegol, nisoldipine, quetiapine, ruxolitinib, saquinavir, sildenafil, simvastatin, sirolimus, 
tacrolimus, ticagrelor, tipranavir, tolvaptan, triazolam, and vardenafil. 
Moderately sensitive substrates: alprazolam, aprepitant, atorvastatin, colchicine, eliglustat, 
pimozide, rilpivirine, rivaroxaban, tadalafil. 
See also further guidance on sensitive and moderately sensitive CYP3A4 substrates at the FDA 
website. 
5.9.2 
Allowed Medications 
See Section 5.9 for a general discussion of concomitant medications. 
5.9.2.1 
Candida Prophylaxis and Concomitant Antifungal Therapy 
F901318 is not active against yeast infections and the use of fluconazole for prophylaxis or 
treatment of concomitant candidiasis is permitted at any time due to fluconazole’s lack of activity 
against mould fungi. Patients who are receiving treatment with isavuconazole or posaconazole 
should be switched to receive treatment with fluconazole. Should a patient start or stop receiving 
fluconazole treatment whilst on study, an extra visit for Unscheduled Trough PK sampling will 
occur 3 to 5 days after starting or stopping such concomitant medication. This Unscheduled 
Trough PK sample will be sent for rapid trough PK analysis of F901318, to assess the impact of 
any dose adjustment made.  
In order to meaningfully analyse the efficacy of F901318, it is important to avoid concomitant 
use of other systemic antifungal agents with known or potential activity against the primary 
fungal infection. That said, the constraints on choice of additional agents may be complex and 
thus use of any other systemic concomitant antifungal or combination treatment (such as addition 
of terbinafine for confirmed Lomentospora prolificans infections or an echinocandin to manage 
infection due to Candida) is permitted but is discouraged. 
For all other infections, antifungal combinations should be based on the Investigator’s clinical 
judgement with efforts made to minimize use where possible. Use of concomitant antifungal 
therapy must be discussed and agreed with the MM. 
5.10 Medical Care of Patients after End of Study 
The EOS for each patient is defined as the last assessment (scheduled or unscheduled) assigned to 
the study which that patient completes.  
The Sponsor will not provide any additional care to patients after they discontinue F901318 
therapy under this protocol because such care should not differ from what is normally expected 
for patients with IFD. 


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5.11 Treatment Compliance  
Study drug must be administered in accordance with the dose and frequency schedule as 
described in Section 5.1. Any departures from the intended regimen must be recorded in the 
eCRF. The Sponsor will inform the Investigator in writing of any changes to the study treatment 
regimen resulting from ongoing review of study data by the IDSMB. Any Investigator-initiated 
changes to the study treatment regimen resulting from clinical assessments must be discussed 
with the MM and approved by the MM. 
At each visit, prior to dispensing study drug tablets, previously dispensed study drug tablets will 
be retrieved by the Investigator or designee and compliance assessed. Patients exhibiting poor 
compliance should be counselled on the importance of good compliance to the study dosing 
regimen, and the reason for poor compliance should be investigated. Proper instructions on drug 
dosing must be provided to the patient by the Investigational staff.  
The time of each oral dose will be recorded in a patient dosing diary. Patients who participate as 
an out-patient at any time on the study will be given the drug dosing diary to take home and 
complete. Proper instructions on drug dosing and diary completion must be provided to the 
patient by the Investigational staff. This diary will be reviewed by site staff at each oral drug 
dispensing visit.  
5.12 Study drug Accountability 
The Investigator, a member of the investigational staff, or a hospital pharmacist must maintain an 
adequate and current record of the receipt and distribution of all study drug using the Drug 
Accountability Form. These forms must be available for inspection at any time. 
The Investigator or designee is responsible for recording the date of first and last study treatment 
administration. The Investigator or designee is also responsible for recording the details required 
to perform drug accountability and compliance assessments: 
• Oral - number of tablets dispensed and the number of tablets returned at each visit, missed 
doses (including cases of vomiting that may affect dosing) and the reason 
Dosing interruptions are to be avoided but may be necessitated by patient care circumstances. 
The reason for dosing interruption should be recorded wherever possible.  
All empty tablet bottles must be kept at the pharmacy or at a place where the study monitor has 
access to perform drug accountability. 
For Out-Patients, oral medication will be supplied in bottles sufficient for 2 weeks of dosing. A 
maximum of 4 weeks of dosing may be supplied to a patient at any given time without Sponsor 
approval up to the end of the 84 to 90 day main study phase. Requests for supply to cover more 
than 4 weeks of dosing will be considered on a case by case basis and must be approved by the 
Sponsor prior to being supplied to the patient. For those patients receiving ET beyond 84 to 90 


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days, sufficient medication may be supplied for 8 weeks of dosing. Unused medication may be 
returned to the patient at the ET visits, to ensure the patient has sufficient study drug to cover 
possible delays between ET visits. During the informed consent process, the Investigator should 
discuss with the patient the need to return to the study site between visits for oral drug re-supply. 
Patients will be given an oral drug dosing diary to take home and complete. This diary will be 
reviewed by site staff at each oral drug dispensing visit. 
All study drug supplies should be accounted for at the termination of the study and a written 
explanation provided for discrepancies. Patients receiving ET beyond Day 90 should switch to 
use of drug supplied by that mechanism. All unused study drug supplies and packaging materials 
are to be inventoried and either returned to 
 by the Investigator or destroyed locally if 
suitable facilities are available. The Investigator is not permitted to return or destroy unused 
clinical drug supplies or packaging materials unless authorized by 
 
Further details on drug accountability are outlined in the Pharmacy Manual. Study medication 
must not be used for any purpose other than the study. Study medication must not be used after 
the retest date unless the study medication is reassessed and its release date extended.  


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6.0 ASSESSMENTS AND PROCEDURES 
The objectives of the study are to describe the efficacy, safety and tolerability of F901318 as 
treatment for infections due to Lomentospora prolificans, Scedosporium spp., Aspergillus spp., 
and other resistant fungi in patients lacking suitable alternative treatment options. For the 
schedule and timing of efficacy and safety assessments, see Table 1. 
Assessments of the F901318 PK profile include trough (pre-dose) concentrations to be evaluated 
throughout treatment, and Intensive PK to be evaluated across a dosing interval 
 
 For the schedule 
and timing of PK assessments, see Table 2. 
6.1 
General Considerations 
6.1.1 
Schedule of Assessments 
Day 1 is defined as the first day of administration of study drug. There is no Day 0; Day -1 is the 
day before administration of first dose of study drug, days preceding this are Day -2, Day -3, etc. 
Day 2 is the second day of administration of study drug, Day 3 is the third day of administration 
of study drug, etc.   
Study assessments (visits) are scheduled in relation to days of administration of study drug. 
Screening assessments are to be completed within the 7 days prior to start of treatment unless 
otherwise specified and agreed with the MM. Assessments scheduled between Day 1 and Day 10 
must be completed within the scheduled windows. Subsequent visits are permitted some 
flexibility to facilitate completion of the assessments; ± 2 days for the visits between study Day 
14 and study Day 35 (Visits 8 to 12a) and ± 3 days at study Days 42, 49, 56, 70 and main study 
phase EOT (Visits 13 to 15, and 17). The Day 84 assessment (Visit 16) is permitted ± 6 days to 
allow treatment up to Day 90. The post-treatment FU visit (Visit 18) will be performed 4 weeks 
(±7 days) after the last dose of study drug (this may not be the last patient visit). For patients 
planning to receive ET beyond Day 90, the Day 84 visit and the main study phase EOT visit will 
be combined into a single Day 84/EOS/EOT visit on approximately Day 90. Subsequent visits 
will be every 4 weeks to assess the safety of continued treatment and to assess the need for 
further treatment, and there will be a FU visit 4 weeks after ET is completed.   
6.1.2 
Informed Consent 
Written informed consent must be obtained prior to performing any study specific assessments in 
accordance with the inclusion criterion described in Section 4.3.1. Procedures that are part of 
standard care may occur before informed consent is obtained. 
A separate informed consent is required for those patients who receive ET beyond Day 90, in 
accordance with the inclusion criterion described in Section 4.3.1.1. 


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6.2 
Procedures 
6.2.1 
Demography 
At screening, the following demographic characteristics will be recorded in the eCRF: patient 
initials, gender, race, ethnicity, date of birth. Demographic data collection will be done in 
accordance with local regulations. Height and body weight will also be recorded. 
It is not known if the efficacy or safety profile of F901318 is influenced by race or ethnicity. 
Recording race and ethnicity in this study will facilitate future evaluation of the potential 
influence of these factors on the safety and efficacy profile of F901318. The patient will be 
informed that race and ethnicity will be recorded, and that collection of this information is 
voluntary. 
6.2.2 
Pregnancy Test 
At screening, all female patients of childbearing potential will submit a urine or serum sample for 
a human chorionic gonadotrophin pregnancy test that will be analysed locally. Female patients 
complying with all other eligibility criteria must have a negative pregnancy test to be enrolled 
into the study. 
If the patient is not hospitalised, additional pregnancy tests will be required 
 
 in the main study phase visits. The 
result of the pregnancy test will be recorded in the eCRF.  
If the patient is not hospitalised, pregnancy tests will be required at the visits every 4 weeks for 
patients who receive ET and at the FU visit 4 weeks after the last dose of F901318. The result of 
the pregnancy test will be recorded in the eCRF.  
6.2.3 
Underlying Disease or Condition 
At screening, all underlying diseases or conditions that predispose the patient to IFD will be 
recorded in the appropriate section of the eCRF. 
Information to be collected will include the diagnosis for the underlying disease, type of 
chemotherapy received, whether the patient has received a bone marrow transplant or organ 
transplant, steroid use and duration, duration of neutropenia, antifungal prophylaxis and duration. 
6.2.4 
Infectious Disease History and Microbiological Assessments 
Fungal 
History of all fungal infections (including the IFD under study) within the 6 months prior to study 
drug administration. All history relating to the study-qualifying infection should be recorded, 
regardless of the time prior to study drug administration. For mycological assessments and 
responses, please refer to Section 6.3.1.4. 


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Viral 
History of all viral infections within the 6 months prior to study drug administration. 
All virology assessments performed within 6 months prior to the first administration of study 
drug, during the study and including the 4 weeks post-treatment period will be recorded.  
Bacterial 
History of all bacterial infections within 1 month prior to study drug administration. 
For bacteriology, all assessments yielding bacterial growth performed within 1 month prior to the 
first administration of study drug, during the study and including the 4 weeks post-treatment 
period will be recorded.  
6.2.5 
Medical History 
At screening, all existing clinically significant baseline conditions and/or clinically relevant 
medical conditions occurring within the 3 months prior to study drug administration will be 
recorded in the appropriate section of the eCRF. In addition, major medical history occurring at 
any prior time should be recorded, e.g. there is no time restriction for recording previous medical 
conditions with the potential to affect immune status.  
6.2.6 
Prior and Concomitant Medication 
Prior medication will be reported in the eCRF as follows: 
• All T-cell immunosuppressants (e.g. cyclosporine, tacrolimus, monoclonal antibodies or 
nucleoside analogues) given within 90 days prior to screening or any dosing prior to study 
entry that support the host factor criteria “Treatment with other recognized T-cell 
immunosuppressants” at the time of the initial diagnosis of the fungal infection. 
• All chemotherapy given during 12 weeks prior to screening (summary of regimens should 
be provided). 
• All other medications given within 4 weeks prior to screening or any dosing prior to study 
entry that support the host factor criteria “Prolonged use of Corticosteroids”. 
• All medications taken during the treatment period. 
• All medications taken during the 4-week post-treatment FU period. 
In the eCRF, prior and concomitant antifungal medication will be recorded separately from other 
prior and concomitant medications. 
6.2.7 
Non-medication Procedures 
All non-medication procedures (e.g. radiation therapy, blood transfusions, dialysis,surgery) 
received within 2 weeks prior to the first dose of study drug, during the treatment period or 
during the 4 weeks post-treatment FU period will be recorded in the appropriate section of the 
eCRF.  


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6.2.8 
Hospitalization Status 
The reason, date of admission and discharge, type of ward (intensive care unit, non-intensive care 
unit) and any changes in any of these parameters will be recorded in the eCRF from screening up 
to the end of the 4 weeks post-treatment FU period. Details of the definition of hospitalization 
and when hospitalization is not considered to be an SAE are given in Section 6.4.1.   
6.3 
Efficacy Assessments 
The key efficacy measure for each patient will be the combination of improvement in clinical 
findings combined with changes in the diagnostic assay(s) used prior to study enrolment to 
determine the eligibility of the patient to receive treatment with F901318. It is essential that the 
same methodology, where possible, is used for the diagnostic assessments at baseline and for 
efficacy assessment during treatment to enable a valid evaluation of the response to treatment. 
Any additional assessments performed during the course of the study to assess the patients status 
may also be used to support efficacy response assessments. 
All efforts should be made to have main study phase EOT assessments performed in all patients. 
Patients with a successful overall outcome at the main study phase EOT that is prior to Day 42 
must return for Day 42 and Day 84 Visits, even if they are no longer on study treatment. If 
administration of systemic antifungals as prophylaxis is anticipated following successful therapy 
patients should remain on study drug through Day 42. 
Patients with an unsuccessful overall outcome at the main study phase EOT and requiring 
alternative systemic antifungal therapy will not be asked to return for Day 42 and/or Day 84 
Visits; however the survival status at these timepoints will be collected at a minimum 
(confirmation by phone contact is acceptable and will be documented in the eCRF). For patients 
who complete treatment during the main study phase, a Follow-Up Visit will be performed 4 
weeks after the last dose of study drug.  
For patients who receive ET, subsequent visits in the ET phase will be every 4 weeks to assess 
the safety of continued treatment and to assess the need for further treatment, and there will be a 
FU visit 4 weeks after ET is completed.  
6.3.1 
Investigator’s Assessment of Overall Response 
Diagnostic assessments used to support the Investigators assessment of response include 
mycological culture, histology/cytology, GM, PCR, other mycology assessments, bronchoscopy 
and radiology tests used to confirm enrolment of the patient. It is essential, where possible, that 
the same methods are used for both diagnosis and assessment of overall response. Any additional 
assessments performed during the course of the study to assess the patients status may also be 
used to support efficacy response assessments. 


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The Investigator’s assessment of response will be recorded at Day 7, Day 14, Day 28, Day 42, 
Day 84/EOT main study phase and 4 weeks after EOT in the main study phase. The Investigator 
will provide his/her opinion of the patient’s response, based on the efficacy criteria as described 
in Section 6.3.1.1 (clinical), Section 6.3.1.2 (radiological), Section 6.3.1.3 (bronchoscopic), 
Section 6.3.1.4 (mycological) and Section 6.3.1.5 (overall response). 
For patients who receive ET with F901318, the Investigator’s assessment of overall response will 
be recorded at each visit to support continued treatment.  
If multiple fungal mould pathogens are present, the DRC will separately analyse outcome for 
each relevant pathogen. Pathogens which were known at baseline to be F901318-resistant and for 
which alternative concomitant therapy was provided are not separately scored by the DRC. For 
example, a patient treated with F901318 and isavuconazole for simultaneous azole-resistant 
aspergillosis and mucormycosis would receive an overall score only for the response of the 
aspergillosis. As appropriate, the Investigator may provide per-fungus comments on the clinical, 
radiological, and mycological elements but per-fungus scores for each of these sub-elements are 
not required. 
6.3.1.1 
Clinical Response 
Clinical response will be based on clinical signs, physical findings, and symptoms relevant to 
each patient. The Investigator will be responsible for identifying and assessing clinical signs, 
physical findings, and symptoms related to the IFD reported for each patient. Assessment of 
clinical response will be based on changes from baseline signs, findings, and symptoms. Clinical 
signs, physical findings, and symptoms will be assessed 
 
 
 as 
shown in Table 1. Assessment at Day 42 and at Day 84 is required for all patients, including 
those who completed treatment before these visits.   
For patients who receive ET with F901318, the Investigator’s assessment of clinical response will 
be recorded at each visit to support continued treatment.  
Baseline symptoms may need to include symptoms present at the time of the initial diagnosis of 
the qualifying infection. This situation may arise when a patient has had a prior therapy, 
responded to that therapy, but then developed intolerance to the therapy and is hence started on 
F901318 therapy without active symptoms at the point of study enrolment. Such prior symptoms 
will be recorded in the appropriate section of the eCRF. 
The results of assessments of clinical signs, physical findings, and symptoms (including those 
performed outside of these mandatory scheduled timepoints) will be recorded in the eCRF. 


