A Phase 1, Multicentre, Open-Label Study to Evaluate the PK, Safety, and Tolerability of a Single IV Dose of Rezafungin in Paediatric Subjects, Receiving Systemic Antifungals as Prophylaxis for IFI or to Treat a Suspected or Confirmed FI
Phase: PHASE1
Conditions: Invasive Fungal Infections
Sponsor: Mundipharma Research Limited

 
 
 
 
Clinical Study Protocol 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 1 of 86 
Title Page 
Protocol Title: 
A Phase 1, Multicentre, Open-Label Study to Evaluate the 
Pharmacokinetics, Safety, and Tolerability of a Single IV 
Dose of Rezafungin Acetate in Paediatric Subjects from Birth 
to <18 Years of Age, Receiving Systemic Antifungals as 
Prophylaxis for Invasive Fungal Infection or to Treat a 
Suspected or Confirmed Fungal Infection 
Protocol Number: 
MR907-1501 
Amendment Number:  
3 
Investigational Medicinal 
Product: 
Rezafungin acetate (MR907) 
Brief Title: 
Rezafungin Paediatric PK study 
Study Phase: 
1 
Regulatory Agency 
Identifier Number: 
EU CT number 2022-501985-23-00 
Name and Address of the 
Sponsor: 
Mundipharma Research Ltd. 
Unit 196, Cambridge Science Park, Milton Road, 
Cambridge CB4 0AB, United Kingdom 
Sponsor Medical Monitor: 
Gu-Lung Lin, MD, DPhil 
Mundipharma Research Ltd. 
Unit 196, Cambridge Science Park, Milton Road, 
Cambridge CB4 0AB, United Kingdom 
Mobile: +44 (0) 7810 334530 
Email: gu-lung.lin@mundipharma-rd.eu 
Version, Date: 
Version 4.0, 18 Jul 2023 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 2 of 86 
Good Clinical Practice 
(GCP) Statement 
This study will be performed in compliance with the principles 
of GCP and applicable local regulations. 
 
 
 
Confidentiality 
The information in this document is confidential and is proprietary to Mundipharma Research 
Limited (the Sponsor). Any viewing or disclosure to any third party without prior consent from 
the Sponsor is strictly prohibited. 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 3 of 86 
PROTOCOL SIGNATURE PAGE – SPONSOR 
This protocol has been reviewed and approved by the representative(s) listed below. Any 
modification of the protocol must be agreed upon by the Sponsor and the Investigator and must 
be documented in writing. 
Mundipharma representative(s): 
 
Gu-Lung Lin, MD, DPhil 
 
Senior Manager, Clinical Development 
Print Name 
 
Title 
 
 
 
Signature 
 
Date 
 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 4 of 86 
 
APPROVAL 
Principal Investigator/Co-ordinating Investigator Signature Page 
Study Title 
A Phase 1, Multicentre, Open-Label Study to Evaluate the 
Pharmacokinetics, Safety, and Tolerability of a Single IV Dose of 
Rezafungin Acetate in Paediatric Subjects from Birth to <18 Years of Age, 
Receiving Systemic Antifungals as Prophylaxis for Invasive Fungal 
Infection or to Treat a Suspected or Confirmed Fungal Infection 
Protocol No. 
MR907-1501 
Version Date 
18 Jul 2023 
Version 
4.0 
I, the undersigned, have read and understood the Clinical Study Protocol (CSP) specified above 
and agree on its content. I agree to perform and conduct the clinical study as described in this 
CSP and in accordance with the Declaration of Helsinki, International Conference on 
Harmonisation (ICH) GCP, local applicable laws and regulations. 
 
Name: 
 
Signature: 
Date: 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 5 of 86 
Protocol Amendment Summary of Changes 
Document History 
Document 
Date 
Protocol Version Number 
Amendment 3 
18 Jul 2023 
4.0 
Amendment 2 
26 May 2023 
3.0 
Amendment 1 (UK) 
17 Apr 2023 
2.0 (UK) 
Amendment 1 
16 Mar 2023 
2.0 
Original Protocol 
16 Sep 2022 
1.0 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 6 of 86 
1 
CLINICAL PROTOCOL SYNOPSIS  
Protocol Title: A Phase 1, Multicentre, Open-Label Study to Evaluate the 
Pharmacokinetics, Safety, and Tolerability of a Single IV Dose of Rezafungin Acetate in 
Paediatric Subjects from Birth to <18 Years of Age, Receiving Systemic Antifungals as 
Prophylaxis for Invasive Fungal Infection or to Treat a Suspected or Confirmed Fungal 
Infection 
Protocol Number: MR907-1501 
Study Phase: 1 
Sponsor: Mundipharma Research Ltd. 
Study Rationale: This study will assess the pharmacokinetics (PK), safety, and tolerability 
of a single intravenous (IV) dose of rezafungin in paediatric subjects from birth to 
<18 years who are receiving concomitant systemic antifungals as clinically indicated. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To evaluate the pharmacokinetics (PK) of a 
single IV dose of rezafungin in paediatric 
subjects from birth to <18 years, receiving 
concomitant systemic antifungals as 
prophylaxis for invasive fungal infection (IFI) or 
to treat a suspected or confirmed fungal 
infection 
Parts 1 and 2: The following PK parameters 
will be assessed: 
Cmax, Tmax, AUC0-t, AUC0-∞, CL, Vss, Vz, t1/2 
 
Part 3: Rezafungin plasma concentrations 
Secondary 
 
To assess the safety and tolerability of a single 
IV dose of rezafungin in paediatric subjects 
from birth to <18 years, receiving concomitant 
systemic antifungals as prophylaxis for IFI or to 
treat a suspected or confirmed fungal infection 
The safety evaluation will be based on clinical 
review of the following parameters: 
• 
Incidence of treatment-emergent adverse 
events (TEAEs)  
• 
Clinical laboratory evaluations (including 
haematology, blood chemistry and 
urinalysis) 
• 
Vital signs 
• 
12-lead electrocardiograms (ECGs): 
clinically significant abnormalities 
• 
Physical examination findings  

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 7 of 86 
Number of Subjects and Key Inclusion/Exclusion Criteria: 
It is planned to enrol 32 subjects (up to a maximum of 40 subjects [10 per age group] to 
achieve 32 subjects evaluable for primary analysis).  
Eligible subjects will be enrolled into one of the following 4 age groups (8 patients planned 
per age group): 
• 
Group 1 (12 to <18 years): 8 subjects  
• 
Group 2 (6 to <12 years): 8 subjects 
• 
Group 3 (2 to <6 years): 8 subjects 
• 
Group 4 (birth to <2 years): 8 subjects 
Subjects who are withdrawn from the study before completing all PK sampling may be 
replaced (up to 2 replacement subjects per group is allowed). 
Key Inclusion Criteria  
Male or female paediatric subjects from birth to <18 years of age who are receiving 
concomitant systemic antifungals (oral or IV) as prophylaxis for invasive fungal infection 
(IFI) or to treat a suspected or confirmed fungal infection. 
Key Exclusion Criteria 
History of anaphylaxis, hypersensitivity, or any serious reaction to the echinocandin class 
of antifungals and/or excipients of this formulation; Previous or current medical conditions 
of severe ataxia, persistent tremors, intracranial haemorrhage or neuropathy, or a 
diagnosis of epilepsy, multiple sclerosis, or a movement disorder (including, but not limited 
to, cerebral palsy and muscular dystrophy); Subjects with impaired renal or hepatic 
functions (alanine aminotransferase or aspartate aminotransferase >3 times the upper limit 
of normal, conjugated bilirubin >24 µmol/L [1.4 mg/dL], serum creatinine >177 µmol/L 
[2 mg/dL], or receiving renal replacement therapy); Subjects with intestinal hypoxia, 
ischaemia, necrosis, or necrotising enterocolitis; Subject status is unstable (e.g., with 
sepsis or disseminated intravascular coagulation), and subject is unlikely to complete 
required study procedures; Participation in another interventional treatment trial with an 
investigational agent or presence of an investigational device at the time of informed 
consent or within 28 days preceding the informed consent. 
Summary of Study Design: 
This is a Phase 1, multicentre, open-label, single-dose study. The study will be conducted 
at approximately 10 sites across at least 3 countries in Europe. 
The study will be conducted in 3 parts:  
• 
Part 1 will include subjects aged 12 to <18 years (Group 1) 
• 
Part 2 will include subjects aged 6 to <12 years (Group 2), and subjects aged 2 to 
<6 years (Group 3). 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 8 of 86 
• 
Part 3 will include subjects from birth to <2 years (Group 4)  
The study design for the 3 parts is similar and comprises a Screening (pre-treatment) 
period from Day -3 to Day -1, Dosing on Day 1 (single IV infusion of rezafungin) followed 
by multiple PK sampling, and a Follow-up visit on Day 30 (± 5 days) (Figure 1Figure 1, 
Table 1, Table 2). PK sampling will be performed at specified timepoints for each group.  
Part 1: Subjects in Group 1 (12 to <18 years) will be dosed first. For this group, the 
formulation to be used will be same as the one used in the adult clinical trials at a dose of 
3 mg/kg (not to exceed a total dose of 200 mg). PK sampling will be performed at the 
following 5 timepoints: at end-of-infusion ± 15 minutes, and thereafter between 3 and 
4 hours after start of the infusion, between 6 and 8 hours after start of the infusion, at 
48 hours (± 4 hours) after start of the infusion (Day 3), and at 168 hours (± 12 hours) after 
start of the infusion (Day 8). The exact date and time of the PK samples must be recorded. 
An interim review of safety and PK data will be conducted by the Data Safety Monitoring 
Board (DSMB) after completion of Group 1. The data will be reviewed by the DSMB to 
ensure that exposure achieved in the subjects from this group is safe and well tolerated. 
This will allow for a decision to proceed to Part 2.  
In parallel to this study a formulation development programme is being undertaken to 
identify a paediatric specific formulation for use in subjects <12 years of age. Once the 
paediatric formulation is available for use, after completion of Part 1, the study will be 
paused and a substantial amendment will be submitted to enable use of the paediatric 
formulation in Part 2 and Part 3 (for dosing in subjects <12 years of age).  
Part 2: Enrolment for Group 2 and Group 3 will commence after safety has been 
confirmed by the DSMB and the paediatric formulation has been identified and ready to be 
used. The planned dose in these age groups is 4 mg/kg (not to exceed a total dose of 
200 mg). The PK sampling timepoints for Part 2 will be the same as that dosefor Part 1: at 
endofinfusion ± 15 minutes, and thereafter between 3 and 4 hours after start of the 
infusion, between 6 and 8 hours after start of the infusion, at 48 hours (± 4 hours) after 
start of the infusion (Day 3), and at 168 hours (± 12 hours) after start of the infusion 
(Day 8). The dose and PK sampling timepoints may be adjusted as appropriate after 
assessment of the PK and safety data of Part 1. 
A second interim review of safety and PK data will be performed when data from 50% of 
the subjects enrolled in Part 2 (Group 2 and Group 3) are available. The dose and PK 
sampling timepoints may be adjusted as appropriate after review of the PK and safety data 
(DSMB review 2). After completion of Groups 2 and 3; there will be another interim DSMB 
review (DSMB review 3) of the safety, tolerability, and PK data from the subjects in 
Groups 1, 2, and 3 (all subjects in Part 1 and Part 2). 
A series of juvenile animal toxicity studies will be conducted in parallel with this PK study to 
investigate the effect of rezafungin on the growing and developing nervous system. 
Enrolment for Group 4 will not start until the juvenile animal toxicity studies are completed, 
Formatte
Color(RGB
Formatte
Custom C
grammar

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 9 of 86 
the animal safety data have been reviewed, and the safety and tolerability from the 
preceding parts have been confirmed by the DSMB. 
Part 3: Subjects from birth to <2 years (Group 4) will be enrolled in Part 3. The planned 
dose for this age group is 5 mg/kg. Due to blood volume restriction, PK sampling will be 
done at only 3 timepoints for Group 4: at the end of infusion (± 15 minutes), at 24 hours 
(± 4 hours) after start of infusion, and at 168 hours (± 12 hours) after start of infusion. A 
maximum total of 1 mL of blood will be collected for PK sampling. The dose, PK sampling 
timepoints, extent of safety laboratory data required, and length of the Follow-up period 
may be adjusted as appropriate after review of the PK and safety data from Part 1 and 
Part 2 (DSMB review 3). 
Investigational Medicinal Product: Rezafungin acetate (MR907) 
Rezafungin is a sterile product of lyophilised powder for reconstitution with sterile water for 
injection prior to dilution into infusion bags containing normal saline, half-normal saline, or 
5% dextrose. Each single-dose vial contains rezafungin acetate (200 mg of active 
rezafungin). 
Dose: The dose for Group 1 is 3 mg/kg (not to exceed a total dose of 200 mg). The 
planned dose for both Group 2 and Group 3 is 4 mg/kg (not to exceed a total dose of 
200 mg), and for Group 4, the planned dose is 5 mg/kg. However, the doses for Groups 2, 
3, and 4 will be confirmed after a review of the interim PK and safety data from the 
preceding part(s) by the DSMB (DSMB review 1 and review 3). The dose may be adjusted 
as appropriate after the review. 
Mode of administration: IV infusion over 2 hours (± 5 minutes). 
Reference Product: Not applicable 
Treatment Duration: This is a single-dose study. Subjects will receive a single IV infusion 
of rezafungin over a period of 2 hours (± 5 minutes). 
Statistical Methods: In general, continuous data will be summarised by group using the 
descriptive statistics. Categorical data will be summarised by group as the number and 
percentage of subjects in each category.  
Baseline is defined as the last value prior to the IV infusion of rezafungin (Screening). 
Sample Size: No formal sample size calculation was performed. It is estimated that at 
least 8 subjects per age range will enable estimation of rezafungin PK in subjects from 
birth to <18 years of age.  

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 10 of 86 
Data Analyses: 
Pharmacokinetic analysis:  
The following PK parameters will be derived for subjects in Groups 1 to 3 only:  
• 
Cmax 
Maximum observed plasma concentration 
• 
tmax 
Time at which the maximum plasma concentration was observed 
• 
AUC0-t Area under the plasma concentration-time curve from time 0 to the time of 
the last quantifiable concentration  
• 
AUC0-∞ Area under the plasma concentration-time curve from time 0 extrapolated to 
infinity 
• 
t1/2 
Terminal elimination half-life 
• 
λz 
Terminal elimination rate constant 
• 
CL 
Total clearance 
• 
Vss 
Volume of distribution at steady-state 
• 
Vz 
Apparent volume of distribution during the terminal phase 
For subjects in Group 4, the plasma concentrations of rezafungin will be summarised using 
descriptive statistics. 
All subjects who receive the single IV infusion of rezafungin and provide at least one blood 
sample for measurement of rezafungin plasma concentration will be included in the PK 
analysis set. The PK analysis set will be used for PK analysis. 
Individual and mean plasma concentrations of rezafungin at each sampling timepoint will 
be presented by listings and descriptive statistics including: n, mean, standard deviation 
(SD), standard error (SE), geometric mean, coefficient of variation expressed as percent 
(CV%), median, minimum and maximum, as well as quartiles (Q1 and Q3). 
All PK parameters will be calculated by non-compartmental analysis and detailed analysis 
will be included in the Statistical Analysis Plan. 
The PK data from all groups may also be analysed using nonlinear mixed-effects 
modelling. Any PK modelling will be subject to a separate analysis plan and will be 
reported separately from the clinical study report for this study. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 11 of 86 
Safety Analysis 
The Safety Analysis Set (i.e., all subjects who have received any amount of rezafungin) 
will be used for the analysis of safety data. 
Safety will be evaluated through treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), adverse events of special interest (AESIs), clinical laboratory, vital 
signs, electrocardiogram (ECG), and physical examination findings. TEAEs are defined as 
adverse events (AEs) with an onset on or after administration of the investigational product 
(IP; rezafungin) until the Follow-up. 
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA). 
The number and percentage of subjects experiencing TEAEs will be summarised by 
group, severity, and relation to IP. Treatment-emergent adverse events will be summarised 
by MedDRA System Organ Class and Preferred Term. The number and percentage of 
subjects reporting at least one TEAE will be summarised for each group (Groups 1, 2, 3, 
and 4), and overall. All AEs will be listed by subject. 
Clinical laboratory data to be summarised include haematology, blood chemistry, and 
urinalysis. Laboratory data will be converted to International System of Units for reporting 
and processing purposes. Absolute values and changes from baseline will be presented 
descriptively. Laboratory data outside the reference ranges will be flagged, and clinical 
significance of the laboratory value change will be stated. Vital signs and 12-lead ECG 
data will be summarised by group and listed by subject. The number and percentage of 
subjects with clinically significant ECG findings will be summarised by group for each 
time-point. A summary of abnormal physical examination findings by group and scheduled 
visit (Study day) will be presented. 
Interim Analysis 
No formal interim analysis is planned for this study. 
A DSMB has been appointed for this study to monitor the safety. Three interim reviews by 
the DSMB are planned during the study: The first interim review will be performed after 
completion of Part 1 (Group 1). The enrolment for Part 2 (Group 2 and Group 3) will 
commence only after DSMB review of Group 1 data and a decision to go ahead.  
A second interim review by the DSMB is planned when data from 50% of the subjects 
enrolled in Part 2 are available. 
A third DSMB review will be performed when Part 2 is completed. Enrolment for Part 3 
(Group 4) will not start before review of safety and PK data from Part 1 and Part 2 is 
complete.  
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 12 of 86 
Figure 1 
Study Schema 
 