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An assessment of the patient’s clinical response (all non-radiological clinical signs, physical 
findings, and symptoms related to IFD) will be recorded 
 
 
 (Note that for patients planning to receive ET beyond Day 90, the Day 84 visit and the main 
study phase EOT visit will be combined into a single Day 84/EOS/EOT visit on approximately 
Day 90.) 
• 
Resolution-Complete:   
For patients with attributable clinical symptoms and physical findings of IFD present at 
baseline, Resolution-Complete is assigned if  
a) there is resolution of all attributable clinical symptoms and physical findings of IFD 
present at baseline or that appeared at a subsequent prior visit  
AND  
b) no new clinical symptoms and physical findings of IFD are noted at the current visit.  
For patients lacking attributable clinical symptoms and physical findings of IFD present at 
baseline*, Resolution-Complete is assigned if  
a) there is resolution of all attributable clinical symptoms and physical findings that 
appeared at a subsequent prior post-baseline visit 
AND  
b) no new clinical symptoms and physical findings of IFD are noted at the current visit. 
AND 
c) patient meets mycological criteria for Eradication or Presumed Eradication 
 
• 
Resolution-Partial:  
For patients with attributable clinical symptoms and physical findings of IFD present at 
baseline, Resolution-Partial is assigned if  
a) there is some persistence of the attributable clinical symptoms and physical findings of 
IFD noted either at baseline or at a subsequent prior post-baseline visit but there is 
improvement in at least some of these same symptoms and findings 
AND 
b) no worsening of any of these same symptoms and findings 
AND 
c) no new clinical symptoms and physical findings of IFD at the current visit.  
For patients lacking attributable clinical symptoms and physical findings of IFD present at 
baseline*, Resolution-Partial is assigned if  
a) there is some persistence of the attributable clinical symptoms and physical findings of 
IFD noted at a subsequent prior post-baseline visit but there is improvement in at least 
some of these same symptoms and findings 
AND 


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b) no worsening of any of these same symptoms and findings 
AND 
c) no new clinical symptoms and physical findings of IFD at the current visit. 
AND 
d) patient meets mycological criteria for Eradication or Presumed Eradication. 
* If the qualifying infection was diagnosed before baseline, data regarding the prior symptoms 
and prior evaluation(s) of the invasive fungal infection may need to be considered. 
• 
Failure-Stable: Neither worsening nor improvement in any attributable clinical symptoms 
and physical findings present at baseline or that appeared at a subsequent prior visit AND no 
new clinical symptoms and physical findings of IFD at the current visit. 
• 
Failure-Progression: Shows EITHER worsening in one or more attributable clinical 
symptoms and physical findings present either at baseline or that appeared at a subsequent 
prior visit OR appearance of new clinical symptoms and physical findings of IFD at the 
current visit. 
• 
Results not available/patient unevaluable (i.e. visit and/or assessment of clinical symptoms 
and physical findings of IFD was not performed). 
Note that the rules defining success are tested in sequence beginning with Success-Complete. 
6.3.1.2 
Radiological Response 
As relevant for the IFD under study, baseline radiological assessments of IFD should be 
performed during the screening period and during the course of the study. The assessment of the 
patient’s radiological response related to IFD will be recorded at
 
 as clinically 
indicated. Note that radiological response assessments can be made using all available radiology 
since the last response assessment visit or within the visit window of the visit in question. 
Radiological assessments of IFD should be made in accordance with local practice and as 
clinically indicated. The same methodology should be used for each radiological assessment 
performed for a patient throughout the study. All radiological images taken up to Day 84/Day 90 
and the post-treatment FU must be forwarded to the appropriate central reading laboratory for 
independent review. Images taken during ET or at the post-ET FU should not be sent for 
independent review. Further details will be provided in a Central Reading Laboratory Manual, 
including instructions for recording and shipping of radiological images. 
The results of all IFD-related radiology performed during the study will be recorded in the eCRF 
and the reports will be collected. 
Radiological response for all pathogens will be described as: 


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• 
≥ 90% improvement in aggregate (across all lesions if more than one lesion) 
• 
≥ 50 to < 90% improvement in aggregate (across all lesions if more than one lesion) 
• 
≥ 25% to < 50% improvement in aggregate (across all lesions if more than one lesion) 
• 
No change (0%) to < 25 % improvement in aggregate (across all lesions if more than one 
lesion) 
• 
Worsening in aggregate (across all lesions if more than one lesion)  
• 
No signs on radiological images at screening  
• 
Results not available (i.e. visit and/or radiological assessment was not performed at the 
scheduled timepoint [Day 7, Day 14, Day 28, Day 42, main study phase EOT, Day 84 or 4-
week FU]). This category is only applicable if there was no radiology performed since the last 
response assessment visit.  
(Note that for patients planning to receive ET beyond Day 90, the Day 84 visit and the main 
study phase EOT visit will be combined into a single Day 84/EOS/EOT visit on approximately 
Day 90). 
6.3.1.3 
Bronchoscopic Assessment 
Bronchoscopy should be performed as clinically indicated, in accordance with local practice, and 
samples should be obtained for culture and histology/cytology testing during the same procedure. 
If bronchoalveolar lavage (BAL) samples are taken for local GM and PCR testing, additional 
aliquots must be obtained for shipping to the appropriate central laboratory. This applies for all 
respiratory samples taken up to the Day 84/Day 90 visit and the post-treatment FU visit, but 
samples for central laboratory assessment are not required during ET or at the post-ET visit. 
6.3.1.4 
Mycological Assessments and Responses 
Mycological criteria to be used for enrolment of patients are described in Appendix 2. 
Mycological assessments include culture, histology/cytology, GM (in the case of IA), PCR, and 
other mycology assessments depending on the IFD under study. Mycological assessments will be 
performed according to local practice using local laboratories and central laboratories up to the 
Day 84/Day 90 visit and the post-treatment FU visit, but samples for central laboratory 
assessment are not required during ET or at the post-ET visit.  
Samples to be assessed include those suitable for fungal culture and isolation and/or biopsy or 
biological fluid samples from the infected site for histology/cytology, GM, and PCR. For each 
sample obtained, an additional sample must be collected for shipment to the appropriate central 
laboratory.  
If available, baseline pathogen isolates, tissues, or biological fluid samples associated with the 
IFD will be stored and shipped to the appropriate central laboratory for confirmation of infection, 
identification of the fungal species, and susceptibility testing. Any available pre-study (baseline) 
isolates, tissues, or biological fluid samples should be shipped regardless of date of collection 
relative to study initiation. If infection is due to multiple fungi, relevant isolates, tissues, or 


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biological fluid samples for all infecting species should be shipped. Materials relating to yeast 
isolates do not need to be shipped. 
*If it is not possible to send isolates, tissues, or biological fluid samples to confirm the EORTC 
classification, where available, relevant digital images should be submitted to the appropriate 
central laboratory for review. If there are no isolates, samples or images available for shipment to 
the central laboratory, local laboratory reports confirming the EORTC criteria will be used to 
support the EORTC classification. Local laboratory report details documenting the EORTC 
classification for ALL patients should be submitted to the eCRF. 
If the identities of the pathogens differ between the central and local laboratories, the central 
laboratory results will take precedence over the local results for all study purposes. 
Guidelines for collection, culture and shipping of fungal isolates and handling of other samples 
(for GM and PCR) will be provided in the Central Laboratory Manual.  
The results of all mycological assessments performed during the study will be recorded in the 
eCRF. 
Culture: Isolates obtained by culture should be sent to central laboratory testing. Please refer to 
the laboratory manual for shipping details for fungal cultures as shipping details vary depending 
on the organism under study. Considerations for culture include: 
• Suitable samples for fungal culture and isolation (blood/CSF/tissue cultures). 
• Follow-up culture samples from non-bloodstream infections, if obtained, results should be 
recorded. 
• For outcome assessment of fungal blood stream infections, confirmed (two consecutive) 
negative blood cultures are required. 
• All isolates should be identified to species level.  
• Biopsy/biological fluid samples from the infected site for histology and cytology. 
• If patient has LRTD and is able to produce sputum, samples should be sent for culture and 
histology / cytology. 
All baseline and main study phase EOT isolates will be stored and shipped for central retesting. 
Due to the nature of the relevant infections, baseline isolates may include cultures collected 
weeks or months before enrolment. The central laboratory results will be considered definitive. 
Galactomannan Antigen: Galactomannan (GM) is a cell wall polysaccharide component of 
Aspergillus species that can be detected in serum samples using an immune-enzymatic sandwich 
micro-plate assay (Platelia™ Bio-Rad assay), with results expressed as an optical density index. 
This assay has been approved by the FDA, with a serum GM index of ≥1.0 or two consecutive 


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values each of ≥0.5 (i.e., from 2 separate blood draws) as the cut off for positivity. Further details 
of the criteria relating to GM values and the restrictions that should be applied in relation to this 
assay are provided in Appendix 2.  
All sites with the capability to perform serum GM testing locally should split samples for serum 
GM analysis into 2 aliquots, and send 1 aliquot for local testing and 1 aliquot to the appropriate 
central laboratory for testing. These specimens will have the same date and time of collection 
noted in the eCRF. 
For all patients with IA, GM testing must be conducted 
 
. If 
Screening and Day 1 occur on the same day 2 serum GM samples should be obtained pre-dose, at 
least 1 hour apart. Screening GM samples must be taken within 10 days prior to the first dose of 
study drug. Local laboratory results of serum GM obtained within 10 days prior to the first dose 
of study drug may be used to support the ‘probable IA’ eligibility criteria and must be reported in 
the eCRF. 
BAL GM (Aspergillus only): Values ≥1.0 (2 aliquots of the same sample should be tested) will be 
assessed as a positive result for Probable LRTD IA. Culture and histology must be obtained from 
the same sample and serum GM must be obtained in accordance with the protocol. Plasma-
LyteTM (Baxter) may not be used as the lavage fluid. 
Polymerase Chain Reaction Assay: The polymerase chain reaction (PCR) assay is widely used 
as a diagnostic tool in clinical laboratories as an aid in the diagnosis of IFD. When diagnosis of 
the pre-study fungal infection is based on or supported by PCR findings, additional samples must 
also be provided for PCR testing by the appropriate central laboratory. 
CSF Findings for Coccidioidomycosis Patients:  
a. The analysis of CSF is widely used as a diagnostic tool in clinical laboratories as an aid in the 
diagnosis of Coccidioidomycosis. Further details of the criteria relating to CSF testing for 
study entry are provided in Appendix 2.  
b. When diagnosis of the pre-study fungal infection is based on or supported by CSF findings, 
additional samples collected during the study must also be provided for CSF serology testing 
by the appropriate central laboratory. If baseline samples are not available for shipment to the 
appropriate central laboratory, patient eligibility will be based on local laboratory findings. 
c. Even if local CSF coccidioidal serodiagnostic testing is available, an aliquot should be 
shipped to the appropriate central laboratory for testing. These specimens will have the same 
date and time of collection noted in the eCRF. 
d. Other CSF findings supportive of a coccidioidomycosis diagnosis (e.g. protein elevation, low 
glucose etc.) will be collected and reported in the eCRF. 


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Mycological Response 
The Investigator will be asked to provide an assessment of the mycological response for each 
patient at Day 7, Day 42, Day 84/EOT and 4 weeks after EOT in the main study phase and at 
other visits as clinically indicated (note that for patients planning to receive ET beyond Day 90, 
the Day 84 visit and the main study phase EOT visit will be combined into a single Day 
84/EOS/EOT visit on approximately Day 90. ). Outside of these timepoints, mycological 
assessment will be performed as clinically indicated and/or in line with standard clinical 
management for the patient’s specific IFD and anatomic site involved. 
The Investigator will provide an assessment of the mycological response as follows: 
• 
Eradication (eradication of the original causative organism cultured or identified by 
histology/cytology at baseline and no emergence of new causative organisms at that visit). 
• 
Presumed eradication (missing documentation of the eradication of the original causative 
organism cultured or identified by histology/cytology at baseline and no documentation of 
emergence of new causative organisms at that visit plus resolution of all or some attributable 
clinical symptoms and physical findings of IFD present at baseline and/or of those that 
appeared at a subsequent visit and no appearance of new attributable clinical symptoms and 
physical findings of IFD at that visit). 
• 
Persistence (persistence of the original causative organism cultured or identified by 
histology/cytology at baseline or emergence of a new causative organism at that visit). 
• 
Presumed persistence (missing documentation of the persistence of the original causative 
organism cultured or identified by histology/cytology at baseline and no documentation of 
emergence of new causative organisms at that visit plus either (i) no resolution or (ii) 
worsening of any attributable clinical symptoms and physical findings of IFD present at 
baseline and/or of those that appeared at a subsequent visit and/or appearance of new 
attributable clinical signs and physical findings of IFD at that visit). 
• 
No mycological Follow-up results available, for whatever reason (no diagnostic test done at 
the scheduled timepoint AND other data are insufficient to support assigning Presumed 
Eradication or Presumed Persistence). 
• 
No mycological evidence at baseline (negative diagnostic test(s) results at baseline, or not 
done at baseline). 
Mycological Response after Initial Success 
If relevant mycology findings occur after successful mycological response (proven or presumed 
eradication), an evaluation will be made as to whether the infection is recurrent (same species as 
at baseline) or emergent (different species compared with baseline). Patients with recurrent or 


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emergent infection will be classified as mycological failure from the visit onwards where positive 
cultures were reported. 
Recurrent – Re-appearance of same species after apparent negative culture PLUS additional 
antifungal treatment becomes necessary. 
Emergent – Appearance of new species after apparent negative culture PLUS additional 
antifungal treatment becomes necessary. New species emerging during the first 7 days of therapy 
with F901318 are presumed to have been present at baseline and are classified as Baseline 
secondary infections rather than Emergent infections. 
6.3.1.5 
Investigator’s Assessment of Overall Response 
The Investigator’s assessment of overall response will be based on all available assessments 
(clinical, radiological and mycological) as described in Sections 6.3.1.1, 6.3.1.2 and 6.3.1.4. It is 
essential that the same methods and assessments are used to define the IFD diagnosis at baseline 
and to evaluate the response to treatment. 
Treatment “success” is defined as complete or partial. 
Treatment “failure” is defined as stable response or progression of IFD.  
Of the three components of overall response, only clinical and mycological responses are 
required. Patients who lack data at a visit (e.g., the visit data were not collected for some reason) 
or who are not evaluable at the visit because these data cannot be collected are considered 
failures. 
The criteria for assessment of overall response are summarised in Table 5: 


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Table 5 
Criteria for Assessment of Overall Response 
Success -
complete*: 
• 
Clinical: Meets criteria for Resolution-Complete; 
        AND 
• 
Radiological (if assessed): Shows resolution of radiological abnormalities (≥90% 
response); 
        AND 
• 
Mycological: Meets criteria for presumed or documented eradication. 
Success -
partial*: 
• 
Clinical: Meets criteria for Resolution-Complete or Resolution-Partial; 
        AND 
• 
Radiological (if assessed): Shows resolution or improvement of radiological 
abnormalities (at least 25% response); 
        AND 
• 
Mycological: Meets criteria for presumed or documented eradication. 
Failure -
stable: 
• 
Clinical: No improvement and no worsening of any attributable clinical 
symptoms and physical findings previously noted and no new attributable clinical 
symptoms or physical findings of IFD (Failure-Stable); 
        OR 
• 
Radiological: Shows no evidence of progression OR < 25% improvement of 
radiological abnormalities; 
        OR 
• 
Mycological: Had mycological evidence at baseline AND does not meet criteria 
for presumed or documented eradication. 
Failure -
progression: 
• 
Clinical: Either worsening of attributable clinical symptoms or physical findings 
of IFD or appearance of new attributable symptoms or findings of IFD (Failure-
Progression); 
        OR 
• 
Radiological: Worsening or new radiological abnormalities; 
        OR 
• 
Mycological: Has mycological evidence for a recurrent or emergent IFD, OR 
alternative systemic antifungal treatment required. 
*For these categories, the only required data are the clinical and mycological data. The absence 
of radiological evaluations at a given time point does not prevent assignment to Success-
Complete or Success-Partial. The rules defining success are tested in sequence with Success-
Complete assigned if its rules are met and Success-Partial otherwise assigned. 
6.3.2 
Survival 
All-cause mortality has been used historically as an endpoint in other similar clinical studies in 
IFD. All-cause mortality will be assessed using survival status and, if applicable, death details 
will be recorded in the eCRF. If the patient has died, the date and cause of death will be recorded, 
in addition to details required for SAE reporting (see Section 6.4.1.2). 
Survival status will be recorded at Day 42, main study phase EOT, Day 84 and at the 4-week FU 
and included in the CSR. Information on survival status on Days 42 and 84 will be collected in all 


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patients, irrespective of when treatment was discontinued (note that for patients planning to 
receive ET beyond Day 90, the Day 84 visit and the main study phase EOT visit will be combined 
into a single Day 84/EOS/EOT visit on approximately Day 90).  
Survival status will also be recorded at each ET visit and at the post-ET FU visit, and will be 
presented in the report addendum. 
6.3.3 
Data Review Committee Assessment of Overall Response 
Independent assessment of overall response during the main study phase will be performed by the 
DRC for visits up to Day 84/Day 90, and for the post-treatment FU visit for patients who do not 
receive ET. The DRC will not assess overall response at any ET visits or at the post-ET FU. 
Details of the process and overall response definitions will be documented in the DRC charter.  
6.3.4 
Patient-Reported Outcomes 
Patient-reported outcomes will be assessed in this study using the EQ-5D-5L questionnaire. The 
EQ-5D-5L questionnaire will be completed by the patient during screening to provide a baseline, 
at the Day 42 and Day 84/EOT main study phase visits, and every 4 weeks during the ET phase. 
The questionnaire, translated as required in the local language, will be distributed by the site staff 
but completed entirely by the patient. To ensure instrument validity and that data standards meet 
health authority requirements, the questionnaire should be self-administered and checked for 
completion at the site staff prior to the completion of other study assessments. 
6.4 
Safety 
The Investigator will evaluate safety by AE monitoring, physical examination, vital signs, 
laboratory tests, ECG, imaging and concomitant medication/surgery, as outlined in the Schedule 
of Assessments (Table 1 and Table 3). 
6.4.1 
Adverse Events 
The Investigator is responsible for recording all AEs observed during the study period (main 
study phase and ET phase) including 4-week post-treatment follow-up. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a preexisting condition (e.g., increase in its severity or 
frequency). An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study treatment. Lack of efficacy or insufficient clinical response should not be recorded as an 
AE. 


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Events which meet the definition of an AE include: 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should 
be reported regardless of sequelae. 
Events which do not meet the definition of an AE include: 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be 
more severe than expected for the patient’s condition. Changes in laboratory findings that 
fulfil the definition of an AESI must ALWAYS be reported as an AESI (AND as an SAE 
if any seriousness criteria are also met). 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence (whether considered to be related to study drug or 
not) that at any dose: 
• 
Results in death 


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• 
Is life-threatening (the patient is at a risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization: Hospital 
admissions and/or surgical operations planned before or during a study are not considered 
AEs if the illness or disease existed before the patient was enrolled in the study, provided that 
it did not deteriorate in an unexpected way during the study 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital abnormality/birth defect 
• 
Other: Medically significant events, which do not meet any of the criteria above, but may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other serious outcomes listed in the definition above. Examples of such events are blood 
dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion) or convulsions that do 
not result in hospitalization. 
An adverse drug reaction (ADR) is defined as any noxious and/or unintended response to a 
medicinal product related to any dose. 
An unexpected ADR is defined as any adverse reaction, the nature of which is not consistent with 
the applicable product information. The Reference Safety Information Section of the IB identifies 
expected ADRs.   
Each AE is to be evaluated for duration, severity, seriousness and causal relationship to the 
investigational drug. The action taken and the outcome must also be recorded. 
Adverse Events of Special Interest 
An AESI is defined as a serious or non-serious event of scientific and medical concern specific to 
the investigational product, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor is necessary.  
All AESIs will be recorded on the Adverse Event form in the eCRF, and in source documents. 
Any AESI which occurs during this study, whether or not related to the study drug, must be 
recorded in the electronic data capture (eDC) system within 24 hours of study staff becoming 
aware of the event. This entry into the eDC system will automatically trigger an e-mail alert to 
the Sponsor and to the MM. 
If for any reason it is not possible to record the AESI information electronically, i.e., the eCRF 
database is not functioning, record the AESI on the paper AESI reporting form and submit within 
24 hours as described above. 
As soon as it is possible to do so, any AESI reported via paper must be transcribed into the eCRF 
database according to instructions in the eCRF completion guidelines. 