DSMB=Data Safety Monitoring Board; IV=intravenous; PK=pharmacokinetic 
*Adult formulation; † paediatric formulation; ‡ DSMB review 2 to be held when 50% data from Group 2 and Group 3 
are available; # Interim DSMB review 3: Interim review of safety and PK data of all subjects from Part 1 and Part 2 
(Groups 1, 2 and 3). 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
 
 
 
Page 13 of 86 
Table 1 
Schedule of Assessments for Part 1 (Group 1: 12 to <18 Years) and Part 2 (Group 2: 6 to <12 Years; 
and Group 3: 2 to <6 Years) 
Study Period 
Screening 
Dosing 
PK Sampling Postdose 
Follow-
up / ETa 
Study Day 
Day -3 to 
Day -1 
Day 1 
Day 1 
Day 3 
Day 8 
Day 30 
± 5 Days 
Procedure 
 
Predose 
Single IV 
infusion of 
rezafungin 
end-of-
infusion 
± 15 mins 
Between 
3 and 4 
hrs after 
start of 
infusion 
Between 
6 and 8 
hrs after 
start of 
infusion 
48 hrs 
± 4 hrs 
after start 
of infusion 
168 hrs 
± 12 hrs 
after start 
of 
infusion 
 
Informed consent/assent 
for minorsb 
x 
 
 
 
 
 
 
 
 
Assess inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
Demography (age, sex, 
and race) 
x 
 
 
 
 
 
 
 
 
Baseline characteristics 
(height, weight, BMI*, and 
disease characteristics 
[indication for antifungal 
prophylaxis/treatment]) 
x 
 
 
 
 
 
 
 
 
Hospitalisation status at 
Screening (general 
ward/ICU)c 
x 
 
 
 
 
 
 
 
 
Medical/surgical history 
and current medical 
conditions 
x 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication used 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examinatione 
x 
x 
x 
x 
x 
x 
x 
x 
x 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
 
 
 
Page 14 of 86 
Study Period 
Screening 
Dosing 
PK Sampling Postdose 
Follow-
up / ETa 
Study Day 
Day -3 to 
Day -1 
Day 1 
Day 1 
Day 3 
Day 8 
Day 30 
± 5 Days 
Procedure 
 
Predose 
Single IV 
infusion of 
rezafungin 
end-of-
infusion 
± 15 mins 
Between 
3 and 4 
hrs after 
start of 
infusion 
Between 
6 and 8 
hrs after 
start of 
infusion 
48 hrs 
± 4 hrs 
after start 
of infusion 
168 hrs 
± 12 hrs 
after start 
of 
infusion 
 
Vital signs (temperature, 
pulse rate, respiratory 
rate, and blood pressure)f 
x 
x 
xf 
xf 
x 
x 
x 
x 
x 
Clinical laboratory tests 
(haematology, 
biochemistry, urinalysis)g 
x 
 
 
 
 
 
 
 
x 
Urine pregnancy test for 
postmenarchal females 
x 
 
 
 
 
 
 
 
x 
12-lead ECGh 
x 
 
 
 
x 
 
 
 
 
IP administrationi 
 
 
x 
 
 
 
 
 
 
Continuous vital sign and 
ECG monitoring (only 
during IP infusion)j 
 
 
x 
 
 
 
 
 
 
PK Sampling (venous or 
arterial samples)k 
 
 
 
x 
x 
x 
x 
x 
 
AE/SAE monitoring 
 
 
x 
x 
x 
x 
x 
x 
x 
Infusion-related reaction 
monitoring (collected as 
AEs) 
 
 
x 
x 
x 
x 
 
 
 
AE=adverse event; BMI=body mass index; ECG=electrocardiogram; ET=early termination; ICU=intensive care unit; IP=investigational product; IV= intravenous; 
PK=pharmacokinetics; SAE=serious AE. 
Note: When coinciding with each other, ECGs, vital signs, and pharmacokinetic blood collections should be performed in said order. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
 
 
 
Page 15 of 86 
* BMI=kg/m2 where kg is a subject’s weight in kilograms and m2 is their height in metres squared (Appendix 6). 
a. 
ET assessments can be performed at the time of discontinuation. In case of ET, the reason for discontinuation must be documented. 
b. 
Written parental (or appropriate legal representative) informed consent and/or age-appropriate assent/consent. 
c. 
Record whether the subject is in the general ward or ICU. If the subject is in the ICU, record the Paediatric Index of Mortality 2 (PIM2) variables (Appendix 7). 
d. 
All medication taken up to 7 days prior to the informed consent, medication ongoing after the informed consent, and all medication given to the subjects during 
the study until Follow-up (Day 30 ± 5 days) must be recorded. 
e. 
A complete physical examination is to be performed at Screening and Follow-up. At all other time points, a brief targeted examination is to be performed as 
clinically indicated, driven by the subject’s symptoms and signs. A complete and brief targeted physical examination will include, at a minimum, assessments 
of the cardiovascular, respiratory, gastrointestinal, and central and peripheral neurological systems. 
f. 
Vital signs will be taken after subject is sitting or supine for at least 5 minutes and will include temperature, pulse rate, respiratory rate, and blood pressure. On 
the day of dosing (Day 1) vital signs will be taken predose, 15-30 minutes after the start of IP infusion, and 30-60 minutes after the completion of IP infusion. 
g. 
Clinical laboratory tests (haematology, biochemistry, urinalysis): The following tests will be performed at Screening and at Follow-up: Complete blood count, 
alkaline phosphatase (ALP), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and conjugated bilirubin, 
creatinine, total protein and albumin, glucose (fasting or non-fasting), potassium, sodium, calcium (see Appendix 2 for details). 
h. 
12-lead ECG: at Screening and between 3 and 4 hours after start of IP infusion on Day 1. 
i. 
The IP will be administered as a single IV infusion over a period of 2 hours (± 5 minutes). The formulation used for Group 1 will be same as the one used in 
the adult clinical trials. For Group 2 and Group 3, a paediatric specific formulation that is currently under development will be used. 
j. 
Continuous vital sign and ECG monitoring will begin with start of IP infusion until completion of infusion. 
k. 
PK blood samples will be collected at the following 5 timepoints: at end-of-infusion ± 15 minutes, then between 3 and 4 hours after start of infusion, between 
6 and 8 hours after start of infusion, at 48 hours (± 4 hours) after start of infusion (Day 3), and at 168 hours (± 12 hours) after start of infusion (Day 8). In cases 
where a subject is discontinued before all PK samples have been collected (Day 8), a last PK sample may be collected at the time of discontinuation if the 
subject and/or his/her parent(s)/legally authorised representative consents. The exact date and time of the PK samples must be recorded. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
 
 
 
Page 16 of 86 
Table 2 
Schedule of Assessments for Part 3 (Group 4: birth to <2 Years) 
Study Period 
Screening 
Dosing 
PK Sampling Postdose 
Follow-up / 
ETa 
Study Day 
Day -3 to 
Day -1 
Day 1 
Day 1 
Day 2 
Day 8 
Day 30 ± 5 
Days 
Procedure 
 
Predose 
Single IV 
infusion of 
rezafungin 
end-of-
infusion 
± 15 mins 
24 hrs 
± 4 hrs after 
start of 
infusion 
168 hrs 
± 12 hrs after 
start of 
infusion 
 
Informed consent (parental 
consent/LAR)b 
x 
 
 
 
 
 
 
Assess inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
Demographics (age, sex, race, 
gestational age, and birth 
weight) 
x 
 
 
 
 
 
 
Baseline characteristics (height, 
weight, and disease 
characteristics [indication for 
antifungal 
prophylaxis/treatment]) 
x 
 
 
 
 
 
 
Hospitalisation status at 
screening (general ward/ICU)c 
x 
 
 
 
 
 
 
Medical/surgical history and 
current medical conditions 
x 
 
 
 
 
 
 
Prior and concomitant 
medication used 
x 
x 
x 
x 
x 
x 
x 
Physical examinatione 
x 
x 
x 
x 
x 
x 
x 
Vital signs (temperature, pulse 
rate, respiratory rate, and blood 
pressure)f 
x 
x 
xf 
xf 
x 
x 
x 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
 
 
 