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Relationship 
The causal relationship between the study drug and the AE has to be characterized as unrelated, 
unlikely, possible, probable or unknown (unable to judge).  
Events can be classified as “unrelated” if there is not a reasonable possibility that the study drug 
caused the AE. 
An “unlikely” relationship suggests that only a remote connection exists between the study drug 
and the reported AE. Other conditions, including chronic illness, progression or expression of the 
disease state or reaction to concomitant medication, appear to explain the reported AE. 
A “possible” relationship suggests that the association of the AE with the study drug is uncertain; 
however, the AE is not reasonably supported by other conditions. 
A “probable” relationship suggests that a reasonable temporal sequence of the AE with drug 
administration exists and, in the Investigator’s clinical judgment, it is likely that a causal 
relationship exists between the drug administration and the AE, and other conditions (concurrent 
illness, progression or expression of disease state or concomitant medication reactions) do not 
appear to explain the AE. 
All efforts should be made to classify the AE according to the above categories. The category 
“unknown” (unable to judge) may be used only if the causality is not assessable, e.g., because of 
insufficient evidence, conflicting evidence, conflicting data, or poor documentation. 
All AEs encountered during the clinical study will be reported in the eCRF. If possible, a 
diagnosis should be documented rather than a list of individual signs and symptoms. All AEs 
should be recorded in English. 
6.4.1.1 
Reporting of Adverse Events 
All AEs which occur after the patient has provided informed consent, regardless of severity and 
whether or not they occurred during study enrolment, treatment or follow-up, are to be recorded 
on the appropriate AE pages (either ‘serious’ or ‘non-serious’) in the eCRF. The Investigator 
should complete all the details requested including dates of onset, severity, action taken, outcome 
and relationship to study drug. Each event should be recorded separately. 
Each AE will be assessed to determine whether it meets seriousness criteria. If the AE is 
considered serious, the Investigator should record this event in the eDC system within 24 hours 
of becoming aware of the event. This entry into the eDC system will automatically trigger an e-
mail alert to the Sponsor and to the MM. 
An event may qualify for expedited reporting to regulatory authorities if it is an SAE, unexpected 
per reference safety information and considered related (Suspected Unexpected Serious Adverse 
Reaction [SUSAR]) in line with relevant legislation. All Investigators will receive a safety letter 


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notifying them of relevant SUSAR reports. The Investigator should notify the Ethics Committee 
as soon as is practical, of serious events in writing where this is required by local regulatory 
authorities, and in accordance with the local institutional policy. 
Any SAE, including death due to any cause, which occurs during this study, whether or not 
related to the study drug, must be reported immediately (within 24 hours of the study centre’s 
knowledge of the event) in the eCRF. The report will contain as much available information 
concerning the SAE to enable the Sponsor (or an authorized representative) to file a report, which 
satisfies regulatory reporting requirements.  
If for any reason it is not possible to record the SAE information electronically, i.e., the eCRF 
database is not functioning, record the SAE on the paper SAE reporting form and submit within 
24 hours as described above. 
— As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF database according to instructions in the eCRF completion guidelines. 
— If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. 
Paper CRF reports are to be submitted by telephone or fax to the Sponsor (or an authorized 
representative). Contact details for submitting paper CRF SAE reports will be provided to each 
site, including telephone number, fax number, and an e-mail address. 
In addition to the initial 24-hour report, additional information is required to be added to the 
eCRF or a paper report sent to the Sponsor (or an authorized representative) via fax or mail 
within 48 hours of the event. These timelines apply to initial reports of SAEs and to all follow-up 
reports. 
All SAEs will be recorded on the SAE Report form, the Adverse Events form in the eCRF, and 
source documents. Criteria for documenting the relationship to study drug as well as severity and 
outcome will be the same as those previously described.  
All SAEs that are spontaneously reported within 30 days of a patient's last visit (EOS visit) are to 
be collected and reported as previously described. 
The information must include the following as a minimum: 
• 
Name, address and telephone number of the reporting Investigator. 
• 
Investigational product and study code. 
• 
Patient identification number, initials, sex and date of birth. 
• 
Description of the AE, measures taken and outcome. 


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• 
Preliminary classification of causal relationship by the Investigator.  
In the case of fatal or life-threatening events, the Investigator should immediately telephone the 
Sponsor’s Safety Surveillance and Reporting Unit (or an authorized representative). Contact 
details will be provided to the site. Additional follow-up information should be completed on an 
SAE follow-up form with a copy sent to the Sponsor (or an authorized representative) and the 
original placed in the SAE section of the eCRF binder. 
6.4.1.2 
Reporting of Serious Adverse Events to Regulatory Authorities and Investigators 
Investigators will be notified by the Sponsor (or an authorized representative) of all SAEs that 
require prompt submission to their Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC). Investigators should provide written documentation of IRB/IEC notification 
for each report to the Sponsor (or an authorized representative). The Sponsor (or authorized 
representative) will ensure that all SAEs are reported to the appropriate regulatory authorities 
within the required timelines. 
Any hepatic AESI which meets biochemical Hy’s Law criteria (i.e. ALT/AST > 3x ULN and 
total bilirubin > 2x ULN) or has transaminase elevations which meet CTCAE criteria grade 4 (i.e. 
ALT/AST> 20 x ULN), must be reported as a medically signficant SAE, regardless of causality. 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
treatment under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB)/IEC, and Investigators. 
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
A suspected unexpected serious adverse reaction is known as a SUSAR. The SUSAR, SAEs and 
other cases required by the concerned competent authorities will be reported by the Sponsor or 
the Sponsor’s representative to all concerned parties within the prescribed timeframe. The 
Sponsor or representative will also submit periodic safety reports (e.g. Development Safety 
Update Reports) as required by international regulations. 


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6.4.1.3 
Follow-up of Adverse Events 
Any AEs observed from the date of informed consent up to the EOS will be followed up to 
resolution. Resolution means that the patient has returned to a baseline state of health or the 
Investigator does not expect any further improvement or worsening of the AE. All AEs that occur 
after the patient completed a clinical study (within 30 days of the last dose of study drug) should 
also be reported to the Sponsor (or an authorized representative). 
For hepatic AESIs, even though the AE may appear to have resolved, a longer follow-up may be 
requested by the HAC, in which case results of additional blood samples (analysed in a local 
laboratory for liver biochemistry) and other relvant clinical data will be collected and provided to 
the HAC for review. 
For patients receiving ET, all AEs will be followed up to resolution. 
6.4.1.4 
Procedures for Documenting Pregnancy During Study 
Patients who are pregnant or expect to become pregnant during the course of the study will be 
excluded from participation in the study. Should a patient become pregnant after enrolling in the 
study, the Investigator will report this event to F2G or its designee within 24 hours and to the 
IRB/EC. No embryotoxicity or teratogenicity associated with F901318 treatment has been 
detected in the rat or rabbit. Nonetheless, as a new molecular entity, F901318 should not be given 
to pregnant women unless the benefit clearly outweighs the risk. The Investigator should consult 
with the MM to review any available new or supplemental information. The Investigator should 
then counsel the patient and discuss risks of continuing or discontinuing therapy with F901318, 
risks of continuing with the pregnancy and the possible effects on the foetus. Sites must request 
the patient’s permission to query pregnancy outcome and follow each patient to determine the 
outcome of the pregnancy.  
Results will be summarized in the CSR. 
Patients who become pregnant at any point during the study (including during ET) should 
continue to be followed for safety assessments whether or not the patient is receiving further 
study treatments. Procedures that are contraindicated during pregnancy must not be performed. 
Investigators should use clinical judgment regarding subsequent study-related blood collection 
based on the presence or absence of anaemia in each patient. Patients who are not withdrawn 
from the study should continue to be followed for safety assessments to study discharge per 
protocol. 
All pregnancies that occur from the time of the first screening procedure through the follow-up 
visits must be reported. Monitoring of the patient and the outcome of the pregnancy should be 
followed by the Investigator. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to F2G. 


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Male patients will be instructed through the Informed Consent Form to immediately inform the 
Investigator if their partner becomes pregnant until the end of follow-up period. A Pregnancy 
Form should be completed by the Investigator and submitted to the Sponsor within 24 hours after 
learning of the pregnancy. Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to Study Treatment. The 
pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy. Once the authorization has been signed, the 
Investigator will update the Pregnancy Form with additional information on the course and 
outcome of the pregnancy. 
An Investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the foetus, to support an 
informed decision in cooperation with the treating physician and/or obstetrician. 
The Investigator will follow the medical status of the mother, as well as the foetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor. 
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried foetus)], the Investigator should respond in accordance with the report procedure for 
SAEs. Additional information regarding the outcome of a pregnancy (which is categorized as an 
SAE) is outlined below: 
• 
“Spontaneous abortion" includes abortion and missed abortion 
• Death of infant within 1 month after birth regardless of its relationship with study drug 
• If infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the Investigator 
• In case of a delivery of a living newborn, the "normality" of the infant is evaluated at birth 
• 
"Normality" of the miscarried foetus is evaluated by visual examination unless test results 
which indicate a congenital anomaly are obtained prior to miscarriage. 
Progression of Disease under Study 
Progression of disease under study (i.e. the qualifying fungal infection) will not constitute an AE. 
However, if the progression of disease leads to a serious outcome, such as death, this will be 
reportable within the same timeframe using the same format as for an SAE. 
6.4.2 
Clinical Laboratory Evaluations 
The laboratory safety tests include haematology, biochemistry and urinalysis (including urine 
dipstick for protein and blood). Samples for the full clinical laboratory evaluation will be 
collected at as outlined in Table 1.  


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All blood samples for laboratory safety testing will be collected in the morning prior to 
administration of study drug and sent to the appropriate central laboratory where the testing will 
be performed. 
In accordance with local practise, a duplicate sample will be taken and sent to a local laboratory 
for testing.  
At Screening, local laboratory testing will be performed to determine patient eligibility. 
Laboratory tests for Screening should be obtained as close to the time of enrolment as possible. A 
list of clinical laboratory tests is provided in Table 7. 
Table 7 
List of Clinical Laboratory Tests 
Serum Biochemistry  
Albumin 
Creatininea 
Alkaline phosphatase 
Gamma glutamyltransferase 
Alanine aminotransferase 
Glucose (non-fasted)b 
Aspartate aminotransferase 
Potassium 
Bilirubin (total and direct) 
Prothrombin time and activated Partial Thromboplastin Timec 
Calcium 
Sodium 
Chloride 
Urea 
Creatine phosphokinase 
β-human chorionic gonadotropin in female patients  
(if applicable) 
Haematology  
Absolute neutrophil countd 
Platelet count 
Haemoglobin 
Red blood cells 
Haematocrit 
White blood cells and differential count  
(absolute values and percentages) 
a) 
For assessment of creatinine clearance. 
b) 
Non-fasted is preferred and must be used consistently in each patient.  
c) 
To be measured at baseline and Day 28, 56 and 84 or withdrawal and at the visits every 4 weeks for patients who receive ET. 
d) 
For assessment of neutropenic status (see Section 6.4.2.2). 
 
Samples of urine will be collected and analysed locally. Analysis of urine samples includes the 
dipstick for pH, glucose, blood and protein, and microscopic examination of sediment if dipstick 
test results are positive or strongly positive for blood or protein. 
Clinical laboratory tests will be reviewed for results of potential clinical significance at all 
timepoints throughout the study. The Investigator will evaluate any change in laboratory values. 
 
. If the Investigator determines any other 
laboratory abnormality to be clinically significant, it is considered a laboratory AE and reported 
as an AE in the eCRF; however, if the abnormal laboratory value is consistent with a current 
diagnosis, it may be recorded accordingly in source documents but should not be reported in the 


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eCRF. Where appropriate descriptions have been developed, changes in laboratory test values 
will be assigned CTCAE severity grades, in accordance with National Cancer Institute (NCI) 
CTCAE version 5.0.  
Details of central laboratory reference ranges, sample handling and shipment will be provided in 
the Laboratory Manual. 
6.4.2.1 
Creatinine Clearance 
At Screening, creatinine clearance will be calculated by the laboratory according to the 
Cockcroft-Gault formula, as shown below. 
Creatinine 
clearance 
(mL/min) 
= 
(140 – age [years]) x body 
weight (kg) 
× 
Gender correction 
factor 
(male: 1.00; 
female: 0.85) 
Plasma creatinine (mg/dL) x 72 
 
6.4.2.2 
Neutropenic Status 
Neutropenic status relating to the study-qualifying infection should be recorded, regardless of the 
time prior to study drug administration. Neutropenic status will be recorded for all patients for the 
period within 4 weeks prior to the screening visit. In addition, neutropenic episodes supporting 
the Host Factor criteria of “Neutropenia” related to the study-qualifying infection should be 
recorded, regardless of the time prior to study drug administration. Neutropenic status will be 
recorded throughout the main study phase and 4-week FU, and throughout the ET phase and 
post-ET FU for those patients who receive ET. 
Absolute neutrophil count (ANC) will be used to determine neutropenic status, with neutropenia 
defined as ANC < 0.5 × 109/L [< 500/mm3]. The presence or absence of neutropenia and 
subsequent persistence or resolution (resolution defined as consecutive ANC values > 0.5 × 109/L 
on two separate days) will be determined from the ANC values recorded in the eCRF. 
All ANC values obtained (or calculated) at local laboratories during a neutropenic episode must 
be recorded in the eCRF with the corresponding sample dates. When differentials cannot be 
performed due to insufficient white blood cells (WBCs), the total WBC value must be recorded 
for that day in the eCRF. 
6.4.2.3 
Liver enzymes and bilirubin 
The Liver Biochemistry Management Algorithm (Appendix 3) provides guidance on the 
management of patients in the event that certain thresholds are met relating to increased levels of 
liver enzymes and/or bilirubin. 


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Whether taken as a protocol-scheduled sample as outlined in Table 1 
 
 samples for assessments of liver 
enzymes and bilirubin are to be taken as duplicate samples with 1 sample to be sent to the 
appropriate central laboratory and 1 sample to be sent to the local laboratory. Samples taken 
during ET will be sent only to the local laboratory. 
Patients must report immediately to the Investigator if there is onset of otherwise unexplained 
nausea, jaundice, right upper abdominal pain, fever, or rash, and a Full Liver Panel assessment 
must be conducted. 
6.4.3 
Vital Signs, Physical Findings and Other Safety Assessments 
6.4.3.1 
Vital Signs 
Assessments will comprise: systolic blood pressure (mmHg), diastolic blood pressure (mmHg), 
pulse rate (beats per minute), respiratory rate and body temperature (C° or F°). Body temperature 
should be measured by the same method throughout the study. Vital signs will be assessed at the 
timepoints shown in Table 1, and the method (supine, sitting, or standing) should be consistently 
used for the same patient and will be recorded in the eCRF. During the study treatment period, 
vital signs will be assessed prior to study drug intake.  
Body weight will be recorded
 
 (note that for patients 
who will receive ET beyond Day 90, the Day 84 visit and the main study phase EOT visit will be 
combined into a single Day 84/EOS/EOT visit on approximately Day 90 and there will be a FU 
visit 4 weeks after the last dose of F901318). 
No vital signs assessments will be recorded during ET, unless clinically indicated or associated 
with an AE. 
6.4.3.2 
Physical Examination 
A physical examination should be conducted at the timepoints shown in Table 1 and at any other 
time during the study when clinically indicated, as determined by the Investigator. The following 
body systems/areas should be examined: head, eyes, ears, neck, trunk, respiratory, 


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cardiovascular, gastrointestinal, musculoskeletal, neurological, endocrine/metabolic, 
lymphatic/haematologic, dermatological, psychological, genitourinary and other (to be specified). 
Any new abnormalities or worsening of existing abnormalities must be recorded in the eCRF as 
AEs.  
Physical examination will not be recorded during ET, unless clinically indicated or associated 
with an AE. 
6.4.3.3 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) recording will be obtained at the timepoints shown in Table 
1. For patients receiving study drug (i.e., Day 1 onwards), the ECG assessment should be 
conducted between 30 minutes and 4 hours after oral dosing. All patients must also have an ECG 
at the main study phase EOT. At the Post-treatment Follow-up visit, ECG recordings will only be 
required for patients with abnormalities observed at the main study phase EOT. 
Each abnormality observed on ECG must be reported and, if not related to the underlying disease, 
must be confirmed as clinically not significant or repeated at intervals determined by the 
Investigator until they return to baseline levels. Abnormalities should be reported as AEs in the 
eCRF only if they result in a clinically relevant condition, as determined by the Investigator. Each 
ECG recording is to be signed and dated by the Investigator or his designee. 
Additional monitoring may be required if a QT-prolonging medication is initiated during the 
course of the study. See Section 5.9.1.1 for details. 
Study-related ECGs are not required during ET, unless clinically indicated or associated with an 
AE. 
6.4.3.4 
 
 
 
 
 
  
 
 
 
6.4.4 
Safety Monitoring 
6.4.4.1 
Independent Data and Safety Monitoring Board 
An IDSMB consisting of members who are independent from the Sponsor will be established. 
The IDSMB will have at least 3 members. The IDSMB will be responsible for reviewing 


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outcomes, AEs and F901318 trough concentrations. The IDSMB will also review safety data for 
patients receiving ET. The first IDSMB meeting will be held after approximately 8 patients have 
completed treatment. The frequency of subsequent meetings will be decided by the IDSMB, but 
will be not less than every 6 months. The IDSMB may also meet in ad hoc meetings at its 
discretion as needed in response to events occurring in the study. Additional responsibilities for 
the Committee include confirmation of the safety and appropriateness of the selected dosing 
regimen. After each meeting, the IDSMB will recommend that the study can continue, or may 
recommend changes to the study or stopping the study. 
Details of the membership and responsibilities of the IDSMB will be included in the IDSMB 
Charter. 
6.4.4.2 
Data Review Committee 
A DRC will be responsible for independent assessment of study data (see Section 8.13 for further 
details). 
6.4.4.3 
Hepatic Safety Review  
The hepatic-specific safety data from the Main Study Phase and from the Extended Treatment 
Phase of the study will be subject to review and surveillance: 
• Narratives will be prepared for all hepatic AESIs (regardless of Investigator-assigned 
causality) which are subject to expedited review by the HAC. 
• An Integrated Hepatic Safety Summary (a summary of hepatic safety across the entire 
clinical program) will be prepared at appporiate intervals for review by the HAC who will 
recommend, from a hepatic safety perspective, whether the study can continue or whether 
changes to the study are required. This report will also be provided to the IDSMB. 
6.5 
Pharmacokinetics (PK) and Rapid Trough Sample Analysis 
Pharmacokinetics 
Sampling for pharmacokinetic (PK) analysis will be performed in all patients.  
The date and time of all blood sample collections for PK (Trough and Intensive PK) will be 
recorded in the eCRF. The date and time of the dose and meal given prior to each trough PK 
sample (scheduled and unscheduled) and prior to the start of intensive PK sampling, and 
date/time of any meals given during the Intensive PK sampling will also be recorded in the CRF. 
Full details regarding sample labelling, handling, shipping and storage will be outlined in the 
study laboratory manual.  
A total of 3 categories of PK samples will be taken as follows: 