Page 17 of 86 
Study Period 
Screening 
Dosing 
PK Sampling Postdose 
Follow-up / 
ETa 
Study Day 
Day -3 to 
Day -1 
Day 1 
Day 1 
Day 2 
Day 8 
Day 30 ± 5 
Days 
Procedure 
 
Predose 
Single IV 
infusion of 
rezafungin 
end-of-
infusion 
± 15 mins 
24 hrs 
± 4 hrs after 
start of 
infusion 
168 hrs 
± 12 hrs after 
start of 
infusion 
 
Clinical laboratory tests 
(haematology, biochemistry, 
urinalysis)g 
x 
 
 
 
 
 
x 
12-lead ECGh 
x 
 
 
 
x 
 
 
IP administrationi 
 
 
x 
 
 
 
 
Continuous vital sign and ECG 
monitoring (only during IP 
infusion)j 
 
 
x 
 
 
 
 
PK Sampling (venous or arterial 
samples)k 
 
 
 
x 
x 
x 
 
AE/SAE monitoring 
 
 
x 
x 
x 
x 
x 
Infusion-related reaction 
monitoring (collected as AEs) 
 
 
x 
x 
x 
 
 
AE=adverse event; ECG=electrocardiogram; ET=early termination; ICU=intensive care unit; IP=investigational product; IV= intravenous; LAR=legally authorised 
representative; PK=pharmacokinetics; SAE=serious AE. 
Note: When coinciding with each other, ECGs, vital signs, and pharmacokinetic blood collections should be performed in said order. 
a. 
ET assessments can be performed at the time of discontinuation. In case of ET, the reason for discontinuation must be documented. 
b. 
Written parental (or appropriate legal representative) informed consent. 
c. 
Record whether the subject is in the general ward or ICU. If the subject is in the ICU, record the Paediatric Index of Mortality 2 (PIM2) variables (Appendix 7) 
d. 
All medication taken up to 7 days prior to the informed consent, medication ongoing after the informed consent, and all medication given to the subjects during 
the study until Follow-up (Day 30 ± 5 days) must be recorded. 
e. 
A complete physical examination is to be performed at Screening and Follow-up. At all other time points, a brief targeted examination is to be performed as 
clinically indicated, driven by the subject’s symptoms and signs. A complete and brief targeted physical examination will include, at a minimum, assessments 
of the cardiovascular, respiratory, gastrointestinal, and central and peripheral neurological systems. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
 
 
 
Page 18 of 86 
f. 
Vital signs will be taken in supine position and will include temperature, pulse rate, respiratory rate, and blood pressure. On the day of dosing (Day 1) vital 
signs will be taken predose, 15-30 minutes after the start of IP infusion, and 30-60 minutes after the completion of IP infusion. 
g. 
Clinical laboratory tests (haematology, biochemistry, urinalysis): The following tests will be performed at Screening and at Follow-up: Complete blood count, 
alkaline phosphatase (ALP), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and conjugated bilirubin, 
creatinine, total protein and albumin, glucose (fasting or non-fasting), potassium, sodium, calcium (see Appendix 2 for details). Glucose can be measured by 
point-of-care testing to minimise the blood volume taken for the clinical laboratory tests if the point-of-care glucose meter is calibrated regularly as per the 
site’s standard operating procedure. 
h. 
12-lead ECG: at Screening and at 24 ± 4 hours after start of IP infusion (Day 2). 
i. 
The IP will be administered as a single IV infusion over a period of 2 hours (± 5 minutes). 
j. 
Continuous vital sign and ECG monitoring will begin with start of IP infusion until completion of infusion. 
k. 
PK blood samples will be collected at the following 3 timepoints: at end-of-infusion ± 15 minutes, at 24 hours ± 4 hours (Day 2) after start of infusion, and at 
168 hours ± 12 hours (Day 8) after start of infusion. In cases where a subject is discontinued before all PK samples have been collected (Day 8), a last PK 
sample may be collected at the time of discontinuation if the subject and/or his/her parent(s)/LAR consents. The exact date and time of the PK samples must 
be recorded. A maximum total of 1 mL of blood will be taken for PK sampling. 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 19 of 86 
2 
TABLE OF CONTENTS 
 
Title Page ...................................................................................................................... 1 
PROTOCOL SIGNATURE PAGE – SPONSOR ............................................................. 3 
1 
CLINICAL PROTOCOL SYNOPSIS ........................................................................ 6 
2 
TABLE OF CONTENTS ......................................................................................... 19 
List of Tables ............................................................................................................... 22 
List of Figures ............................................................................................................. 22 
3 
INTRODUCTION .................................................................................................... 23 
 Therapeutic Area/Background .......................................................................... 23 
 Rationale for Conducting the Study ................................................................. 24 
 Benefit and Risk Evaluation .............................................................................. 24 
4 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 31 
5 
STUDY DESIGN ..................................................................................................... 31 
 Overall Study Design ......................................................................................... 31 
5.1.1 Recruitment .................................................................................................. 33 
5.1.2 Informed Consent ........................................................................................ 34 
5.1.3 Screening ..................................................................................................... 34 
5.1.4 Dosing on Day 1 and Subsequent Pharmacokinetic Assessments ........ 35 
5.1.5 Follow-up or Early Termination .................................................................. 36 
 Scientific Rationale for Study Design .............................................................. 36 
 Justification for Dose ........................................................................................ 37 
 End-of-Study Definition ..................................................................................... 38 
6 
STUDY POPULATION ........................................................................................... 38 
 Inclusion Criteria ................................................................................................ 38 
 Exclusion Criteria .............................................................................................. 39 
 Lifestyle Considerations ................................................................................... 41 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 20 of 86 
 Screen Failures .................................................................................................. 41 
7 
STUDY TREATMENT ............................................................................................ 42 
 Study Treatment Administered ......................................................................... 42 
 Administration .................................................................................................... 43 
 Preparation/Handling/Storage/Accountability ................................................. 44 
 Measures to Minimise Bias: Randomisation and Blinding ............................. 44 
 Treatment Compliance ...................................................................................... 44 
 Dose Modification .............................................................................................. 45 
7.6.1 Treatment Overdose .................................................................................... 45 
 Concomitant Therapy ........................................................................................ 45 
7.7.1 Rescue Medication ...................................................................................... 46 
8 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/ WITHDRAWAL .......................................................................... 47 
 Discontinuation of Study Treatment ................................................................ 47 
 Subject Discontinuation/Withdrawal from the Study ...................................... 48 
 Lost to Follow-up ............................................................................................... 48 
9 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 50 
 Efficacy and/or Immunogenicity Assessments ............................................... 50 
 Safety Assessments .......................................................................................... 50 
9.2.1 Adverse Events, Serious Adverse Events, and Other Safety Reporting 51 
9.2.2 Time Period and Frequency for Collecting AE and SAE Information...... 51 
9.2.3 Follow-up of AEs and SAEs ........................................................................ 51 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 51 
9.2.5 Pregnancy .................................................................................................... 52 
9.2.6 Adverse Event of Special Interest .............................................................. 52 
9.2.7 Physical Examination .................................................................................. 53 
9.2.8 Vital Signs .................................................................................................... 53 
9.2.9 Electrocardiograms ..................................................................................... 53 
9.2.10 Clinical Safety Laboratory Tests .............................................................. 53 
 Pharmacokinetic Assessment .......................................................................... 54 
9.3.1 Collection of Blood Samples for Pharmacokinetic Assessment ............. 54 
9.3.2 Pharmacokinetic Assessments for Part 1 and Part 2 ............................... 54 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 21 of 86 
9.3.3 Pharmacokinetic Assessments for Part 3 ................................................. 55 
 Genetics OR Pharmacogenomics .................................................................... 55 
 Biomarkers ......................................................................................................... 55 
 Immunogenicity Assessment ........................................................................... 55 
 Health Economics OR Medical Resource Utilisation and Health Economics
 ................................................................................................................................... 55 
10 STATISTICAL CONSIDERATIONS ....................................................................... 56 
 Sample Size Determination ............................................................................. 56 
 Statistical Hypotheses ..................................................................................... 56 
 Analysis Sets .................................................................................................... 56 
 Statistical Analyses ......................................................................................... 56 
10.4.1 General Considerations ............................................................................ 56 
10.4.2 Demographic and Baseline Characteristics ............................................ 56 
10.4.3 Primary Endpoints Analyses .................................................................... 57 
10.4.4 Secondary Endpoints Analyses ............................................................... 57 
10.4.5 Adverse Events .......................................................................................... 57 
10.4.6 Laboratory Values ..................................................................................... 58 
10.4.7 Vital Signs, Electrocardiogram, and Physical Examination ................... 58 
 Pharmacokinetic Measurements and Analyses ............................................ 59 
10.5.1 Drug Concentration Measurements and Analysis .................................. 59 
10.5.2 Pharmacokinetic Parameters .................................................................... 59 
10.5.3 Pharmacokinetic Evaluation ..................................................................... 59 
 Interim Analysis ............................................................................................... 59 
 Population PK Modelling ................................................................................. 60 
11 APPENDICES FOR SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ...................................................................................................... 61 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............. 61 
Appendix 2: Clinical Laboratory Tests ................................................................... 66 
Appendix 3: AEs and SAEs: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .................................................................... 67 
Appendix 4: List of Prohibited Concomitant Neurotoxic Medications ................ 73 
Appendix 5: Reference Ranges for Vital Signs ..................................................... 74 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 22 of 86 
Appendix 6: BMI Charts........................................................................................... 75 
Appendix 7: Paediatric Index of Mortality 2 (PIM2) ............................................... 77 
Appendix 8: Abbreviations ...................................................................................... 79 
Appendix 9: Protocol Amendment History ............................................................ 81 
12 REFERENCES ....................................................................................................... 85 
 