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1. Trough PK Analysis 
Samples for trough PK analysis will be taken within 15 minutes prior to the observed 
F901318 dose 
 
 
The dose selected on each visit can be at the Investigator discretion. Samples 
will be split into 2 aliquots with 1 aliquot shipped to the regional hub for rapid trough PK 
analysis and 1 aliquot shipped to the appropriate central laboratory. For patients proceeding to 
ET, the Day 84 and main study phase EOT trough PK samples will be combined into a single 
trough sample at the time of the final visit for the main study phase. A sample for trough PK 
analysis will also be taken every 4 weeks during ET and shipped to the regional hub for rapid 
trough PK analysis. 
2. Intensive PK Analysis 
Samples for assessing the PK profile of F901318 
 will be 
evaluated in detail (Intensive PK) on 
 
 
Timing of samples is relative to the oral dose. Recent (within the previous 7 days) and 
current concomitant medications will be fully documented to permit analysis of potential 
DDIs. These samples will be shipped to the appropriate central laboratory.  
3. Unscheduled Trough PK Analysis  
Unscheduled Trough PK samples may be collected as needed in discussion with the MM 
(e.g., to evaluate drug-drug interactions). Trough samples will be taken within 15 minutes 
prior to an observed dose. These samples will be split into 2 aliquots with an aliquot shipped 
to (a) the regional hub for rapid trough PK analysis and (b) the appropriate central laboratory.  
Samples shipped to the regional hub for rapid trough PK analysis (Scheduled and Unscheduled 
Trough PK samples) will be tested for F901318 alone. All PK samples (Scheduled and 
Unscheduled Trough PK, Intensive PK) will be shipped to the appropriate central laboratory and 
will be tested for both F901318 
 
Rapid trough PK analysis:  
Regional hubs will set up by the Sponsor for the rapid analysis all predose PK samples for 
F901318 (both Scheduled and Unscheduled). Dose adaptations may only be made in consultation 
with the MM when concomitant medications are required and the Investigator suspects there may 
a risk of a clinically relevant DDI or when the Investigator believes there may be sub-optimal 
therapeutic response with the current dose or where elevated liver function results suggest a dose 
reduction is appropriate. Permitted and excluded concomitant medications are defined in the 
protocol. 
Concomitant Medications:  


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PK sampling requirements when F901318 is given concomitantly with either a sensitive CYP3A 
substrate, a CYP3A inducer, a CYP3A inhibitor or other antifungal medication are detailed in 
Section 5.9.1.4.  
6.6 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
6.7 
Appropriateness of Measurements 
The primary endpoint of overall response is a combined measure of efficacy assessments to 
evaluate the use of F901318 in the treatment of IFD in patients with no alternative treatment 
options. It reflects the general clinical approach to the treatment of IFD. 
Other assessments, such as measures to evaluate disease progression and all-cause mortality are 
standard outcome criteria, which are accepted to demonstrate efficacy and treatment response in 
IFD. In addition, independent assessment of overall response and measurement of drug 
concentration will support the efficacy and safety analyses. 
The EQ-5D-5L is a validated questionnaire to evaluate the effect of treatment on the patients 
quality of life, and will provide additional insight into the benefit profile of F901318. 


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7.0 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the Guidelines of GCP (CPMP/ICH/135/95), the Sponsor is responsible for 
implementing and maintaining quality assurance and quality control systems with written 
Standard Operating Procedures (SOPs). For this study, many of these responsibilities are 
delegated to a CRO, 
. 
Quality control will be applied to each stage of data handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• 
Investigator meetings 
• 
Central laboratories for analysis of clinical laboratory parameters and plasma levels of 
F901318 
 
• 
Central reading of radiological images 
• 
Independent review of safety data by IDSMB 
• 
Independent adjudication of eligibility and response data by a DRC 
• 
Centre Initiation visit 
• 
Early centre visits post-enrolment 
• 
Routine centre monitoring 
• 
Ongoing centre communication and training 
• 
Data management quality control checks 
• 
Continuous data acquisition and cleaning 
• 
Internal review of data 
• 
Quality control check of the final CSR. 
Protocol deviations will be identified as soon as possible by the site, the on-site clinical monitor, 
the MM and the data management team. While every effort should be made to avoid protocol 
deviations, should a deviation be discovered, Sponsor must be informed. Any protocol deviation 
impacting Patient safety must be reported to the MM immediately and to the Sponsor. 
The Investigator should not implement any deviation from or changes to the protocol without 
approval by Sponsor and prior review and documented approval/favourable opinion from the IRB 
of a protocol amendment, except where necessary to eliminate immediate hazards to study 


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patients, or when the changes involve only logistical or administrative aspects of the study (e.g., 
change in monitors, change of telephone numbers). 
In addition, Sponsor and/or 
Clinical Quality Assurance (CQA) Department may conduct 
periodic audits of the study processes, including, but not limited to, study centre, centre visits, 
central laboratories, vendors, clinical database and final CSR. When audits are conducted, access 
must be authorised for all study-related documents including medical history and concomitant 
medication documentation to authorised Sponsor’s representatives and regulatory authorities. 
7.1.1 
Monitoring 
The Sponsor has engaged the services of a CRO, 
 to perform all monitoring functions 
within this clinical study. The monitoring service applies to all study visits, including the ET 
visits and post-ET FU. 
monitors will work in accordance with 
 SOPs and have 
the same rights and responsibilities as monitors from the Sponsor organisation. Monitors will 
establish and maintain regular contact between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each study centre, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study, monitors 
will check that written informed consent has been obtained from all patients correctly and that 
data are recorded correctly and completely. Monitors are also entitled to compare entries in 
eCRFs with corresponding source data and to inform the Investigator of any errors or omissions. 
Monitors will also check and ensure adherence to the protocol at the study centre. They will 
arrange for the supply of investigational product and ensure appropriate storage conditions are 
maintained. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards. Regular monitoring visits will be made to each centre while patients are enrolled in the 
study. The monitor will make written reports to the Sponsor on each occasion contact with the 
Investigator is made, regardless of whether it is by phone or in person. 
During monitoring visits, all entries in the eCRFs will be compared with the original source 
documents (source data verification).  
7.1.2 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the 
Data Management and Biostatistics departments 
.  
Electronic Data Capture will be used for this study, meaning that all eCRF data will be entered in 
electronic forms at the study centre. Data collection will be completed by authorised study centre 
staff designated by the Investigator. Appropriate training and security measures will be 
completed with the Investigator and all authorised study centre staff prior to the study being 
initiated and any data being entered into the system for any study patients. 


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All data must be entered in English. The eCRFs should always reflect the latest observations on 
the patients participating in the study. Therefore, the eCRFs are to be completed as soon as 
possible during or after the patient’s visit. To avoid inter-observer variability, every effort should 
be made to ensure that the same individual who made the initial baseline determinations 
completes all efficacy and safety evaluations. The Investigator must verify that all data entries in 
the eCRFs are accurate and correct. If some assessments are not done, or if certain information is 
not available or not applicable or unknown, the Investigator should indicate this in the eCRF. The 
Investigator will be required to electronically sign off on the clinical data. 
The monitor will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections and alterations are to be made by the responsible 
Investigator or his/her designee. The monitor cannot enter data in the eCRFs. Once clinical data 
of the eCRF have been submitted to the central server, corrections to the data fields will be audit 
trailed, meaning that the reason for change, the name of the person who performed the change, 
together with time and date will be logged. Roles and rights of the study centre staff responsible 
for entering the clinical data into the eCRF will be determined in advance. If additional 
corrections are needed, the responsible monitor or Data Manager will raise a query in the eDC 
application. The appropriate study centre staff will answer queries sent to the Investigator. This 
will be audit trailed by the eDC application, meaning that the name of investigational staff, time 
and date stamp are captured. 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used by 
the Investigator or hospital that relate to the patient’s medical history, that verify the existence of 
the patient, the inclusion and exclusion criteria and all records covering the patient’s participation 
in the study. They include laboratory notes, ECG results, memoranda, pharmacy dispensing 
records, patient files, etc. 
The Investigator is responsible for maintaining source documents. These will be made available 
for inspection by the study monitor at each monitoring visit. The Investigator must submit a 
completed eCRF for each patient who receives study drug, regardless of duration. All supportive 
documentation submitted with the eCRF, such as laboratory or hospital records, should be clearly 
identified with the study and patient number. Any personal information, including patient name, 
should be removed or rendered illegible to preserve individual confidentiality. 
Electronic CRF records will be automatically appended with the identification of the creator, by 
means of their unique UserID. Specified records will be electronically signed by the Investigator 
to document his/her review of the data and acknowledgement that the data are accurate. This will 
be facilitated by means of the Investigator’s unique UserID and password; date and time stamps 
will be added automatically at time of electronic signature. If an entry on an eCRF requires 
change, the correction should be made in accordance with the relevant software procedures. All 


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changes will be fully recorded in a protected audit trail, and a reason for the change will be 
required. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medications will be coded using the World Health Organisation Drug dictionary. 
Concomitant diseases/medical history will be coded using MedDRA. 
7.1.3 
Quality Assurance Audit 
Study centres, the study database and study documentation may be subject to Quality Assurance 
audit during the course of the study by the Sponsor 
 on behalf of F2G. In addition, 
inspections may be conducted by regulatory bodies at their discretion. 


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8.0 STATISTICS 
This is a single-arm open-label, Phase IIb study, and there is no requirement for the Biostatistics 
Team responsible for the final analysis to be blinded to treatment allocation, nor for a separate, 
independent Biostatistics Team to provide data on an ongoing basis for IDSMB review. 
Data collected in the main study phase up to Day 84/Day 90 and the subsequent 4-week FU visit 
will be included in the data analyses and presented in the CSR. Data collected during ET will not 
be included in the data analyses for the CSR, and will be presented in the report addendum. 
8.1 
Determination of Sample Size 
This is a single-arm, open-label, Phase IIb study, with no randomization. Four proven invasive 
fungal infection enrolment categories (disease categories) are defined and there is no upper limit 
to the enrolment of patients within each culture-proven category. 
 
 
. Total enrolment into the study is anticipated to be 
approximately 200 patients. Given the challenges of recruiting this patient population and the fact 
that a control arm is not possible in patients with no treatment options, no formal sample size 
justification is possible. However, it is important to gain as much information as possible to 
support the treatment of these difficult to treat patients whilst randomized controlled data is also 
being collected in another trial.
 
 
 The efficacy, safety, tolerability and PK of 
F901318 will be compared in a pre-planned superiority comparison with external control data 
from the literature and from recent patient databases. 
F901318 has been granted Breakthrough Therapy Designation based on preliminary clinical 
evidence that demonstrates that F901318 may provide substantial improvement over available 
therapy. As this designation is intended to expedite the development and review of important 
products, an initial analysis of data will be performed when the first 100 patients have completed 
treatment to enable the Sponsor to formally consider the possibility that initial approval might be 
achievable based on these data for the population of patients with limited or no treatment options 
for life-threatening fungal infections. 
 
 
The efficacy, safety, tolerability and PK of F901318 will be compared with external data 
generated from a pre-specified plan for matched cases from the 
 
  


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8.2 
Statistical Methods 
8.2.1 
General Considerations 
Full details of all analyses and data presentations to be performed will be documented in the 
Statistical Analysis Plan (SAP). Further, the SAP will include details of the initial analysis and 
final analysis which will compare the data from this study to the external control data. 
Analyses will generally be descriptive in nature with data presented overall and by DRC-
adjudicated disease category using appropriate summary statistics. Categorical data will be 
described using absolute and relative frequencies (n and %). Continuous data will be presented 
using descriptive statistics (n, mean, standard deviation, minimum, median, and maximum).  
Summary statistics will be presented for observed data only. If a Baseline value is missing, no 
change from Baseline will be calculated. Missing data will be presented as part of a “Missing” 
category or statistic, if relevant. 
Baseline is defined as the last non-missing (scheduled or unscheduled) assessment up to and 
including Day 1 prior to the first administration of study drug. End of Treatment in the main 
study phase is defined as the last assessment (scheduled or unscheduled) assigned to treatment, 
The EOS in the main study for each patient is defined as the last assessment (scheduled or 
unscheduled) assigned to the study which that patient completes. For patients receiving ET with 
F901318, EOS and EOT will be the same visit and will occur at approximately Day 90. 
Relevant raw and derived variables will be listed in individual by-patient data listings, sorted by 
DRC-adjudicated disease category, region, centre and patient number.  
Data on key endpoints may be summarised separately for the group requiring ET and those who 
do not require ET. Detail of these presentations will be provided in the SAP. 
A sub-group for consideration will be patients receiving extended treatment beyond Day 90. 
Details on sub-group analyses will be provided in the SAP. 
All analyses and data presentation will be performed using SAS® software (Version 9.3 or 
higher). 
Further details of the statistical analysis methods will be provided in the detailed SAP and Tables, 
Lists and Figures Shells. 
8.2.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the DRC-adjudicated overall response at Day 42 as 
determined by an independent DRC using a combination of clinical, mycological and radiological 
results and will be presented overall and by each of the five DRC-adjudicated disease categories 
as:  


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• Success 
• Failure (where failure includes those patients for whom data at Day 42 cannot be 
collected or who are considered not evaluable at Day 42) 
The criteria for assessment and categorisation of the DRC-adjudicated overall response will be 
detailed in the DRC Charter and subsequently specified in the detailed SAP. 
Patients withdrawn from study drug due to an unsuccessful overall outcome are required per 
protocol to return for the main study phase EOT visit but will not be asked to return for the 
Day 42 and/or Day 84 visits; however, these patients will be considered as failures at all 
subsequent timepoints. 
8.2.3 
Secondary Efficacy Endpoints 
• DRC-adjudicated overall response (overall and by DRC-adjudicated disease category) at 
Day 7, Day 14, Day 28, main study phase EOT, Day 84 and 4-week FU* (as determined by 
an independent DRC using a combination of clinical, mycological and radiological results) 
categorised as: 
o Success 
o Failure 
 
• Investigator-assessed overall response (overall and by DRC-adjudicated disease 
category as determined by Investigator using all available assessment results including 
clinical, mycological and radiologic results) at Day 7, Day 14, Day 28, Day 42, main study 
phase EOT, Day 84 and 4-week FU* will be categorized as: 
o Success 
o Failure (where failure includes those patients with missing clinical responses 
or considered not evaluable) 
• DRC-adjudicated and Investigator-assessed clinical response overall and by DRC-
adjudicated disease category at Day 7, Day 14, Day 28, Day 42, main study phase EOT, Day 
84 and 4-week FU* will be categorised as: 
o Success (categories of Resolution-Complete and Resolution-Partial) 
o Failure (categories of Failure-Stable, Failure-Progression, and Results not 
available) 
 
• Where appropriate for the IFD, DRC-adjudicated and Investigator-assessed radiological 
response at Day 7, Day 14, Day 28, Day 42, main study phase EOT, Day 84 and 4-week 
FU*. will be presented overall, by the 5 DRC-adjudicated disease categories and in addition 
by baseline susceptibility category. 
 
• 
DRC-adjudicated and Investigator-assessed mycological response at Day 7, Day 14, Day 


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28, Day 42, main study phase EOT, Day 84 and 4-week FU* will be presented overall, by the 
five DRC-adjudicated disease categories and in addition by baseline susceptibility category 
based on the categorised response of: 
o Success (Proven or presumed eradication) 
o Failure (Persistence, presumed persistence, Recurrent or emergent infection 
or any other response except proven or presumed eradication) 
 
• 
All-cause mortality rate will be summarised overall and by each of the five DRC-adjudicated 
disease categories at Day 42, main study phase EOT, Day 84 and 4-week FU*. In addition, 
overall survival (median time to death) will be presented. 
Patients with complete clinical response to study drug treatment will also be evaluated for relapse 
of the treated IFD and for newly emergent IFD at selected study visits up to the main study phase 
EOT visit (Day 84 to Day 90). 
If deemed relevant, the aforementioned endpoints may also be summarised by subgroups judged 
relevant (e.g., the subgroup of patients who continued therapy beyond Day 90 and who thus have 
only a single combined main study phase EOT visit encompassing Day 84 and EOT). 
*For patients planning to receive ET beyond Day 90, the Day 84 visit and the main study phase 
EOT visit will be combined into a single Day 84/EOS/EOT visit on approximately Day 90 and 
there will be no 4-week FU visit in the main study phase. 
8.2.4 
Safety Endpoints 
Descriptive statistics will be used to present the safety outcomes including: 
• 
Changes in concurrent medication dose and/or frequency resulting from potential DDIs 
• 
Hospitalisations 
• 
Overall exposure, individual dose modification, dose intensity. 
• 
Incidence of treatment-emergent and other (including but not limited to): 
− AEs 
− SAEs (including deaths) 
− AEs leading to death 
− Liver-related AEs 
− AEs leading to premature treatment discontinuation 
− AEs leading to premature study withdrawal 
− AEs by relationship 


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− AEs by severity (CTCAE grade) 
− AESIs 
• 
Change from baseline in clinical laboratory test results and incidence of pre-defined 
treatment-emergent abnormalities (CTCAE) 
• 
Liver-related toxicity: Incidence and time-to-event analyses of elevations in ALT, AST, 
bilirubin, as described in detail in Section 6.4.2.3. 
• 
Change from baseline in ECG results and incidence of pre-defined treatment-emergent 
abnormalities (CTCAE) 
• 
Change from baseline in vital signs (including weight and BMI) and incidence of pre-defined 
treatment-emergent abnormalities (CTCAE) 
• 
 
• 
Physical examination: Any abnormal clinically significant findings, as judged by the 
Investigator, will be listed in a by-patient data listing only. 
A treatment-emergent AE (TEAE) is defined as any AE starting or worsening on or after the first 
dose of study drug up to and including last dose of study drug or during the post-treatment FU. 
Treatment-emergent AEs which occur in the main study phase or FU will be presented in the 
study report; TEAEs which occur in the ET phase or post-ET FU will be presented in the report 
addendum. 
8.2.5 
Pharmacokinetic Analyses 
All PK blood sample collections and concentrations from the main study phase will be listed and 
summarised. Trough samples and post-dose samples will be used for a population PK analysis of 
F901318. The population PK analysis will be performed in accordance with a separate modelling 
data analysis plan and reported outside of the CSR. 
Parameters for the Intensive PK analysis set will be determined using non-compartmental 
analysis. All PK parameters will be listed and summarised using appropriate descriptive statistics. 
The PK data from samples collected during the extended treatment phase will be presented in the 
report addendum. 
8.2.6 
Data to be Analysed 
Data handling and statistical analysis will be the responsibility of 
. The data will be 
inspected for inconsistencies by performing validation checks. 
All details regarding the statistical analysis and the preparation of tables, listings and figures will 
be described in the SAP prepared by 
 and authorised by F2G prior to database lock. 


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8.2.7 
Analysis Sets 
The different analysis sets to be used in this study are described below: 
• All Patients Enrolled analysis set: all patients who provide written informed consent. 
• Safety analysis set (SAF): all patients who receive at least one dose of study drug (or part 
thereof). The SAF will be used for the analysis of all safety data. 
• Intent-to-treat (ITT) population: all patients who receive at least one dose of study drug.  
• Modified Intent-to-treat (mITT) population: all patients who receive at least one dose of study 
drug and who are assigned to a DRC-adjudicated disease category. The mITT population and 
sub-populations based on DRC-adjudicated disease categories will be used for the analysis of 
efficacy data. 
• Trough PK analysis set (Trough PK set): all patients who received at least one dose of study 
drug and have at least one measured trough F901318 plasma concentration. 
• Intensive PK analysis set (Intensive PK set): a subset of the SAF population who have 
. Further details on sub-categories (dose level and concomitant 
medication dependent) will be provided in the modelling analysis plan. 
8.2.8 
Missing Data 
Data from patients who withdraw from the study, including AEs and any follow-up, will be 
included in the analyses of primary and secondary outcomes as relevant. Further details will be 
provided in the SAP. 
8.3 
Patient Disposition 
The number of patients enrolled, completed or prematurely withdrawn from study participation 
together with the primary reason for premature study withdrawal will be presented overall and by 
DRC-adjudicated disease category, for each region, centre, as relevant, and overall, using 
absolute and relative frequencies (n and %). 
Similarly, the number of patients enrolled, treated, completed or prematurely discontinued 
treatment together with the primary reason for premature treatment discontinuation will be 
summarised. 
The decision to exclude patients from any of the analysis sets will be finalised at a data review 
meeting with F2G prior to final database lock. Such patients will be listed and a summary of the 
main reason(s) for exclusion will be provided.  
The number of patients included in each analysis set will be summarised. Reason(s) for exclusion 
can be protocol deviations or other factors that may affect the efficacy outcome or treatment of 
the patient. 


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Major/critical protocol deviations as collected during the conduct of the study and as authorised 
prior to final database lock will be summarised in a similar manner and listed per patient, 
describing the nature of the deviation.  
8.4 
Patient Characteristics 
Patient characteristics may include, but are not limited to: age, gender, race/ethnicity, height, 
weight, and BMI. Patient characteristics will be summarised for observed data only, overall and 
by DRC-adjudicated disease category, using descriptive statistics for continuous variables 
(sample size [n], mean, standard deviation, median, minimum, and maximum) and for categorical 
variables (sample size [n], absolute and relative frequencies [n and %]). Missing data will be 
included as part of a missing category or statistic as relevant. 
8.5 
Disease Characteristics  
Disease characteristics of the underlying infection (IFD) will be listed and summarised in a 
similar manner as described above and may include (but not limited to): 
• Duration from initial diagnosis to first administration of study drug. 
• Diagnostic method 
• Causative organism (in the event a patient has multiple organisms, information for all 
relevant organisms will be listed) 
• Treatment regimen and response to previous treatment 
In addition, history of all other fungal, viral and bacterial infections within the 6-month period 
prior to first administration of study drug will be presented.  
8.6 
Medical History 
Medical history will be presented by MedDRA System Organ Class and Preferred Term using the 
most recent version of MedDRA. 
8.7 
Medications and Procedures 
With reference to Section 6.2.6 and Section 6.2.7, medications and procedures will be categorised 
based on dates of administration/occurrence as either prior, concomitant or post-treatment. 
Medications will be coded using the World Health Organisation Drug Dictionary and presented 
overall and by DRC-adjudicated disease category, by Anatomical Therapeutic Chemical class 
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8.8 
Efficacy Analyses 
In addition to the below, efficacy data will be summarised descriptively, overall and by DRC-
adjudicated disease category. If deemed relevant, summary statistics may be presented by 
relevant subgroups considered to impact the efficacy outcome. Efficacy data collected for the 
main study phase up to Day 84/Day 90 and the subsequent 4-week FU visit will be included in 
the data analyses and presented in the CSR. 
 
 
8.8.1 
Primary Efficacy Analysis 
With reference to Section 8.2.2, based on the DRC-adjudicated overall response categorized as 
success or failure a response rate will be calculated based on all patients included in the mITT 
population where missing clinical responses or patients considered not evaluable at Day 42 will 
be included as a failure. A 95% CI for the single binomial proportion will be calculated. 
 
 
 
Corresponding estimated historical response rates in relevant control populations will be assessed 
using analyses of available clinical databases 
 
and presented in a similar manner as the calculated Study 32 response rate.  
8.8.2 
Secondary Efficacy Analyses 
With reference to Section 8.2.3 and based on definitions in Section 6.3 and the DRC Charter: 
DRC-adjudicated overall response at Day 7, Day 14, Day 28, main study phase EOT, 
Day 84 and 4-week FU* (as determined by an independent DRC using a combination of 
clinical, mycological and radiological results) 
Results for DRC-adjudicated overall response at Day 7, Day 14, Day 28, main study phase EOT, 
Day 84 and 4-week FU will be presented in a similar manner as described for the primary 
efficacy analysis. 
Investigator-assessed overall response (as determined by Investigator using combined 
clinical, mycological and radiological results) at Day 7, Day 14, Day 28, Day 42, main study 
phase EOT, Day 84 and 4-week FU* 
Based on the Investigator-assessed overall response categorised as success/failure, a response rate 
will be calculated based on all patients included in the mITT population where patients 
considered not evaluable at Day 42 due to missing data will be included as failures. In addition a 
95% CI for a single binomial proportion will be calculated. The 95% CI of this response rate will 
be compared with an estimated historical response rate, overall and by DRC-adjudicated disease 
category. 


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DRC-adjudicated and Investigator-assessed clinical response overall and by DRC-
adjudicated disease category at Day 7, Day 14, Day 28, Day 42, main study phase EOT, 
Day 84 and 4-week FU* 
Based on the DRC-adjudicated and Investigator-assessed clinical response categorised as 
success/failure, a response rate will be calculated based on all patients included in the mITT 
population where patients considered not evaluable due to missing clinical data will be included 
as failures. In addition a 95% CI for a single binomial proportion will be calculated. 
DRC-adjudicated and Investigator-assessed mycological response overall and by DRC-
adjudicated disease category at Day 7, Day 14, Day 28, Day 42, main study phase EOT, 
Day 84 and 4-week FU* 
Based on the DRC-adjudicated and Investigator-assessed mycological response categorized as 
Success/Failure, a response rate will be calculated based on all patients included in the mITT 
population with a baseline culture result available. Patients with a mycology evaluation of “No 
mycological Follow-up results available” will be assigned an outcome of presumed eradication if 
they are deemed a clinical success and a presumed failure if they are deemed a clinical failure, or 
clinical response is missing. Mycological success will include patients classified as a success or a 
presumed eradication. In addition a 95% CI for a single binomial proportion will be calculated. 
All-cause mortality at Day 42, main study phase EOT, Day 84 and 4-week FU* 
Mortality rates will be derived at Day 42, main study phase EOT, Day 84 and 4-week FU* based 
on all patients in the mITT population. In addition a 95% CI for a single binomial proportion will 
be calculated. Also, Kaplan-Meier analyses will be performed at Day 42, main study phase EOT, 
Day 84 and 4-week FU*, summarising median time to death (stratified by DRC-adjudicated 
disease category). A reported death will be carried forward for all future visits. A patient without 
reported death for the specific visit analysed (Day 42, main study phase EOT, Day 84 or 4-week 
FU*) will be censored for the specific visit analysed. 
*Note: For patients planning to receive ET beyond Day 90, the Day 84 visit and the main study 
phase EOT visit will be combined into a single Day 84/EOS/EOT visit on approximately Day 90 
and there will be no 4-week FU visit in the main study phase. As judged relevant, subanalyses 
will be performed to account for this difference in observation periods. 
8.8.3 
Patient-Reported Outcomes 
The EQ-5D-5L qualitative items will be presented as the number and % of patients with each 
rating of health for each quality of life category (such as mobility), summarised over all 


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scheduled visits. The number and % of patients with each shift item from baseline to EOT and 
from baseline to EOS will also be summarized. 
The EQ-5D-5L qualitative items will be presented by means of a stacked bar chart over all 
applicable scheduled visits. 
Descriptive statistics will be summarized for the visual analogue scale score. 
8.9 
Safety 
Frequency tables will be used to present the safety outcomes including incidences of TEAEs, 
SAEs (including deaths), TEAEs leading to death, treatment-emergent AESIs, liver-related 
TEAEs, TEAEs leading to premature treatment discontinuation, TEAEs leading to premature 
study withdrawal, TEAEs by relationship and TEAEs by severity. 
Change from baseline and incidence of pre-defined treatment-emergent newly occurring 
abnormalities in vital signs, clinical laboratory test results and ECG results will be summarised. 
Graphical presentations will also be used to help describe vital signs, selected laboratory test 
values and ECG parameters. 
Other safety outcomes include physical examination 
 
Safety data collected for the main study phase up to Day 84/Day 90 and the subsequent 4-week 
FU visit will be included in the data analyses and presented in the CSR. Safety data collected 
during ET and ET FU will not be included in the data analyses or in the CSR, and will be 
presented in the report addendum. 
8.9.1 
Exposure 
Overall exposure will be summarised by taking individual dose modification and dose intensity 
into account. 
8.9.2 
Adverse Events 
Adverse events will be coded using MedDRA. Number of events and incidence rates will be 
tabulated by System Organ Class and Preferred Term. An event that occurs at least once on the 
date of, or subsequent to first administration of study drug will contribute one observation to the 
numerator of the incidence rate. The denominator of the rate will comprise all patients exposed to 
the study drug (SAF analysis set). If the intensity or seriousness of the AE changes, the overall 
severity or seriousness will be the worst severity or seriousness of the multiple occurrences. 
TEAEs, SAEs (including deaths), TEAEs leading to death, treatment-emergent AESIs, liver-
related TEAEs, TEAEs leading to premature treatment discontinuation and TEAEs leading to 
premature study withdrawal will be tabulated. In addition, TEAEs by relationship and severity 
(using CTCAE grading) will be summarised. 


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8.9.3 
Clinical Laboratory Evaluations 
All central laboratory test results will be summarised using descriptive statistics at each visit for 
observed data and change from baseline. 
Based on the laboratory reference range, laboratory test results will be categorised as: 
• Low 
• Normal 
• High 
Change from baseline to each post-baseline visit, main study phase EOT and EOS in 
aforementioned reference range laboratory category will be presented as shift tables. Abnormal 
laboratory values, categorised per reference range as high or low will be flagged in by-patient 
data listings. 
In addition, pre-defined treatment-emergent abnormalities (newly occurring), as defined by 
CTCAE criteria, will be presented in tables where the incidence rate will be based on the total 
number of patients ‘at risk’: 
For example: 
• 
If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a pre-dose and at least 1 post-dose value recorded 
• 
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post-dose value recorded. 
In the event that a laboratory value does not comply with the CTCAE criterion, the laboratory 
value will be categorised as normal. 
In the event of a retest of the same sample due to, for example, a laboratory error (same visit 
number assigned), the last available assessment will be used for by-visit summaries, including 
identification of pre-defined treatment-emergent abnormalities (newly occurring), regardless of 
whether the laboratory assessment for that particular nominal visit is available or not. 
The handling of laboratory values below limit of quantification (LOQ) will be described in the 
detailed SAP for each laboratory test separately. 
It should be noted that for glucose, only non-fasting values will be included in any summary 
presentations although all results will be listed in by-patient listings. 
As per the FDA Liver Safety Guidance, the following treatment-emergent incidence tables will 
be presented, including time-to-event analyses, and by-patient data listings: 
• 3 ×-, 5 ×-, 10 ×-, and 20 × ULN elevations of AST, ALT, and either ALT or AST. 
• Any elevations of total bilirubin, elevated total bilirubin > 2 × ULN. 
• Any elevations of alkaline phosphatase (ALP) > 1.5 × ULN. 


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• Elevation of AST or ALT > 3 × ULN accompanied by elevated total bilirubin (> 1.5 × 
ULN, > 2 × ULN). 
• Elevation of AST or ALT > 3 × ULN in temporal association with nausea, vomiting, 
anorexia, abdominal pain, or fatigue. 
Treatment-emergent is defined as any event (scheduled or unscheduled) which started or 
worsened on or after the first dose of study drug or during the post-treatment FU. Treatment-
emergent AEs which occur in the main study phase or FU will be presented in the study report; 
TEAEs which occur in the ET phase or post-ET FU will be presented in the report addendum. 
In addition, figures and listings will be presented for possible treatment-emergent Hy’s Law cases 
(patients with any elevated AST or ALT > 3 × ULN, ALP < 2 × ULN and associated with an 
increase in total bilirubin ≥ 2 × ULN). 
 
 
 
 
 
 
8.9.4 
Vital Signs Measurements, ECG, Physical Findings and Other Safety 
Evaluations 
8.9.4.1 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, body 
temperature, weight and BMI) will be summarised using descriptive statistics at each visit for 
observed data and change from baseline. 
Pre-defined treatment-emergent abnormalities (newly occurring), as defined by CTCAE criteria, 
will be presented in tables and listed, where the incidence rate will be based on the total number 
of patients ‘at risk’ (see example in Section 8.9.3).  
A similar approach as for laboratory values will be followed for vital signs with regards to retests 
and values not complying with CTCAE criterion. 
8.9.4.2 
ECG 
ECG results will be summarised using descriptive statistics at each visit for observed data and 
change from baseline. 
Pre-defined QT interval treatment-emergent abnormalities, as defined by CTCAE criteria, will be 
presented in tables and listed, where the incidence rate will be based on the total number of 
patients ‘at risk’ (see example in Section 8.9.3). 


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A similar approach as for laboratory values will be followed for ECG with regards to retests and 
values not complying with CTCAE criterion. 
Change from baseline to each post-baseline visit, main study phase EOT and EOS in 
Investigator-judged abnormal classification will be presented as shift tables: 
• 
Abnormal and clinically significant 
• 
Abnormal and not clinically significant 
• 
Normal. 
8.9.4.3 
Other Safety Evaluations 
Any abnormal physical examination findings, as judged by the Investigator, will be listed in a by-
patient data listing only. 
 
  
Any abnormal physical examination findings, as judged by the Investigator, will be listed in a by-
patient data listing only. 
8.10 Hospitalisation Status 
The reason, date of admission and discharge, type of ward (intensive care unit, non-intensive care 
unit) and any changes in any of these parameters recorded in the eCRF will be summarised 
descriptively (sample size [n], absolute and relative frequencies [n and %]). 
8.11 Pharmacokinetic Analyses 
Blood samples for analysis of plasma concentrations of study drug will be collected as specified 
in the Schedule of Events (Table 1). 
 
All PK sample collections and concentrations will be listed and summarised by visit. 
Pharmacokinetic data collected for the main study phase up to Day 84/Day 90 and the subsequent 
4-week FU visit will be included in the data analyses and presented in the CSR. Pharmacokinetic 
data collected during ET and ET FU will not be included in the data analyses or in the CSR, and 
will be presented in the report addendum. 


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8.11.1 
Trough Sampling Data Analysis 
All drug concentrations will be listed and presented in tabular summaries using descriptive 
statistics, including n, arithmetic mean, standard deviation, coefficient of variation, median, 
geometric mean, geometric coefficient of variation, minimum and maximum values.  
The trough concentrations and post-dose concentrations will be used for a population PK analysis 
of F901318. The population PK of F901318 will be characterised by nonlinear mixed-effects 
modelling. From this analysis, the influence of various demographic covariates (e.g., body 
weight, gender) and other patient-specific factors on F901318 trough levels and drug exposure 
may be assessed. Correlations between exposure and response or safety data will be evaluated as 
appropriate. 
The data from this study may be combined with data collected from other studies and from the 
Intensive PK component of this study to supplement model development. The population PK 
analysis will be performed in accordance with a separate modelling data analysis plan and may be 
reported outside of the CSR. 
8.11.2 
Intensive PK Data Analysis 
The Intensive PK study will include densely sampled PK to allow parameters to be determined 
using standard noncompartmental analysis. All PK parameters where possible to estimate will be 
listed and summarised using appropriate descriptive statistics including maximum plasma 
concentration (Cmax), time to maximum plasma concentration (tmax), area under the curve over the 
12 hour dosing interval (AUCtau), trough concentration 12 hours post-dose (Cmin), apparent 
clearance (CL/F) and apparent volume of distribution (Vz/F). Data will be listed and summarised 
using n, arithmetic mean, standard deviation, coefficient of variation, median, minimum and 
maximum values. Geometric mean and geometric coefficient of variation will also be included 
for any PK parameter calculations, except for tmax which will be summarised using n, minimum, 
median and maximum only. Full details of the analysis will be provided in the SAP supporting 
this clinical study. 
8.12 
 
 
8.13 Interim Analyses 
An analysis of the data will be conducted when the first 100 patients have completed the main 
study phase. 
Independent Data and Safety Monitoring Board (IDSMB) 
See Section 6.4.4.1 for details. 
Data Review Committee (DRC) 


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A DRC will be established to conduct a review of all patient cases to determine diagnosis and 
overall outcome. Members of the DRC will be independent from the Sponsor and also will not 
participate as Investigators in the study. The DRC will consist of experts in the field of clinical 
mycology.  
The DRC assessment will include the clinical diagnosis at enrolment as well as primary and 
secondary criteria for efficacy evaluation. The DRC will not review data from the ET visits or the 
post-ET FU. Objectives, composition, process and documentation of the DRC are described in 
more detail in the DRC Charter and SAP. 