List of Tables 
Table 1 
Schedule of Assessments for Part 1 (Group 1: 12 to <18 Years) and 
Part 2 (Group 2: 6 to <12 Years; and Group 3: 2 to <6 Years)............ 13 
Table 2 
Schedule of Assessments for Part 3 (Group 4: birth to <2 Years) .... 16 
Table 3 
Study Treatment Administered ............................................................ 43 
Table 4 
Definition of Analysis Populations ...................................................... 56 
Table 5 
Safety Laboratory Tests........................................................................ 66 
 
List of Figures 
Figure 1 Study Schema ....................................................................................... 12 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 23 of 86 
3 
INTRODUCTION 
Rezafungin is a semi-synthetic echinocandin antifungal agent that is being developed to treat 
invasive candidiasis (IC) and as a single agent for prevention of invasive fungal disease (IFD) 
caused by Candida species (spp.), Aspergillus spp., and Pneumocystis jirovecii in patients 
undergoing allogeneic blood or bone marrow transplantation. 
Additional details related to the pharmaceutical properties and mechanism of action of the 
investigational product (IP) are available in the rezafungin Investigator’s Brochure (IB; 
Edition 10, dated 07 September 2021).1 
Currently, rezafungin does not have a Marketing Authorisation in any country. Clinical studies 
are ongoing in the United States (US), Europe, Asia Pacific and South America.  
In the US, rezafungin was granted Orphan Drug designation for the treatment of candidemia 
and IC infections caused by susceptible Candida spp. by the US Food and Drug Administration 
(FDA) on 08 February 2016.  
It was also granted Orphan designation status in the EU by the European Medicines Agency 
(EMA) on 06 January 2021 for treatment of IC. 
 
 Therapeutic Area/Background 
Invasive fungal disease is a cause of significant morbidity and mortality among recipients of 
allogeneic haematopoietic stem cell transplant and patients receiving cytotoxic chemotherapy 
for haematologic malignancies.2 Three of the most common IFDs are IC, invasive aspergillosis, 
and Pneumocystis pneumonia. Antifungal agents are routinely used in high-risk patients to 
prevent IFDs as attributable mortality is high after infection becomes established. 
Invasive candidiasis is a serious infection caused by Candida spp. This is the most frequently 
detected yeast in the human microbiome3, and can cause widely disseminated and/or 
bloodstream infections.4 
These serious and life-threatening infections represent a significant public health issue, 
particularly in highly vulnerable patient populations such as the elderly, postsurgical, critically ill, 
and other hospitalised patients with serious medical conditions.5,6,7  
In addition, because of increasing resistance to existing antifungal drugs, there is an urgent 
need to develop new and more effective antifungal agents to treat these serious 
infections.8,9,10,11,12 About 7% of bloodstream infections have been reported to be caused by 
drug-resistant Candida spp. in the US. Furthermore, cases of multidrug-resistant C. auris are 
increasing globally over the past few years, and this has been considered as a serious threat to 
public health.13,14 
Invasive candidiasis is not an uncommon infection in newborns, with an incidence of 7% to 20% 
in critically ill neonates.15 As birth weight decreases, the risk of IC progressively increases. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 24 of 86 
Additionally, extremely-low-birth-weight (birth weight <1000 grams) neonates are particularly 
susceptible to central nervous system (CNS) infection, with 50 to 64% of cases reported to 
display CNS symptoms early in the disease.15 CNS involvement is associated with high 
mortality (30 to 60%), compared with a Day-30 all-cause mortality of 14.4% in a recent study 
including neonatal and paediatric populations (0 to ≤18 years) with candidemia.16 Long-term 
complications, including neuromotor developmental disorders, chronic lung disease, and severe 
retinopathy of prematurity, have also been documented in preterm neonates with CNS 
candidiasis.15  
 
 Rationale for Conducting the Study 
In children, echinocandins are first-line agents for the treatment of IC. The European Society of 
Clinical Microbiology and Infectious Diseases has given caspofungin and micafungin an A-I 
recommendation, and anidulafungin a B-II recommendation (however, this was prior to the 
approval of anidulafungin in children). Liposomal amphotericin B is an alternative first-line 
therapy in this population.17 
Rezafungin exhibited a low clearance and long half-life (t1/2) following intravenous (IV) 
administration across all animal species tested (mice, rabbits, rats, dogs, and non-human 
primates). In man, rezafungin also has a low clearance (~0.2 L/h) and a long t1/2 of around 5 to 
6 days.1 This enables rezafungin to be dosed once weekly, achieving a high front-loaded 
exposure, which differentiates it from the marketed echinocandins (caspofungin, micafungin and 
anidulafungin), which have a shorter t1/2 and are dosed daily. 
To date, there are no clinical studies evaluating rezafungin in paediatric subjects. This study will 
assess the pharmacokinetics (PK), safety and tolerability of rezafungin in subjects from birth to 
<18 years of age who are receiving concomitant systemic antifungal treatment as 
standard-of-care. 
This PK study is one of the clinical studies required to be conducted for rezafungin, to comply 
with the Decision of the EMA on the Paediatric Investigation Plan dated 03 January 2019 
(EMEA-002319-PIP01-17), modified as of 24 June 2022 (EMEA-002319-PIP01-17-M02). 
 