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9.0 ETHICS 
9.1 
Institutional Review Board or Independent Ethics Committee 
An Ethics Committee should approve the final protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the patients. The Investigator 
will provide the Sponsor 
 with documentation of IRB/IEC approval of the protocol and 
informed consent before the study may begin at the study centre(s). The Investigator should 
submit the written approval to F2G or representative before enrolment of any patient into the 
study. 
F2G or representative should approve any modifications to the ICF that are needed to meet local 
requirements. 
The Investigator will supply documentation to the Sponsor 
 of required IRB/IEC’s 
annual renewal of the protocol, and any approvals of revisions to the informed consent document 
or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC, any new information that may adversely 
affect the safety of patients or the conduct of the study. Similarly, the Investigator will submit 
written summaries of the study status to the IRB/IEC annually, or more frequently if requested by 
the IRB/IEC. Upon completion of the study, the Investigator will provide the ethics committee 
with a brief report of the outcome of the study, if required. 
F2G 
 will provide Regulatory Authorities, Ethics Committees and Investigators with 
safety updates/reports according to local requirements, including Suspected Unexpected Serious 
Adverse Reactions, where relevant. 
Each Investigator is responsible for providing the IRB/IEC with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the study drug. F2G or 
 will provide this information to the Investigator so that he/she can meet these reporting 
requirements. 
9.2 
Ethical Conduct of the Study 
This study will be conducted and the informed consent will be obtained in accordance with the 
ICH GCP guidelines, the European Union Clinical Trials Directive 2001/20/EC, the provisions of 
the Helsinki Declaration, and relevant legislation in force in the countries where the study will be 
conducted. 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting studies that involve the participation of human 
patients. The study will be conducted in compliance with GCP and the applicable national 
regulations so as to assure that the rights, safety and well-being of the participating study patients 


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are protected consistent with the ethical principles that have their origin in the Declaration of 
Helsinki. 
9.3 
Patient Information and Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the patient in 
simple terms before the patient will be entered into the study. The ICF contains a statement that 
the consent is freely given, that the patient is aware of the risks and benefits of entering the study, 
and that the patient is free to withdraw from the study at any time. Written consent must be given 
by the patient and/or legal representative (if applicable and conforming with local regulations), 
after the receipt of detailed information on the study. A separate written consent must be given by 
the patient and/or legal representative if the patient is to receive ET beyond Day 84/90.  
The Investigator is responsible for ensuring that informed consent is obtained from each patient 
or legal representative and for obtaining the appropriate signatures and dates on the informed 
consent document prior to the performance of any protocol procedures and prior to the 
administration of study drug. The Investigator will provide each patient with a copy of the signed 
and dated consent form. 
9.4 
Patient Data Protection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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10.0 STUDY ADMINISTRATION 
10.1 Administrative Structure 
This study will be outsourced, and the Sponsor has engaged 
 a CRO, to oversee the 
clinical conduct of this study, including project management and monitoring. 
The Sponsor and 
 may also engage other third-party providers as necessary. 
10.2 Data Handling and Record Keeping 
It is the Investigator’s responsibility to maintain essential study documents (protocol and protocol 
amendments, completed eCRFs, signed ICFs, relevant correspondence and all other supporting 
documentation). The study centre should plan on retaining such documents for approximately 15 
years after study completion. The study centre should retain such documents until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years after the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period if required by the applicable regulatory requirements or the 
hospital, institution, or private practice in which the study is being conducted. Patient 
identification codes (patient names and corresponding study numbers) will be retained for this 
same period of time. These documents may be transferred to another responsible party, 
acceptable to the Sponsor, who agrees to abide by the retention policies. Written notification of 
transfer must be submitted to the Sponsor. The Investigator must contact the Sponsor prior to 
disposing of any study records. 
For studies conducted outside the United States under a US IND, the Principal Investigator must 
comply with US FDA IND regulations and with those of the relevant national and local health 
authorities. 
10.3 Direct Access to Source Data/Documents 
The Investigator will prepare and maintain adequate and accurate source documents to record all 
observations and other pertinent data for each patient enrolled into the study. 
The Investigator will allow the Sponsor, 
, and authorized regulatory authorities to have 
direct access to all documents pertaining to the study, including individual patient medical 
records, as appropriate. 


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10.4 Investigator Information 
10.4.1 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP (GCP, 1997; the US CFR Title 21 parts 50, 56, and 312; and European Legislation) and the 
ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator will agree to conduct the clinical study in compliance with this protocol after the 
approval of the protocol by the IEC/IRB in compliance with local regulatory requirements. The 
Investigator and the Sponsor will sign the protocol to confirm this agreement. 
10.4.2 
Protocol Signatures 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 1). By signing the protocol, 
the Investigator confirms in writing that he/she has read, understands and will strictly adhere to 
the study protocol and will conduct the study in accordance with ICH Tripartite Guidelines for 
Good Clinical Practice and applicable regulatory requirements. The study will not be able to start 
at any centre where the Investigator has not signed the protocol. 
10.4.3 
Publication Policy  
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. The publication policy with respect to the 
Investigator and study centre will be set forth in the Clinical Trial Agreement. 
10.5 Financing and Insurance  
The Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the patients participating in this study. The terms of the insurance will be kept in 
the study files. 


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11.0 REFERENCES  
Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, et al. Defining opportunistic 
invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem 
cell transplants: An international consensus. Clinical Infectious Diseases. 2002;34(1):7-14. 
Clopper C, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934 26: 404–413. doi:10.1093/biomet/26.4.404 
Cortez KJ, Roilides E, Quiroz-Telles F, Meletiadis J, Antachopoulos C, Knudsen T, et al. 
Infections caused by Scedosporium spp. Clin Microbiol Rev. 2008;21(1):157-97,CP3.  
CredibleMeds® Combined list of drugs that prolong QT and/or cause Torsades de Pointes (TDP). 
Arizona Center for Education and Research on Therapeutics. Available at: 
https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf   
De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. 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. 
Clinical Infectious Diseases. 2008;46(12):1813-21. 
Denning DW. Invasive aspergillosis. Clinical Infectious Diseases. 1998;26(4):781-803. 
Denning DW. Therapeutic outcome in invasive aspergillosis. Clinical Infectious Diseases. 
1996;23:608-15. 
Dixon C. Statistical Review from 22 Jan 2015 FDA AIDAC review of isavuconazonium 
(transcript page 123). 2015.  
European Center for Disease Prevention and Control. ECDC Technical Report: Risk assessment 
on the impact of environmental usage of triazoles on the development and spread of resistance to 
medical triazoles in Aspergillus species. Accessed 23 Mar 2015 at 
http://ecdceuropaeu/en/publications/Publications/risk-assessment-impact-environmental-usage-
of-triazoles-on-Aspergillus-spp-resistance-to-medical-triazolespdf. 2013. 
FDA guidance on drug-drug interactions, accessed online at 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsl
abeling/ucm093664.htm 
Garcia-Rubio R, Cuenca-Estrella M, Mellado E. Triazole Resistance in Aspergillus Species: An 
Emerging Problem. Drugs. 2017;77(6):599-613. 
Guo-Hao Xie, Xiang-Ming Fang, Qiang Fang, Xin-Min Wu, Yu-Hong Jin, Jun-Lu Wang et al. 
Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort 
study in critically ill surgical patients. Critical Care 2008, 12:R5 
Heath CH, Slavin MA, Sorrell TC, Handke R, Harun A, Phillips M, et al. Population-based 
surveillance for scedosporiosis in Australia: epidemiology, disease manifestations and emergence 
of Scedosporium aurantiacum infection. Clin Microbiol Infect. 2009;15(7):689-93. 


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Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, et al. 
Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 
2002;347(6):408-15.  
Kelly M, Stevens R, Konecny P. Lomentospora prolificans endocarditis--case report and 
literature review. BMC Infect Dis. 2016;16:36. 
Kennedy B, Larcombe R, Chaptini C, Gordon DL. Interaction between voriconazole and 
flucloxacillin during treatment of disseminated Scedosporium apiospermum infection. The 
Journal of antimicrobial chemotherapy. 2015;70(7):2171-3. 
Lamoth F, Chung SJ, Damonti L, Alexander BD. Changing Epidemiology of Invasive Mold 
Infections in Patients Receiving Azole Prophylaxis. Clinical Infectious Diseases. 
2017;64(11):1619-21. 
Lamoth F. Aspergillus fumigatus-Related Species in Clinical Practice. Frontiers in microbiology. 
2016;7:683. 
Maertens JA, Raad, II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. 
Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by 
Aspergillus and other filamentous fungi (SECURE): A Phase 3, randomised-controlled, non-
inferiority trial. Lancet. 2016;387(10020):760-9. 
Magill S, Chiller T and Warnock D. Evolving strategies in the management of aspergillosis. 
Expert Opin. Pharmacother. 2008;9:193-209 
Muilwijk EW, Dekkers BGJ, Henriet SSV, Verweij PE, Witjes B, Lashof A, et al. Flucloxacillin 
Results in Suboptimal Plasma Voriconazole Concentrations. Antimicrobial agents and 
chemotherapy. 2017;61(9).  
Nivoix Y, Velten M, Letscher-Bru V, Moghaddam A, Natarajan-Amé S, Fohrer C, et al. Factors 
associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis. 
2008;47:1176-84 
Rodriguez-Tudela JL, Berenguer J, Guarro J, Kantarcioglu AS, Horre R, De Hoog GS, et al. 
Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases. Med 
Mycol. 2009;47(4):359-70. Steinmann J, Hamprecht A, Vehreschild MJ, Cornely OA, Buchheidt 
D, Spiess B, et al. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in 
Germany. The Journal of antimicrobial chemotherapy. 2015;70(5):1522-6. 
Tammer I, Tintelnot K, Braun-Dullaeus RC, Mawrin C, Scherlach C, Schluter D, et al. Infections 
due to Pseudallescheria/Scedosporium species in patients with advanced HIV disease--a 
diagnostic and therapeutic challenge. Int J Infect Dis. 2011;15(6):e422-9.  
Tortorano AM, Richardson M, Roilides E, van Diepeningen A, Caira M, Munoz P, et al. 
ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: 
Fusarium spp., Scedosporium spp. and others. Clin Microbiol Infect. 2014;20 Suppl 3:27-46. 
van der Linden JW, Snelders E, Kampinga GA, Rijnders BJ, Mattsson E, Debets-Ossenkopp YJ, 
et al. Clinical implications of azole resistance in Aspergillus fumigatus, The Netherlands, 2007-
2009. Emerg Infect Dis. 2011;17(10):1846-54.  


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Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole Resistance in Aspergillus fumigatus: 
Can We Retain the Clinical Use of Mold-Active Antifungal Azoles? Clinical Infectious Diseases. 
2016;62(3):362-8. 
Verweij PE, Donnelly JP, Kullberg BJ, Meis JFGM, De Pauw BE. Amphotericin B versus 
amphotericin B plus 5-flucytosine: Poor results in the treatment of proven systemic mycoses in 
neutropenic patients. Infection. 1994;22:81-5.  
 


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12.0 APPENDICES 


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APPENDIX 1: SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE: 
An open-label single-arm Phase IIb study of F901318 as treatment 
of invasive fungal infections due to Lomentospora prolificans, 
Scedosporium spp., Aspergillus spp., and other resistant fungi in 
patients lacking suitable alternative treatment options. 
PROTOCOL NO: 
F901318/0032 
This protocol is a confidential communication of F2G. I confirm that I have read this protocol, I 
understand it, and I will work according to this protocol. I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from F2G. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and 
the name of the centre in which the study will be conducted. Return the signed copy to IQVIA. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
__________________________ Date: ________ 
Printed Name:                         ___________________________ 
Investigator Title:                    ___________________________ 
 
Name/Address of Centre:  
  ___________________________ 
 
___________________________ 
 
___________________________ 
 


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APPENDIX 2: DEFINITIONS OF INVASIVE FUNGAL DISEASE 
(IFD) AND DIAGNOSTIC CRITERIA IN 
REFERENCE TO EORTC MSG (DE PAUW 2008) 
Definitions of IFD: 
Proven Invasive Fungal Disease (MOULDS) 
Analysis and Specimen 
Moulds 
Microscopic Analysis 
(sterile material) 
Histopathologic, cytopathologic, or direct microscopic 
examinationa of a specimen obtained by needle aspiration or biopsy 
in which hyphae or melanized yeast-like forms are seen 
accompanied by evidence of associated tissue damage 
(microscopically or as an infiltrate or lesion by imaging) OR 
Culture 
(sterile material) 
Recovery of a mould or “black yeast” by culture of a specimen 
obtained by a sterile procedure from a normally sterile and 
clinically or radiologically abnormal site consistent with an 
infectious disease process (e.g. transbronchial biopsy, open-lung 
biopsy, or brain biopsy), excluding bronchoalveolar lavage (BAL) 
fluid, a cranial sinus cavity specimen, and urine 
 
Blood 
Blood culture that yields a mouldb (e.g. Fusarium species) in 
the context of a compatible infectious disease process 
Serological analysis: 
CSF 
Not applicable 
a. Tissue and cells submitted for histopathologic or cytopathologic studies should be stained by Grocott-
Gomorri methenamine silver stain or by periodic acid Schiff stain, to facilitate inspection of fungal 
structures. Whenever possible, wet mounts of specimens from foci related to invasive fungal disease should 
be stained with a fluorescent dye (e.g. calcofluor or blankophor). 
b. Recovery of Aspergillus species from blood cultures invariably represents contamination 
 
Probable Invasive Fungal Disease - Lower Respiratory Tract Disease Invasive 
Aspergillosis (LRTD IA) 
At least one high-risk host factor (definitions see below)  
PLUS, at least one clinical feature (definitions see below)  
PLUS, at least one mycological criterion (definitions, see below) 
Host factors and clinical features are not required for patients with Proven IFD.  
However, if such host factors and clinical features are present at baseline, they will be 
recorded in the eCRF. 
 


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Definitions of Diagnostic Criteria: 
Host Factors: 
• Recently resolved (< 4 weeks) or ongoing neutropenia (neutropenia defined as 
absolute neutrophil count < 0.5 × 109 cells/L [< 500 cells/mm3] for ≥ 10 days), 
temporally related to the onset of fungal disease. 
• Receipt of an allogeneic haematopoietic stem cell transplant (HSCT) or bone marrow 
transplant (BMT). 
• Prolonged use of corticosteroids (excluding among patients with allergic 
bronchopulmonary aspergillosis) at a mean minimum dose of 0.3 mg/kg/day of 
prednisone equivalent for > 3 weeks. 
• Treatment with other recognized T-cell immunosuppressants, such as cyclosporine, 
tacrolimus, monoclonal antibodies or nucleoside analogues during the past 90 days. 
• Inherited severe immunodeficiency (such as chronic granulomatous disease or severe 
combined immunodeficiency). 
 
Clinical Features: 
Lower Respiratory Tract Fungal Disease 
The medical history must be established to exclude alternative aetiologies and to distinguish 
between an acute or subacute presentation rather than a chronic pulmonary infection. Onset 
of clinical symptoms and/or physical findings within approximately 2 weeks prior to the first 
administration of study drug defines an acute or subacute pulmonary infection. 
The presence of at least one of the following “specific” imaging signs on computed 
tomography (CT), high resolution computed tomography (HRCT) or magnetic 
resonance imaging (MRI): 
i. 
Dense well-circumscribed lesion(s) (nodules) with or without halo sign 
ii. 
Air crescent sign 
iii. 
Cavity 
iv. 
Wedge-shaped and segmental or lobar consolidation* 
v. 
Reverse halo sign* 
* Planned updates for 2019 EORTC Guideline Revision and will be considered by the MM 
for study inclusion if applicable.  
OR 
Allogeneic HSCT/BMT or neutropenic patients who have non-specific focal infiltrates, on 
CT scan (or HRCT) or MRI, must have mycological evidence of disease at the time of study 
entry and will be classified as probable. Otherwise, patients with non-specific focal infiltrates 
are not eligible. 
 
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. 
Non Lower Respiratory Tract Fungal Disease 
Probable LRTD IA is the only unconfirmed IFD eligible for this study. Radiology response 
will be assessed for any proven Non-LRTD IFD patients enrolled in the study. 
 


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The Clinical features for Non-LRTD are as follows -  
Tracheobronchitis 
Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on 
bronchoscopic analysis 
 
Sinonasal infection 
Imaging showing sinusitis plus at least 1 of the following 3 signs: 
i. 
Acute localized pain (including pain radiating to the eye) 
ii. 
Nasal ulcer with black eschar 
iii. 
Extension from the paranasal sinus across bony barriers, including into the 
orbit 
 
CNS infection 
Imaging showing 1 of the following 2 signs: 
i. 
Focal lesions on imaging 
ii. 
Meningeal enhancement on MRI or CT 
 
Mycological Criteria: 
Evidence may include cytology, direct microscopy, culture from non-sterile sites, antigen 
detection and polymerase chain reaction (PCR).  
For Proven IFD patients the following will be not be sufficient to enrol the patient into the 
study BUT the results of any mycological assessments (PCR, GM, β-D-glucan etc.) from non 
sterile sites will be documented in the eCRF.  
 
For the Probable LRTD IA Patients they must meet ONE of the following criteria: 
Direct test (cytology, direct microscopy, or culture) 
Either sputum, BAL, bronchial brush samples, or sinus aspirate specimen demonstrating the 
presence of fungal elements either by recovery by culture of a mould or detection by cytology 
or direct microscopy of hyphal forms 
OR 
Indirect tests (detection of antigen or cell wall constituents) 
Serum galactomannan (GM) with a single value of ≥1.0 or two consecutive values each of 
≥0.5 (i.e., from 2 separate blood draws) is acceptable mycological evidence for enrolment as 
probable IFD. Patients with serum GM meeting the protocol-defined requirements drawn 
within 10 days prior to first dose of study drug are eligible for enrolment. Patients receiving 
concomitant amoxicillin/clavulanate, piperacillin/tazobactam or Plasma-Lyte™ (Baxter) 
should be discussed with the Medical Monitor, and these products must be recorded in the 
prior and/or concomitant medication pages of the eCRF. 
Bronchoalveolar lavage fluid: GM index ≥1.0 from testing of two aliquots of a single BAL 
fluid sample is acceptable as mycological evidence for enrolment as probable IFD. 
Note: GM results from other specimens are not acceptable evidence of probable IA but 
results will be reported in the eCRF.  


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Positive Aspergillus PCR result from blood in two separate specimens, performed locally 
and/or centrally. The elected PCR assay and process methodology should be in accordance 
with latest EORTC/MSG recommendations. 
Note: Aspergillus PCR from other fluids is not acceptable as evidence. 
Proven endemic mycosis:  
In a patient with an illness consistent with an endemic mycosis, a history of one of the 
following: 
i. 
Recovery in culture from a specimen obtained from the affected site or from blood 
ii. 
Histopathologic or direct microscopic demonstration of appropriate morphologic 
forms with a truly distinctive appearance characteristic of dimorphic fungi, such as 
Coccidioidesspecies spherules, Blastomyces dermatitidis thick-walled broad-based 
budding yeasts, Paracoccidioides brasiliensis multiple budding yeast cells, and, in the 
case of histoplasmosis, the presence of characteristic intracellular yeast forms in a 
phagocyte in a peripheral blood smear or in tissue macrophages 
iii. 
For coccidioidomycosis, demonstration of coccidioidal antibody in CSF, or a 2-fold 
rise in 2 consecutive serum samples with abnormal CSF findings indicative of 
coccidioidomycosis 
iv. 
For paracoccidioidomycosis, demonstration in 2 consecutive serum samples of a 
precipitin band to paracoccidioidin concurrently in the setting of an ongoing infectious 
disease process. 








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APPENDIX 4: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 06 
28 February 2020 
Yes 
Global 
Amendment 05 
30 October 2019 
Yes 
Global (not implemented) 
Amendment 04 
03 May 2019 
Yes 
Global 
Amendment 03 
28 November 2018 
Yes 
Global 
Amendment 02 
02 May 2018 
Yes 
Global 
Amendment 01-01 
07 March 2018 
Yes 
Local (Belgium) 
Amendment 01 
24 January 2018 
Yes 
Global 
Original Protocol 
19 December 2017 
- 
- 
 
Amendment 05 
30 October 2019 
Amendment 05 was not implemented. Changes introduced to Amendment 05 which are relevant 
to Amendment 06 are included in the Summary of Changes for Amendment 06. 
Amendment 04 
03 May 2019 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for Amendment 04 
An extended treatment phase has been added to the study to allow continued treatment with 
F901318 for those patients who have benefitted from treatment with F901318 during the 90 day 
study treatment period, have no suitable alternative treatment options and would continue to 
benefit from extended treatment. In prior versions of this protocol, extended treatment has been 
provided via a Named Patient mechanism in each territory. As is standard with Named Patient 
mechanisms, the ability of the Sponsor to closely follow and support patients is limited and the 
data from patients utilizing this mechanism is not incorporated into study reports. As it has 
become clear that extended treatment is being found beneficial in approximately 25% of enrolled 
patients, Amendment 04 provides an explicit mechanism for this process that will allow the data 
from these patients to ultimately be provided as an addendum to the primary report for this study.  
Extended treatment is to be requested by the Investigator and must be approved by the Medical 
Monitor. Patients will attend visits every 4 weeks during extended treatment to assess the safety 


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of continued treatment and to confirm by the evaluation of efficacy that continued treatment is 
justified. Assessment of the safety and efficacy of F901318 during extended treatment has been 
added as an exploratory objective. Detail has been presented of the assessments and procedures to 
be completed during extended treatment. 
Patient-reported outcomes have been added as an endpoint, to be collected by completion of the 
EQ-5D-5L questionnaire. This will provide additional insight into the benefits of treatment with 
F901318. 
Further detail has been added for efficacy and safety assessments to clarify the processes for 
these assessments and to improve the consistency of reporting. 
Description of Changes in Amendment 04: 


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Section Number 
and Name 
Description of Change 
Brief Rationale 
Title page 
Sponsor address in the UK has been 
deleted. 
The Project Manager details have 
been updated. 
The Sponsor address is now in 
Austria. 
The 
Project Manager has 
changed. 
Synopsis; 
Section 4.1 
The numbers of centres has been 
increased from 40 to 50. 
The number of centres has been 
increased to facilitate enrolment of 
patients. 
Synopsis; 
Section 3.2; 
Section 4.1; 
Section 6.3.4; 
Section 8.8.3 
Patient-reported outcomes have 
been added, to be collected by 
completion of the EQ-5D-5L 
questionnaire. 
The EQ-5D-5L is a validated 
questionnaire to evaluate the effect of 
treatment on the patients quality of 
life, and will provide additional 
insight into the benefit profile of 
F901318. 
Synopsis; 
Section 3.4 
An Extended Treatment 
Exploratory Objective has been 
added: To describe the efficacy and 
safety of prolonged treatment with 
F901318 for infections due to 
resistant fungi in patients lacking 
suitable alternative treatment 
options. 
It is estimated that approximately 
25% of patients who respond to 
treatment with F901318 may require 
treatment beyond the maximum of 90 
days of treatment included in the 
main phase of this protocol. Safety 
and efficacy data collected from the 
end of the main study phase onwards 
will be evaluated as an exploratory 
objective. 
Synopsis; 
Protocol body text 
throughout 
Reference to treatment with 
F901318 beyond Day 90 ‘via an 
extended dosing mechanism that 
is outside the scope of this 
protocol’ has been replaced by a 
description of ‘an extended 
treatment phase’. 
This change provides a more 
structured approach to management 
of patients who have responded to 
treatment with F901318, and who 
have a clinical need and are likely to 
continue to benefit from extended 
treatment beyond Day 90 of the main 
study. 
Synopsis; 
Protocol body text 
throughout 
The description of the Day 84, End 
of Study (EOS), End of Treatment 
(EOT), and follow-up (FU) visits 
have been amended to describe the 
reporting of these visits for patients 
who complete the study during the 
main study phase and for those who 
require extended treatment. In 
addition, separate EOS, EOT, and 
FU visits are described for the main 
study phase and for the extended 
treatment phase. 
Additional detail has been provided to 
ensure key data from the main phase 
of the study are reported consistently 
and completely for all patients. 
Clarification of the data to be reported 
at the Day 84/EOS/EOT visit for 
patients who will receive extended 
treatment will ensure appropriate data 
are reported to evaluate the secondary 
endpoints of the main study.  


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Section Number 
and Name 
Description of Change 
Brief Rationale 
Synopsis; 
Section 4.1; 
Section 6.1.1; 
Section 6.3; 
Section 6.4.2; 
Section 6.5; 
Table 3 
The frequency of visits and the 
assessments to be conducted during 
the extended treatment phase of the 
study have been added. 
Assessment of the patients 
 
during the extended treatment 
phase will ensure management of 
these patients is monitored, will 
facilitate timely reporting of safety 
issues, and will confirm if continued 
treatment is justified. 
Synopsis; 
Section 4.3.1 
Text has been added to Inclusion 
Criterion 6 to clarify the process of 
susceptibility testing. 
The additional text describes the 
process for situations in which an 
isolate is not available for central 
laboratory testing. 
Synopsis; 
Section 4.1; 
Section 6.3.2; 
Section 8; 
Section 8.2.4; 
Section 8.8; 
Section 8.9; 
Section 8.9.3; 
Section 8.11 
Text has been added to describe the 
inclusion of all efficacy, safety, and 
pharmacokinetics (PK) data from 
the main study phase (treatment up 
to Day 84/90/EOT and the 
subsequent 4-week FU) in the 
primary clinical study report, and 
the inclusion of efficacy, safety, 
and PK data from the extended 
treatment phase in the report 
addendum. 
A two-stage approach to reporting the 
study data will allow timely reporting 
of the data supporting the objectives 
of the main study while allowing 
continued treatment of those patients 
who remain in the extended treatment 
phase of the study.   
Section 2.4: 
Section 4.1 
For patients going on to receive 
ET, the decision to continue to 
ET is based on the Investigator’s 
assessment that the patient has 
benefited from therapy to date 
and that extended therapy will 
offer value and has a favourable 
benefit-risk for the patient has 
been added to the benefit: risk 
statement. 
Extended treatment is provided at the 
request of the Investigator, based on 
the Investigator’s assessment of 
potential continued benefit. Extended 
treatment is to be discussed with the 
Medical Monitor (MM) and must be 
approved by the MM. 
Section 4.1 
Figure 1 (Study Flow Diagram) has 
been extended to describe the 
extended treatment phase of the 
study, and is presented as 2 separate 
figures for different treatment 
scenarios. 
Figure 1 and Figure 2 present a 
description of the progress of patients 
through the main study phase, and 
through the extended treatment phase 
for patients who are to receive 
continued treatment.  
Table 1 
Rows have been added to the table 
for EQ-5D-5L and for Fungal 
Susceptibility testing, with 
explanatory footnotes. 
The addition of these rows provides 
consistency with updates to the 
protocol synopsis and body text. 


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Section Number 
and Name 
Description of Change 
Brief Rationale 
Section 4.1.1; 
Table 3 
Section 4.1.1 and Table 3 have 
been added to provide details of the 
assessments required during the 
extended treatment phase. 
Guidance is provided to ensure 
patients who receive extended 
treatment are managed consistently, 
and data are recorded as required. 
Section 4.2 
‘Extended treatment is justified 
for those patients who have 
benefited from treatment with 
F901318 but whose IFD has not 
completely resolved after 84 to 90 
days of treatment and who would 
continue to benefit from further 
treatment with F901318. No 
alternative treatment options are 
available for these patients, and 
stopping treatment with F901318 
after 84 to 90 days could entail a 
risk of IFD exacerbation’ has 
been added. 
This text provides a rationale for 
extended treatment with F901318 in 
patients who have benefitted from 
treatment with F901318 and will 
continue to receive a benefit from 
continued treatment. 
Section 4.3.1.1 
Inclusion criteria for the extended 
treatment phase have been added. 
The Inclusion Criteria will ensure 
only eligible patients receive 
extended treatment with F901318. 
Section 4.3.2.1 
Exclusion criteria for the extended 
treatment phase have been added. 
The Exclusion Criteria will ensure 
only eligible patients receive 
extended treatment with F901318. 
Section 4.3.4 
‘ALT or AST meet criteria for 
major enzyme elevation AND 
total bilirubin > 1.5x ULN (if 
baseline < ULN) OR > 1.5x 
baseline (if baseline > ULN) 
without evidence of obstruction, 
malignancy, impaired 
glucuronidation capacity or 
another explanation as detailed in 
Appendix 3. Study drug must be 
stopped, and patient follow-up 
must be conducted in accordance 
with Appendix 3’ has been added 
to the description of circumstances 
leading to patient withdrawal. 
This text provides further detail of the 
changes in liver enzymes and 
bilirubin which require a patient to 
stop treatment with F901318, and 
provides consistency with other 
sections of the protocol relating to 
this issue. 
Section 5.1 
Guidance on dose interruptions has 
been added. 
The guidance will improve the 
consistency of management of 
patients when treatment with 
F901318 is interrupted. 


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Section Number 
and Name 
Description of Change 
Brief Rationale 
Section 5.9; 
Section 6.2.6 
Further detail has been added to 
clarify the requirements for 
recording of prior and concomitant 
treatments. 
The additional detail will improve the 
consistency of recording of prior and 
concomitant treatments. 
Section 6.2.4 
Further detail has been added to 
clarify the requirements for 
recording of infectious disease 
history and microbiological 
assessments. 
The additional detail will improve the 
consistency of recording of infectious 
disease history and microbiological 
assessments. 
Section 6.3.1.4 
Detail has been added to describe 
the requirements for shipping of 
isolates, tissues, or biological fluid 
samples to an appropriate central 
laboratory for confirmation of 
diagnosis. 
Text has been added to describe the 
CSF findings for diagnosis of 
patients with coccidioidomycosis. 
Correct collection and shipping of 
samples for central laboratory 
confirmation of diagnosis and 
susceptibility testing is an essential 
requirement of the study. 
 
This text provides additional 
information concerning identification 
of patients with endemic fungal 
infection. 
Section 6.4.1; 
Section 6.4.1.2 
Text has been added to further 
define adverse events and to 
describe in more detail the 
requirements for reporting adverse 
events. 
The additional detail will improve the 
consistency of recording adverse 
events, and reinforces the 
requirements and responsibilities for 
reporting adverse events. 
Section 6.4.2.2 
Text has been added to further 
define neutropenic status. 
The detail clarifies the definition of 
neutropenia. 
Appendix 2 
Changes have been made to 
definitions of invasive fungal 
diseases in anticipation of a planned 
update to the definitions. 
The changes are being made before 
formal update of the definitions to 
improve the consistency of diagnosis 
over the course of the study. 
 
 
 
Further minor changes have been made throughout the protocol to correct typographical errors 
and to clarify text. 
Amendment 03 
28 November 2018 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for Amendment 03: 


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The descriptions of End of Treatment and End of Study have been updated to clarify the process 
for patients who will receive ET with F901318 beyond the 90 days via an ET mechanism outside 
the scope of this protocol. 
Description of the loading and maintenance doses of F901318 have been updated to acknowledge 
the fact that an exact mg/kg dose can not be achieved for most patients when whole 30 mg tablets 
are administered. A description of the formulation of F901318 tablets has been added. 
The inclusion criteria have been updated to describe the process for enrolment of patients with 
multiple fungal infections, and to permit management of patients with resistant isolates in 
accordance with the Investigator’s clinical judgement. 
The exclusion criteria have been updated to clarify criteria or to remove restrictions based on 
current knowledge, and to implement exclusions which may be required by local regulatory 
authorities. 
Information concerning concomitant medications and concomitant antifungal therapy has been 
updated to provide more detailed guidance. 
A description of the possible circumstances and processes for study termination has been added. 
The definitions of treatment success and failure have been updated to improve the consistency 
and clarity of these definitions. Further guidance has been added relating to prior and baseline 
symptoms, and to microbiological assessments.  
The adverse events of special interest have been updated 
 
 
Additional information has been added to provide an improved description of the rationale for the 
sample size and the comparisons to be conducted on the study data. 
Description of Changes in Amendment 03: 
 




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Section Number 
and Name 
Description of Change 
Brief Rationale 
Synopsis; 
Section 4.3.1 
Inclusion Criteria 
In General Inclusion Criterion 6, ‘If 
the isolate is subsequently found to 
be resistant, study therapy may be 
continued or discontinued based 
on clinical response at the 
discretion of the Investigator. 
Patients with infections due to 
multiple fungi can be enrolled 
provided at least one fungus is 
known or predicted to be 
F901318-susceptible AND the 
patient has limited alternative 
treatment options for that fungus 
as defined in Inclusion Criterion 
7. As a specific example, a patient 
with simultaneous IA due to an 
azole-resistant strain and also 
invasive mucormycosis could be 
enrolled and treated with the 
combination of F901318 and 
isavuconazole. The choice of 
additional agents to treat other 
fungi should also consider the 
limitations applied to allowed 
medications. Cases of polyfungal 
infection should be discussed with 
the MM’ has been added. 
Investigator discretion to continue 
treatment of patients with resistant 
isolates has been added to allow 
continued treatment of patients if the 
Investigator is confident a clinical 
benefit is achieved. 
 
Enrolment of patients with infections 
due to multiple fungal species if at 
least one species is susceptible to 
F901318 will allow treatment of 
patients who have a mixture of 
susceptible and resistant fungal 
infections. 
Synopsis; 
Section 4.3.2 
Exclusion Criteria 
Exclusion Criterion 4 has been 
amended: Suspected zygomycosis 
(mucormycosis) as the IFD used 
to qualify for the study has been 
added. Increased vigilance for the 
possibility of zygomycosis is 
required for suspected IA with 
negative baseline GM has been 
added. ‘and treatment should not 
be started or adapted. In 
particular, suspected IA with 
negative baseline galactomannan 
(GM) should generally trigger 
increased vigilance’ has been 
deleted. 
This statement emphasizes to 
Investigators the lack of activity of 
F901318 against this fungal species. 


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Section Number 
and Name 
Description of Change 
Brief Rationale 
Synopsis; 
Section 4.3.2 
Exclusion Criteria 
In Exclusion Criterion 7, 
endocarditis has been deleted as an 
example of a condition that ‘may 
jeopardize adherence to the 
protocol requirements or impede 
the accurate measurement of 
efficacy.’ 
With the implementation of extended 
dosing approaches for selected 
patients, this example was judged 
overly restrictive. 
Synopsis; 
Section 4.3.2 
Exclusion Criteria 
Exclusion Criterion 12d has been 
deleted: Intended use of new 
concomitant medications that 
prolong the QT/QTc interval. 
Nonclinical studies of F901318 have 
demonstrated minimal potential to 
affect the QT/QTc interval, and this 
has been confirmed in clinical studies 
showing a lack of effect on QT/QTc 
interval across the therapeutic 
exposure range. 
Synopsis; 
Section 4.3.2 
Exclusion Criteria 
Detail has been added to Exclusion 
Criterion 14: Concomitant 
administration of inhibitors of 
human DHODH (teriflunomide 
and leflunomide) is prohibited. 
There are currently no other 
absolutely prohibited 
concomitant medications but 
there are medications with 
potentially significant DDIs and 
the management of potential 
interactions should be considered 
before study enrolment. 
The additional text identifies the 
prohibited concomitant medications, 
and provides context for 
consideration of other concomitant 
medications. Even though nonclinical 
biochemical testing predicts a lack of 
cross-over effects between human and 
fungual DHODH, concomitant 
therapy with inhibitors of the human 
DHODH enzyme has been prohibited 
as a precautionary measure. 
Synopsis; 
Section 4.3.2 
Exclusion Criteria 
Exclusion Criterion 15 has been 
added: Additional exclusion 
criteria required by local 
regulatory authorities. 
This exclusion criterion has been 
added to facilitate compliance with 
specific local regulatory authority 
requirements. 


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Section Number 
and Name 
Description of Change 
Brief Rationale 
Synopsis: 
 
Detail has been added to the 
Concomitant medication section: 
Concomitant administration of 
teriflunomide and leflunomide is 
prohibited. There are no other 
absolutely prohibited or 
contraindicated medications. 
However, there are potential 
DDIs with F901318 and the 
choice of concomitant 
medications should take this into 
consideration and  
Data to date suggest that F901318 
does not prolong the QTc 
interval, and concomitant agents 
with known potential to prolong 
the QTc interval may be used 
with caution. Ongoing therapy 
with an agent known to have a 
risk of QT prolongation is not a 
contraindication for enrolment 
provided the patient meets the 
requirements of Exclusion 
Criterion 12. After enrolment, 
initiation of new concomitant 
treatment with known QTc-
prolonging agents must be 
discussed with and approved by 
the MM. 
The revised text provides more 
detailed guidance on the use of 
concomitant medication, and the 
rationale for this guidance. The 
guidance relates to specific 
medication with potential for drug-
drug interaction, and medications 
which may affect the QT/QTc 
interval. 