 Benefit and Risk Evaluation 
Safety of rezafungin has been evaluated in several nonclinical and clinical studies. Summaries 
of findings are located in the IB. 
Nonclinical Studies 
A series of nonclinical studies have been conducted to demonstrate the efficacy of rezafungin in 
various biological models and to support its safe IV dosing in humans. All pivotal nonclinical 
safety studies were conducted in facilities in the US. The studies were performed in accordance 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 25 of 86 
with the US Department of Health and Human Services, Food and Drug Administration, United 
States Code of Federal Regulations, Title 21, Part 58: Good Laboratory Practice for Nonclinical 
Laboratory Studies and as accepted by Regulatory Authorities throughout the European Union 
(Organisation for Economic Co-operation and Development Principles of Good Laboratory 
Practice [GLP]), Japan (Ordinance on GLP from the Ministry of Health, Labour, and Welfare), 
and other countries that are signatories to the OECD Mutual Acceptance of Data Agreement. 
Biological samples were obtained in nonclinical PK studies and toxicokinetic samples from 
toxicology studies aimed at measuring rezafungin concentrations. Concentrations were 
determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the PK 
studies, the methods were not validated due to the exploratory nature of the supported studies. 
For support of GLP toxicology studies, LC-MS/MS methods were developed and validated to 
measure rezafungin in plasma (with K3EDTA [tri-potassium ethylenediaminetetraacetic acid] as 
anticoagulant) from rats and monkeys as part of toxicokinetic analyses. These methods were 
validated in accordance with the FDA Draft Guidance for Industry: Bioanalytical Method 
Validation (2013), and FDA Guidance for Industry: Bioanalytical Method Validation (2001), in a 
manner consistent with the principles outlined in the US Code of Federal Regulations Title 21 
Part 58, GLP for Nonclinical Laboratory Studies.  
Briefly, plasma samples (25 μL for rat and 50 μL for monkey and rabbit) were processed using a 
protein-precipitation extraction procedure followed by analysis. Rezafungin concentrations were 
calculated with a 1/x2 linear regression over a concentration range of 0.100 to 100 μg/mL using 
deuterated-rezafungin (d9-rezafungin) as an internal standard. The mass spectrometer was 
operated in the selected reaction monitoring mode under optimised conditions for detection of 
rezafungin and d9-rezafungin positive ions formed by electrospray ionisation. Method transfer 
validations were also completed for the rat and monkey plasma methods between different 
bioanalytical sites of the Contract Research Organisation (CRO). In addition, method validation 
was conducted in rat milk to support analysis of rat milk samples during rat reproductive 
toxicology studies. 
Studies in the neutropenic mouse systemic candidiasis model show that rezafungin is 
efficacious when administered by either the IV, intraperitoneal or subcutaneous route across a 
wide range of doses. 
Rezafungin was found to be protective when used as prophylaxis in neutropenic as well as 
immunocompetent mouse models when challenged with Candida spp., Aspergillus spp., and 
Pneumocystis murina. These data suggest that rezafungin may provide benefit as antifungal 
prophylaxis in patients with haematological diseases at risk for infection.1 
In the safety pharmacology studies in rats, rezafungin was tested for effects on neurobehavioral, 
cardiovascular (hemodynamic and electrocardiographic), and respiratory functional endpoints. 
There were no clinically significant observations or statistically significant changes in 
neurobehavioral parameters or body temperatures that were attributed to administration of 
rezafungin when administered once every 3 days over one week by IV slow bolus to male rats 
at doses up to 45 mg/kg, nor were there changes in the gross behavioural, physiological, or 
neurological state of the animals.1 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 26 of 86 
Overall, the pharmacodynamic and safety pharmacology profiles of rezafungin support its 
proposed indications for the treatment of candidemia/IC, and as prophylaxis for Candida 
infections, invasive aspergillosis and Pneumocystis jirovecii pneumonia. 
Relative to the marketed echinocandins, good safety margins exist for the observed toxicities 
(6 to 9X), versus the predicted human therapeutic plasma level in patients. Unlike other 
echinocandins, no hepatotoxicity was observed with rezafungin. Testicular degeneration, a 
finding seen with micafungin in rats and dogs, was also seen in rats administered rezafungin, 
but not monkeys. Schwann cell phospholipidosis was observed in peripheral nerves but did not 
lead to adverse findings at any dose up to the no observed adverse effect level (NOAEL) over a 
13-week dosing period in 2 independent studies in monkeys, and a 26-week dosing period in 
rats and monkeys. Tremors, which occurred in some monkeys sporadically over a 9-week 
period (generally starting >4 weeks after Day 1), reversed with no adverse neurohistopathology 
observed, whereas non-adverse Schwann cell phospholipidosis was still present after a 
13-week recovery period. Additionally, the tremors observed during the blinded 26-week 
monkey study had similar incidence and severity between the treated animals and control 
animals. Therefore, it is considered that there is no apparent relationship of the minor tremoring 
seen in monkeys to the non-adverse Schwann cell phospholipidosis. It is important to note that 
during dosing, the animals received reconstituted rezafungin, without the additional dilution into 
0.9% saline as will be done for patients. 
Rezafungin was negative in a complete genotoxicity test battery and showed a minimal 
phototoxic response after multiple doses in rats. 
Rezafungin had no effect on male or female fertility in rats or on embryo-foetal development in 
rats and rabbits and no effect on pre- and postnatal toxicity, maternal reproductive function, and 
offspring development. Measurable concentrations of rezafungin were found in dams and 
foetuses. Repeat doses of rezafungin did cause reversible testicular changes in rats, a finding 
also reported with micafungin. 
Toxicology data generated so far support the repeat dose use of rezafungin in humans from 
adolescent age through to adults. All rats in the toxicology studies of 1 to 6 months duration 
were sexually mature from the start of dosing. All monkeys in the GLP and non-GLP studies of 
1 to 6 months duration were young adults (i.e., adolescents) or sexually mature adults. Based 
on the nonclinical data and safety profiles in adult human studies, single and repeat doses of 
rezafungin is considered safe for administration to 12 to <18-year-old humans.  
Drug-induced phospholipidosis is considered related to lysosomal storage. There are more than 
50 drugs in clinical use that have been identified to induce phospholipidosis in vitro and/or in 
vivo, including drugs that are used in children for prolonged periods (e.g., propranolol).18 There 
are also data suggesting that lysosomal acidification becomes less efficient with ageing, 
indicating there may be age-related differences in the sensitivity to the 
phospholipidosis-inducing effect.19 The human nervous system undergoes a critical period of 
structural and functional growth and development between birth and 2 years of age. Between 
the ages of 2 and 18 years in humans there is a period of growth and functional maturation of 
the nervous system with refinement of sensorimotor control. The effects of phospholipidosis on 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 27 of 86 
the growing and developing nervous system is not known, nor is it known if the sensitivity of the 
nervous system is different in children versus adults (with regard to phospholipidosis or 
tremors). Therefore, a series of juvenile animal toxicity studies will be conducted in parallel with 
this PK study to investigate the condition and effect of phospholipidosis. Until after the juvenile 
animal toxicity studies are completed, no single dose of rezafungin will be administered to 
<2-year-olds, and no repeat doses of rezafungin will be administered to 2 to <12-year-old 
paediatric subjects. 
The rezafungin formulation contains polysorbate 80 (PS80) which is known to cause toxicity in 
paediatrics related to the Cmax of PS80 infusion. The Paediatric Committee’s Formulation 
Working Group in EMA have set a dose limit of PS80 in paediatric formulations (3 mg/kg) based 
on once daily administration, but there are precedents showing that this dose limit can be 
modestly exceeded as long as the infusion rate of PS80 is below a certain threshold 
(0.15 mg/kg/min) and thereby avoiding toxicities related to Cmax of PS80. This dosing regimen 
was successfully used with anidulafungin. Therefore, in order to minimise PS80 effects, a 
formulation development programme is being undertaken to identify a paediatric specific 
formulation with an appropriate PS80 level for use in subjects <12 years of age and it will be 
administered at an infusion rate of PS80 below 0.15 mg/kg/min, a rate considered safe by the 
EMA. Furthermore, administration of rezafungin in this PK study is single dose only, which will 
further reduce the risk from PS80 infusion effects. 
Clinical Studies 
Rezafungin has been assessed in 8 Phase 1 studies (of these, 7 studies were in adult healthy 
volunteers and 1 was in adults with hepatic impairment), including a single ascending dose 
study, a multiple ascending dose study, a definitive QT study, a photosafety study, a hepatic 
impairment study, a radiolabelled mass balance, absorption, metabolism, and excretion study, 
and 2 drug-drug interaction studies, one Phase 2 study (STRIVE [NCT02734862]), and 
two Phase 3 studies (a Phase 3 study for treatment of candidemia and/or IC [ReSTORE 