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Synopsis 
The Concomitant Antifungal 
Therapy section has been revised:  
New text has been added: In order 
to meaningfully analyse the 
efficacy of F901318, it is 
important to avoid concomitant 
use of other systemic antifungal 
agents with known or potential 
activity against the primary 
fungal infection. The constraints 
on the choice of additional agents 
may be complex and thus use of 
any other systemic concomitant 
antifungal or combination 
treatment (such as addition of 
terbinafine for confirmed 
Lomentospora prolificans 
infections or an echinocandin to 
manage infection due to Candida) 
is permitted but is discouraged. 
Antifungal combinations should 
be based on the Investigator’s 
clinical judgement and must be 
discussed with the MM. 
Depending on the treatment 
given, an extra visit for 
Unscheduled Trough PK 
sampling (for TDM analysis of 
F901318) may be required 3 to 5 
days after starting or stopping 
such concomitant medication, to 
assess potential DDIs and to 
enable dose adjustment of 
F901318 as needed. There is also 
the potential for further 
Unscheduled Trough PK samples 
to assess the impact of any dose 
adjustments made. In addition, 
an Unscheduled Intensive PK 
sampling day may be advised to 
evaluate the PK of F901318 and 
 
Original text has been deleted: Use 
of concomitant treatment for 
Candida (or other yeast) infection 
with fluconazole or an 
echinocandin is permitted in all 
patients at any time during the 
study. An extra visit for 
Unscheduled Trough PK 
The revised text provides more 
detailed guidance on the use of 
concomitant antifungal medication, 
and the rationale for this guidance. 


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Section Number 
and Name 
Description of Change 
Brief Rationale 
sampling (for TDM analysis of 
F901318) will occur 3 to 5 days 
after starting or stopping such 
concomitant medication, to assess 
potential DDIs and to enable dose 
adjustment of F901318 as needed, 
with the potential for further 
Unscheduled Trough PK samples 
to assess the impact of any dose 
adjustments made. In addition, 
an Unscheduled Intensive PK 
sampling day is advised to 
evaluate the PK of F901318 and 
  
Use of any other systemic 
concomitant antifungal or 
combination treatment (such as 
addition of terbinafine) for 
confirmed Lomentospora 
prolificans infections is permitted 
but is discouraged. 
Antifungal combinations should 
be based on the Investigator’s 
clinical judgement and must be 
discussed with the MM. 
Synopsis 
A note has been added to the 
Efficacy Endpoints: Note: For 
patients who will continue therapy 
beyond Day 90 under an extended 
dosing mechanism, the Day 84 
visit and the EOT visit will be 
combined into a single Day 
84/EOT visit on approximately 
Day 90 and there will be no 4-week 
FU visit. 
This note describes the consolidation 
of the EOT and EOS visits for 
patients who will receive extended 
treatment with F901318, and that no 
post-treatment follow-up is required 
after EOS/EOT. 




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Section Number 
and Name 
Description of Change 
Brief Rationale 
Section 4.1 Summary 
of Study Design 
Figure 1 has been added. 
 
 
 
Paragraph 4, text has been added: 
Patients with infections due to 
multiple fungi can be enrolled 
provided at least one fungus is 
known or predicted to be 
F901318-susceptible. 
 
Paragraph 5, text has been deleted: 
On Day 1 of treatment, all 
patients weighing 75 kg or more 
will receive 300 mg of F901318 
divided into 2 or 3 doses. 
 
Table 1, Visit 12a at Day 35 has 
been added. 
 
 
 
Table 1, various footnotes have 
been amended. 
Figure 1 is a simple schematic to 
describe the overall design of the 
study. 
 
The text has been added to describe 
the circumstances under which a 
patient with multiple fungal infection 
may be enrolled in the study. 
 
 
 
This text is not required, and has been 
deleted to avoid possible confusion. 
 
 
 
 
This visit is solely to take a blood 
sample to measure liver enzymes and 
bilirubin, to ensure continued 
monitoring and risk management. 
 
Footnotes have been amended to be 
consistent with changes to the 
protocol text. 
Section 4.3.5 Study 
Termination 
Section 4.3.5 has been added. 
The previous version of the protocol 
had no description of the possible 
circumstances and processes for study 
termination. 
Section 5.1 
Treatments 
Administered 
Various minor text changes have 
been made. 
 
 
Table 3 has been added. 
Changes have clarified the text and 
provided further detail related to 
study drug treatment. 
 
Table 3 describes the number and 
frequency of tablets to be 
administered relative to patient body 
weight. 
Section 5.2 Identity 
of Investigational 
Products 
Text has been added to describe the 
formulation of F901318 tablets. 
The previous version of the protocol 
had no description of the formulation 
of F901318 tablets. 


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Section Number 
and Name 
Description of Change 
Brief Rationale 
Section 5.9.1 
Excluded 
Medications 
Text has been added to describe 
prohibited medications. 
 
Section 5.9.1.1 Agents with a 
potential effect on the QT 
interval has been added. 
 
Section 5.9.1.2 Interaction of 
F901318 with Concomitant 
Medication, a brief summary of 
key points has been added. 
 
Section 5.9.2.1 Candida 
Prophylaxis and Concomitant 
Antifungal Therapy; text has been 
added to paragraph 2 to provide 
perspective on the effect of other 
antifungal therapy on the analysis 
of efficacy. 
Additional detail concerning the 
potential issues associated with the 
use of concomitant medications has 
been added to facilitate decisions 
taken by the Investigator. 
Section 6.2.4 
Infectious Disease 
History and 
Microbiological 
Assessments 
The text of Section 6.2.4 Infectious 
Disease History and 
Microbiological Assessments has 
been amended to clarify the 
schedule for mycology, virology 
and bacteriology assessments. 
Additional information has been 
provided to improve the consistency 
of recording data. 
Section 6.3.1 
Investigator’s 
Assessment of 
Overall Response 
Text has been added to Section 
6.3.1 Investigator’s Assessment of 
Overall Response to describe the 
assessment of response for patients 
who have multiple fungal 
infections. 
 
Text has been added to Section 
6.3.1.1 Clinical Response to clarify 
the recording of prior symptoms 
and baseline symptoms, particularly 
for patients who are asymptomatic 
at baseline. 
 
In Section 6.3.1.1 Clinical 
Response, the definitions of 
Resolution-Complete and 
Resolution-Partial have been 
extended to provide further detail. 
Additional information has been 
provided to clarify the issues relating 
to patients with multiple fungal 
infections. 
 
 
 
Additional information has been 
provided to clarify the procedures for 
recording prior symptoms and 
baseline symptoms. These changes 
habe been approved by the Data 
Review Committee.  
 
Additional information has been 
provided to clarify the definitions of 
resolution. 




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The text referring to methods of birth control has been amended to be consistent with the Clinical 
Trial Facilitation Group definition of highly effective methods of contraception. (These changes 
are also included in Local Amendment 01-01.) 
The background information has been updated to describe emerging data from Phase I studies in 
healthy volunteer subjects. 
The definitions of treatment success and failure have been updated to improve the consistency 
and clarity of these definitions. 
Summary of Changes in Amendment 02 


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Section Number and 
Name 
Description of Change 
Brief Rationale 
Synopsis; 
Section 4.1 Summary of 
Study Design; 
Section 4.2 Discussion of 
Study Design; 
Section 5.1 Treatments 
Administered 
The loading dose has been changed from 
120 mg every 12 hours to 4 mg/kg 
divided into 2 or 3 doses. 
The maintenance dose has been changed 
from 60 mg twice daily to 2.5 
mg/kg/day divided into 2 or 3 doses. 
A maximum daily dose of 300 mg, 
divided into 2 or 3 doses, has been 
included. 
The amended text is based on emerging 
data from Phase I studies in healthy 
volunteer subjects. 
The maximum daily dose has not 
previously been defined. 
Synopsis; 
Section 4.3.1 Inclusion 
Criteria 
For Inclusion Criterion 6, Enrolment is 
based on presumed F901318 
susceptibility for categories a-c and 
selected other species as described in 
the IB. For IFD due to isolates from 
species of uncertain susceptibility, 
enrolment may occur with the 
approval of the MM before isolate 
susceptibility is confirmed. If the 
isolate is subsequently found to be 
resistant, study therapy may be 
discontinued has been added. 
This amendment will allow prompt 
enrolment of patients while 
susceptibility testing is underway. 
Synopsis; 
Section 4.3.2 Exclusion 
Criteria 
For Exclusion Criterion 6, In cases 
where HIV infection is first diagnosed 
at the same time as the invasive fungal 
infection, if antiretroviral therapy is 
commenced at the time of enrolment, 
then such patients are eligible for 
enrolment has been added. 
This amendment will allow patients with 
newly diagnosed HIV infection to be 
included in the study. 
Synopsis; 
Section 4.3.2 Exclusion 
Criteria 
The text of Exclusion Criterion 12d, has 
been changed from Use of concomitant 
medications proven to prolong the 
QT/QTc interval to Intended use of 
new concomitant medications proven 
to prolong the QT/QTc interval. 
This amendment will allow patients 
who, at the time off enrolment, are 
receiving a stable dose of concomitant 
medication with the potential to prolong 
the QT/QTc interval and have a QTcF 
interval < 500 msec to be included in the 
study.  
Synopsis; 
Section 5.1 Treatments 
Administered 
An adjustment to loading and/or 
maintenance doses of F901318 may be 
required for patients who are being 
treated with drugs that either inhibit 
or induce CYP enzymes (or if such 
drugs are started or stopped) has been 
added. 
An adjustment to the maintenance 
dose of F901318 may be required if 
patients develop abnormal liver 
enzymes, or if trough plasma levels of 
F901318 are outside the target range 
has been added. 
The amended text clarifies factors which 
can initiate dose adjustment. 


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Synopsis; 
Section 5.1 Treatments 
Administered; 
Section 5.6 Selection and 
Timing of Dose for Each 
Patient 
A dose adjustment may be required 
for patients weighing between 40 kg 
and 60 kg has been deleted. 
This text is no longer required, as the 
amended dosage regimen is based on 
body weight. 
Synopsis 
Section 4.3.1 Inclusion 
Criteria  
The text of Inclusion Criterion 4c has 
been changed from  
(hormonal implants, oral or injected 
hormonal contraceptives, intrauterine 
devices, two barrier methods such as a 
condom and a cervical cap) 
throughout the course of the study 
period. Reliable sexual abstinence is 
acceptable as a highly effective 
method of birth control for the 
purposes of this study. Periodic 
abstinence (e.g. calendar, ovulation, 
symptothermal, or post ovulation 
methods) and withdrawal are not 
acceptable methods of contraception 
to  
throughout the course of the study 
period: 
i)   Established use of oral, injected, 
transdermal, intravaginal or 
implanted hormonal methods of 
contraception associated with 
inhibition of ovulation 
ii)  Placement of an intrauterine 
device or intrauterine hormone-
releasing system 
iii) Male sterilisation (with the 
appropriate post-vasectomy 
documentation of the absence of 
sperm in the ejaculate) 
iv) Bilateral tubal occlusion 
v)  Sexual abstinence (reliable sexual 
abstinence is acceptable but periodic 
abstinence [e.g. calendar, ovulation, 
symptom-thermal, or post ovulation 
methods] and withdrawal are not 
acceptable). 
In the text of Inclusion Criterion 5, 
abstain has been changed to totally 
abstain, and reliable has been changed 
to highly effective. 
The amended text is consistent with the 
Clinical Trial Facilitation Group 
definition of highly effective methods of 
contraception. 
These changes are also included in Local 
Amendment 01-01. 


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Section 4.3.3 Patient 
Restrictions 
In the bullet referring to Female patients 
of child bearing potential: 
Established use of oral, injected or 
implanted hormonal methods of 
contraception  
has been changed to  
Established use of oral, injected, 
transdermal, intravaginal or 
implanted hormonal methods of 
contraception associated with 
inhibition of ovulation. 
Placement of an intrauterine device or 
intrauterine system  
has been changed to 
Placement of an intrauterine device or 
intrauterine hormone-releasing 
system. 
Double barrier method of 
contraception, such as condom and 
occlusive cap (diaphragm or cervical/ 
vault caps) with spermicidal foam/gel/ 
film/cream/suppository has been 
deleted. 
Bilateral tubal occlusion has been 
added. 
Sexual abstinence (reliable sexual 
abstinence is acceptable but periodic 
abstinence [e.g. calendar, ovulation, 
symptom-thermal, or post ovulation 
methods] and withdrawal are not 
acceptable has been added. 
In the bullet referring to Male patients 
with female partners of childbearing 
potential: 
reliable has been changed to highly 
effective. 
 






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Section 6.3.1.1 Clinical 
Response 
Resolution of all attributable clinical 
symptoms and physical findings (i.e. 
resolution of all clinical symptoms and 
physical findings of IFD present at 
baseline and resolution of any clinical 
symptoms and physical findings of 
IFD that appeared at a subsequent 
visit and no new clinical symptoms 
and physical findings of IFD at that 
visit) has been changed to  
Resolution-Complete: Resolution of 
all attributable clinical symptoms and 
physical findings of IFD present at 
baseline or that appeared at a 
subsequent prior visit AND no new 
clinical symptoms and physical 
findings of IFD at the current visit. 
 
Resolution of some attributable 
clinical symptoms and physical 
findings (i.e. resolution of some but 
not all clinical symptoms and physical 
findings of IFD present at baseline 
and/or of some but not all clinical 
symptoms and physical findings of 
IFD that appeared at a subsequent 
visit and no new clinical symptoms 
and physical findings of IFD at that 
visit) has been changed to 
Resolution-Partial: Some persistence 
of the attributable clinical symptoms 
and physical findings of IFD noted 
either at baseline or at a subsequent 
prior visit but there is improvement in 
at least some of these same symptoms 
and findings AND no worsening of 
any of these same symptoms and 
findings AND no new clinical 
symptoms and physical findings of 
IFD at the current visit. 
 
No resolution of any attributable 
clinical symptoms and physical 
findings and/or worsening (i.e. no 
resolution or worsening of any clinical 
symptoms and/or physical findings of 
IFD present at baseline and of clinical 
symptoms and physical findings of 
IFD that appeared at a subsequent 
visit and/or appearance of new clinical 
symptoms and physical findings of 
IFD at that visit) has been changed to  
Failure-Stable: Neither worsening nor 
improvement in any attributable 
clinical symptoms and physical 
findings present at baseline or that 
The amended text clarifies the 
definitions of treatment success and 
treatment failure and improves 
consistency between the definitions. 


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appeared at a subsequent prior visit 
AND no new clinical symptoms and 
physical findings of IFD at the current 
visit. 
 
Failure-Progression: Shows EITHER 
worsening in one or more attributable 
clinical symptoms and physical 
findings present either at baseline or 
that appeared at a subsequent prior 
visit OR appearance of new clinical 
symptoms and physical findings of 
IFD at the current visit has been 
added. 
Section 6.3.1.2 
Radiological Response 
in aggregate (across all lesions if more 
than one lesion) has been added to the 
definitions referring to improvement. 
 
< 25 % improvement has been changed 
to No change (0%) to < 25 % 
improvement. 
 
Worsening in aggregate (across all 
lesions if more than one lesion) has 
been added. 
The amended text clarifies the 
definitions of treatment success and 
treatment failure and improves 
consistency between the definitions. 


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Section 6.3.1.5 
Investigator’s 
Assessment of Overall 
Response 
Table 4 has been updated: 
 
Success-Complete has been changed 
from: 
• Resolution of all clinical symptoms 
and physical findings associated with 
IFD; 
• Resolution of radiological 
abnormalities (≥90% response in 
some cases); 
• Presumed or documented 
eradication. 
to: 
• Clinical: Shows resolution of all 
attributable clinical symptoms and 
physical findings associated with IFD 
(Resolution Complete); 
AND 
• Radiological: Shows resolution of 
radiological abnormalities (≥90% 
response); 
AND 
• Mycological: Meets criteria for 
presumed or documented eradication. 
 
Success-Partial has been changed from: 
• Resolution of some clinical 
symptoms and physical findings 
associated with IFD; 
• Improvement of radiological 
abnormalities (at least 25% response 
at Day 42 or 50% at Day 84); 
• Presumed or documented 
eradication. 
to: 
• Clinical: Shows resolution or 
improvement of some or all 
attributable clinical symptoms and 
physical findings of IFD, with no 
worsening of any previously noted 
clinical symptoms or physical findings 
and no new clinical symptoms or 
physical findings of IFD (Resolution-
Complete or Resolution-Partial); 
AND 
• Radiological: Shows resolution or 
improvement of radiological 
abnormalities (at least 25% response); 
AND 
• Mycological: Meets criteria for 
presumed or documented eradication. 
 
The amended text clarifies the 
definitions of treatment success and 
treatment failure and improves 
consistency between the definitions. 


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Failure-Stable has been changed from: 
• Minor or no change in clinical 
symptoms and physical findings; 
• Radiographic abnormalities 
associated with IFD but no evidence of 
progression OR < 25% improvement 
of radiological abnormalities. 
to: 
• Clinical: No improvement and no 
worsening of any attributable clinical 
symptoms and physical findings 
previously noted and no new 
attributable clinical symptoms or 
physical findings of IFD (Failure-
Stable); 
OR 
• Radiological: Shows no evidence of 
progression OR < 25% improvement 
of radiological abnormalities; 
OR 
• Mycological: Had mycological 
evidence at baseline AND does not 
meet criteria for presumed or 
documented eradication. 
 
Failure-Progression has been changed 
from: 
• Evidence of progression based on 
clinical, radiologic and mycological 
criteria; 
• Worsening or new clinical symptoms 
and physical findings and/or 
radiographic abnormalities associated 
with IFD; 
• Alternative systemic antifungal 
treatment required. 
to: 
• Clinical: Either worsening of 
attributable clinical symptoms or 
physical findings of IFD or 
appearance of new attributable 
symptoms or findings of IFD (Failure-
Progression); 
OR 
• Radiological: Worsening or new 
radiological abnormalities; 
OR 
• Mycological: Has mycological 
evidence for a recurrent or emergent 
IFD, OR alternative systemic 
antifungal treatment required. 


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Throughout 
Minor editorial and document formatting 
revisions 
Minor, therefore have not been 
summarized 
 
Amendment 01: 24 January 2018 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for Amendment 01 
Analysis of pharmacokinetic data from Phase 1 studies in healthy volunteers supports the use of a 
twice daily dosage regimen of F901318 to provide exposure within the predicted therapeutic 
range. The frequency of dosing has been changed from 4 times daily to 2 times daily based on 
these pharmacokinetic data. The frequency of blood sample collection when Intensive PK is 
being assessed has been amended to be consistent with the change in dose frequency. 
Summary of Changes in Amendment 01 




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SAP_001.pdf: 
Statistical Analysis Plan 
 
Clinical trial protocol number: F901318/0032 
 
Protocol Title: An open-label single-arm Phase IIb study of F901318 as treatment of 
invasive fungal infections due to Lomentospora prolificans, Scedosporium spp., 
Aspergillus spp., and other resistant fungi in patients lacking suitable alternative 
treatment options 
 
NCT number: NCT03583164 
 
Document date: 06 April 2023