{NCT03667690} – global study completed], and a Phase 3 study for prophylaxis of IFD in adults 
undergoing allogeneic blood and marrow transplantation [ReSPECT {NCT04368559} – 
ongoing]).  
Single and multiple dose PK parameters of rezafungin have been determined in healthy adult 
subjects with approximately dose proportional increases in exposure over single dose range of 
50 mg to 1400 mg, and multiple dose range of 100 to 400 mg. Rezafungin has a low clearance 
(~0.2 L/h), a long t1/2 (around 5 to 6 days) and a volume of distribution approximately equal to 
total body water (~40 L). Elimination of rezafungin is primarily faecal as the parent compound, 
with less than 1% of the dose eliminated as the parent compound in the urine (Data on file). 
Rezafungin, at a single supratherapeutic dose of 1400 mg, did not prolong the QT interval or 
have any clinically significant effect on other cardiac parameters, including heart rate, PR 
interval and QRS interval, compared to placebo. Postdose echocardiogram results were normal 
in all subjects, indicating no effect on cardiac contractility or ejection fraction. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 28 of 86 
Assessment of rezafungin as an inhibitor or inducer of a range of probe substrates for 
cytochrome P450 (CYP450) drug metabolising enzymes (CYP1A2, CYP3A, CYP2C8 and 
CYP2B6) and drug transporter proteins (P-gp, BCRP, OATP, OCT-1, OCT-2, MATE1 and 
MATE2) showed that rezafungin did not cause any clinically relevant interactions. The need for 
dose adjustments is considered unlikely for drugs that are substrates for these CYP450 
enzymes and drug transporter proteins, when administered with rezafungin. Rezafungin also did 
not cause any clinically relevant drug-drug interaction when administered with tacrolimus, 
cyclosporine, ibrutinib, mycophenolate mofetil and venetoclax, which are commonly 
administered co-medications. Therefore, no dose adjustments are necessary when rezafungin 
is administered with these drugs. Overall, rezafungin has been assessed as having a low drug-
drug interaction liability. 
In subjects with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, the 
mean exposure of a 400 mg dose of rezafungin was reduced by approximately 30% compared 
to matched subjects with normal hepatic function. Rezafungin exposure was similar in subjects 
with moderate and severe hepatic impairment and did not change with increasing degree of 
hepatic impairment. As hepatic impairment did not have a clinically meaningful effect on 
rezafungin PK, dose adjustments in patients with hepatic impairment are not necessary.  
The results of the photosafety study of rezafungin showed there was increased risk of 
phototoxicity to the skin classified as mild, and similar in intensity to the positive control, 
ciprofloxacin. As rezafungin may cause increased risk of phototoxicity, patients should be 
advised to avoid sun exposure and other sources of ultraviolet (UV) radiation without adequate 
protection during rezafungin treatment (including 7 days after the last administration of 
rezafungin). 
The Phase 2 (STRIVE) safety and efficacy study (NCT02734862) was a multicentre, 
prospective, randomised, double-blind study of rezafungin (IV) versus caspofungin (IV) for 
treatment of subjects with candidemia and/or IC. This study had 3 groups. Subjects randomised 
to Group 1 received 400 mg of rezafungin on Day 1 and Day 8, with optional doses of 400 mg 
on Day 15 and Day 22. Subjects randomised to Group 2 received 400 mg of rezafungin on 
Day 1 and 200 mg on Day 8, with optional doses of 200 mg on Day 15 and Day 22. Subjects 
randomised to Group 3 received a 70 mg loading dose of caspofungin on Day 1, followed by 
50 mg of caspofungin daily (with the option of oral step-down therapy with fluconazole), for a 
total of 14 to 28 days. 
The primary efficacy outcome was overall success defined as mycological eradication and 
resolution of systemic signs attributable to candidemia and/or IC at Day 14. Secondary efficacy 
outcomes were overall success at Day 5, Day 28, and follow-up, mycological eradication at 
Day 5, Day 14, Day 28, and follow-up, clinical cure as assessed by the Investigator at Day 14, 
Day 28, and follow-up, and all-cause mortality (ACM) at Day 30. Safety was evaluated by 
adverse events (AEs) and ACM. 
A total of 207 patients were enrolled, of which 183 were included in the microbiological 
intent-to-treat (mITT) population, defined as all patients with documented Candida infection who 
received any amount of study drug. Overall cure was achieved in 60.5% (46/76) patients from 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 29 of 86 
Group 1 (rezafungin 400 mg group), 76.1% (35/46) patients from Group 2 (rezafungin 
400/200 mg group), and 67.2% (41/61) patients from Group 3 (caspofungin group). Excluding 
those with indeterminate responses, overall cure rates were 69.7% for Group 1, 81.4% for 
Group 2, and 70.7% for Group 3.20 
In the mITT population, the clinical cure as assessed by the Investigator at Day 14 was 
achieved in 69.7% (53/76) patients in Group 1, 80.4% (37/46) patients in Group 2, and 70.5% 
(43/61) patients in Group 3. The 30-Day ACM rates were 15.8% (12/76), 4.3% (2/46), and 
13.1% (8/61) in Group 1, Group 2, and Group 3, respectively (Data on file).  
There were no notable differences in treatment-emergent adverse events (TEAEs) across the 
study groups. Between the rezafungin groups, there were no dose-related patterns in study 
drug-related TEAEs, severe TEAEs, serious adverse events (SAEs), or related SAEs. Most AEs 
were mild or moderate in severity (Data on file). Rezafungin was found to be safe and 
efficacious in the treatment of candidemia and/or IC. 
The pivotal Phase 3 trial ReSTORE (NCT03667690) was a multicentre, prospective, 
randomised, double-blind, double-dummy, efficacy and safety study of rezafungin (IV) versus 
caspofungin (IV) followed by optional oral fluconazole step-down therapy (in qualifying subjects) 
in subjects with candidemia and/or IC. Subjects were randomised in a 1:1 ratio to receive 
rezafungin as a 400 mg loading dose in Week 1, followed by 200 mg once weekly, for a total of 
2 to 4 weeks, or caspofungin as a single 70 mg IV loading dose on Day 1 followed by 
caspofungin 50 mg IV once daily (with the option of oral step-down therapy with fluconazole) for 
a total treatment of 14 to 28 days.  
The primary efficacy outcome was global cure (confirmed by the Data Review Committee) at 
Day 14 for the EMA, and ACM at Day 30 (-2 days) for the FDA. Global cure was determined 
from clinical response, mycological response, and radiological response (for qualifying subjects 
with IC).  
Non-inferiority was demonstrated for the EMA primary efficacy outcome of global cure at Day 14 
for rezafungin as compared with caspofungin. The percentage of subjects with a global cure at 
Day 14 were comparable between treatment groups (59.1% [55/93] for rezafungin subjects and 
60.6% [57/94] for caspofungin subjects). The 95% confidence interval (CI) of the treatment 
difference from a stratified analysis was -14.9% to 12.7% for global response at Day 14. 
Non-inferiority was also demonstrated for ACM at Day 30 (- 2 days) in the mITT Population – 
the primary efficacy outcome for the FDA. A total of 23.7% (22/93) of rezafungin subjects and 
21.3% (20/94) of caspofungin subjects were deceased by Day 30 or had an unknown survival 
status (treatment difference = 2.4% [95% CI: -9.7% to 14.4%]).  
Analysis of the safety data obtained in ReSTORE indicates that rates of TEAEs and SAEs were 
comparable between the rezafungin and caspofungin arms. There were no apparent 
imbalances between the treatment groups in System Organ Classes (SOCs) of AEs. Related 
SAEs were similar in number between the two groups. There were no laboratory abnormalities 
that were commonly associated with either study drug, though there were some imbalances in 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 30 of 86 
the 2-grade increases in toxicity for liver function tests that favours rezafungin. Furthermore, 
there were no apparent differences noted between vital sign and ECG data among the 
treatment groups. 
Two specific types of AEs were found to be associated with rezafungin in clinical trials: 
infusion-related reactions and phototoxicity. In ReSTORE, there were 2 cases of infusion 
intolerability associated with rezafungin dosing and one in the caspofungin arm. While an AE of 
sunburn was observed in one subject in the Phase 2 STRIVE study following prolonged 
exposure to the sun, no phototoxicity occurred in the ReSTORE study.1 
Due to the findings of tremors in monkeys exposed to prolonged, high doses (9.2X the exposure 
to the proposed commercial dose in adults), close attention was paid to any neurologic AEs 
(i.e., ataxia, neuropathy, and tremor). These neurologic AEs were balanced between the 
rezafungin and caspofungin study groups, with 2 subjects having tremors in the rezafungin 
group (0 in the caspofungin group) and 2 subjects having neuropathy in the caspofungin group 
(0 in the rezafungin group). These 2 cases of tremors were mild in severity and reversible. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of rezafungin (based on the adult clinical trials) can be found in the IB. 
Summary of Benefit and Risk Evaluation 
As this is a single-dose study, there is no direct clinical benefit expected for the subjects who 
will participate in this study. The information obtained from this study will be used for the further 
clinical development of rezafungin in the paediatric population. 
The risk of AEs is minimised by careful selection of doses and participants for the study, the 
relatively short duration (single dose) of IP exposure, lowered infusion rate, and the extent of 
safety monitoring incorporated into the study.  
Rezafungin will be administered in combination with a polyene or an azole (use of concomitant 
echinocandins is not allowed) used as standard-of-care treatment for IC or as prophylaxis for 
IFD. 
 

 
 
  
 
 MR907-1501 
 
CONFIDENTIAL 
 
Page 31 of 86 
4 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
To evaluate the pharmacokinetics (PK) of a 
single IV dose of rezafungin in paediatric 
subjects from birth to <18 years, receiving 
concomitant systemic antifungals as 
prophylaxis for invasive fungal infection (IFI) or 
to treat a suspected or confirmed fungal 
infection 
Parts 1 and 2: The following PK parameters 
will be assessed: 
Cmax, Tmax, AUC0-t, AUC0-∞, CL, Vss, Vz, t1/2 
 
Part 3: Rezafungin plasma concentrations 
Secondary 
 
To assess the safety and tolerability of a single 
IV dose of rezafungin in paediatric subjects 
from birth to <18 years, receiving concomitant 
systemic antifungals as prophylaxis for IFI or to 
treat a suspected or confirmed fungal infection 
The safety evaluation will be based on clinical 
review of the following parameters: 
• 
Incidence of treatment-emergent adverse 
events (TEAEs)  
• 
Clinical laboratory evaluations (including 
haematology, blood chemistry and 
urinalysis) 
• 
Vital signs 
• 
12-lead electrocardiogram (ECG): clinically 
significant abnormalities 
• 
Physical examination findings  
 
5 
STUDY DESIGN 
 Overall Study Design 
This is a Phase 1, open-label, multicentre study, to evaluate the pharmacokinetics, safety and 
tolerability of a single dose of rezafungin (administered as IV infusion) in paediatric subjects 
from birth to <18 years of age receiving concomitant systemic antifungals as clinically indicated. 
The study will be conducted at approximately 10 sites across at least 3 countries in Europe.  
It is planned to enrol 32 subjects (up to a maximum of 40 subjects [10 per age group] to achieve 
32 evaluable subjects for primary analysis). 
• 
Group 1 (12 to <18 years): 8 subjects  
• 
Group 2 (6 to <12 years): 8 subjects 
• 
Group 3 (2 to <6 years): 8 subjects 
• 
Group 4 (birth to <2 years): 8 subjects 
Subjects who are withdrawn from the study before completing all PK sampling may be replaced 
(up to 2 replacement subjects per group is allowed). 
The study will be conducted in 3 parts:  

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 32 of 86 
• 
Part 1 will enrol subjects aged 12 to <18 years (Group 1) 
• 
Part 2 will enrol subjects aged 6 to <12 years (Group 2), and subjects aged 2 to <6 years 
(Group 3) 
• 
Part 3 will enrol subjects from birth to <2 years (Group 4) 
The study design for the 3 parts is similar and comprises a Screening (pre-treatment) period 
from Day -3 to Day -1, Dosing on Day 1 (single IV infusion of rezafungin) followed by multiple 
PK sampling, and a Follow-up visit on Day 30 (± 5 days). PK sampling will be performed at 
specified timepoints for each group. See Figure 1Figure 1 for the study schema, and see 
Table 1 and Table 2 for the Schedule of Assessments (SoA). 
Part 1 
Subjects in Group 1 (aged 12 to <18 years) will be dosed first. For this group, the formulation to 
be used will be same as the one used in the adult clinical trials at a dose of 3 mg/kg (not to 
exceed a total dose of 200 mg). 
For each participant, the study will consist of: 
• 
Screening between Day -3 and Day -1 
• 
Administration of a single IV infusion of rezafungin over 2 hours (± 5 minutes) on Day 1 
• 
Blood sampling for PK measurements at the following timepoints: at 
end-of-infusion ± 15 minutes, and thereafter between 3 and 4 hours after start of 
infusion, between 6 and 8 hours after start of infusion, at 48 hours (± 4 hours) after start 
of infusion (Day 3), and at 168 hours (± 12 hours) after start of infusion (Day 8). The 
exact date and time of the PK samples must be recorded. 
• 
A Follow-up visit on Day 30 (± 5 days) 
After completion of the Follow-up visit for all subjects in Group 1, there will be an interim review 
of the safety, tolerability, and PK data. The data will be reviewed by the Data Safety Monitoring 
Board (DSMB) to ensure that the exposure achieved in subjects from this group is safe and well 
tolerated. This will allow for a decision to proceed to Part 2. 
In parallel to this study a formulation development programme is being undertaken to identify a 
lower strength paediatric specific formulation with an appropriate PS80 level for use in subjects 
<12 years of age. A lower strength formulation (e.g., 100 mg/vial, compared with 200 mg/vial for 
the formulation used in Group 1) would reduce the risk of a 10-fold overdose in children with a 
weight of <3 kg. Once the paediatric formulation is available for use, after completion of Part 1, 
the study will be paused and a substantial amendment will be submitted to enable use of the 
paediatric formulation in Part 2 and Part 3 (for dosing in subjects <12 years of age). 
Part 2 
Enrolment for Part 2 (subjects aged 2 to <12 years) will commence after safety has been 
confirmed by the DSMB and the paediatric formulation has been identified and ready to be 
used. The dose for this age group is planned to be 4 mg/kg (not to exceed a total dose of 200 
Formatte
Color(RGB
Formatte
Custom C
grammar

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 33 of 86 
mg). The dose and PK sampling timepoints may be adjusted as appropriate after assessment of 
the PK and safety data of Part 1. 
The study design and duration of Part 2 will be similar to that for Part 1: a 3-day Screening 
period, Dosing on Day 1 (a single IV infusion of rezafungin) followed by five PK samplings 
between Day 1 and Day 8, and a Follow-up visit on Day 30 (± 5 days).  
In Part 2, subjects aged 6 to <12 years (Group 2) and 2 to <6 years (Group 3) will be enrolled in 
parallel. The PK sampling timepoints for Part 2 will be the same as that for Part 1: at end-of-
infusion ± 15 minutes, and thereafter between 3 and 4 hours after start of the infusion, between 
6 and 8 hours after start of the infusion, at 48 hours (± 4 hours) after start of the infusion 
(Day 3), and at 168 hours (± 12 hours) after start of the infusion (Day 8). After data from 
approximately 50% of the subjects aged 2 to <12 years are available, there will be a second 
interim review of the safety and PK data by the DSMB to ensure that the exposure achieved in 
subjects from this age group is safe and well tolerated, and inform whether adjustments to the 
dose and PK sampling timepoints are required for the remaining subjects. Recruitment/dosing 
will not be paused during this DSMB review. 
After completion of Part 2, there will be another interim review (interim review 3) of the safety, 
tolerability, and PK data from the subjects in Groups 1, 2, and 3.  
A series of juvenile animal toxicity studies will be conducted in parallel with this PK study to 
investigate the effect of rezafungin on the growing and developing nervous system. Enrolment 
for Group 4 will not start until the juvenile animal toxicity studies are completed, the animal 
safety data have been reviewed, and the safety and tolerability from the preceding parts have 
been confirmed by the DSMB. 
Part 3 
Subjects from birth to <2 years (Group 4) will be enrolled in Part 3. The planned dose for this 
age group is 5 mg/kg. Due to blood volume restriction, PK sampling will be done at only 
3 timepoints for Group 4: at the end-of-infusion (± 15 minutes), at 24 hours (± 4 hours) after start 
of infusion (Day 2), and at 168 hours (± 12 hours) after start of infusion (Day 8). A maximum 
total of 1 mL of blood will be taken for PK sampling. The dose and PK sampling timepoints may 
be adjusted as appropriate after assessment of the PK and safety data of Part 1 and Part 2. 
All subjects will be monitored for AEs and SAEs at timepoints specified in Table 1 and Table 2. 
Laboratory evaluations, electrocardiograms (ECGs), vital signs, and physical examinations will 
be performed at Screening and at timepoints specified in Table 1 and Table 2. 
5.1.1 Recruitment 
The recruitment process will be taking place in the inpatient hospital setting. The Investigators 
will identify potential subjects through review of the medical records and complete a participant 
identification and enrolment log before direct communication with the subjects and/or their 
parent(s)/legally authorised representative (LAR). This document will be reviewed by the 
Sponsor site contact for completeness. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 34 of 86 
The participant identification and enrolment log will be treated as confidential and will be filed by 
the Investigator in the study file. To ensure participant confidentiality, no copy will be made. 
5.1.2 Informed Consent 
Subjects and/or their parent(s)/LAR will sign the study specific informed consent form (ICF) prior 
to any study specific screening procedures being performed. The written informed consent/age-
appropriate assent will be obtained from all subjects and/or their parent(s)/LAR, regardless of 
their eligibility for the study; the signed ICFs will be retained and archived at study site and 
another copy will be provided to the subject. 
5.1.3 Screening 
At Screening, eligibility of the subject to participate in the study will be determined by the 
Investigator based on the inclusion/exclusion criteria. Screening assessments will occur prior 
(Day-3 to Day-1) to rezafungin administration.  
In cases where a participant does not meet the criteria for participation in this study (screen 
failure), the main reason for non-eligibility is to be documented in the electronic Case Report 
Form (eCRF). 
The following Screening assessments will be performed within 3 days prior to dosing: 
• 
Written parental (or LAR) informed consent and/or age-appropriate consent/assent 
(Note: no study procedures may be performed prior to obtaining written informed 
consent) 
• 
Assess eligibility criteria 
• 
Demographics: age, sex, and race (for Groups 1, 2, and 3: 2 to <18-years age group); 
age, sex, race, birth weight and gestational age (for Group 4: birth to <2-years age 
group) 
• 
Baseline characteristics: height, weight, body mass index (BMI; only for Groups 1, 2, and 
3 [Appendix 6]), and disease characteristics (indication for antifungal 
prophylaxis/treatment) 
• 
Medical, surgical history and current medical conditions, including whether the subject is 
in the general ward or ICU. If the subject is in the ICU, record the Paediatric Index of 
Mortality (PIM2) variables (Appendix 7) 
• 
Prior and concomitant medication use: All medication taken up to 7 days prior to signing 
the ICF and medication ongoing at study entry (after informed consent) must be 
recorded. Note: Antifungal medications that the subject was receiving prior to enrolment 
must be recorded (treatment with a non-echinocandin agent [either an azole or a 
polyene as standard-of-care] is allowed during the study). If a subject has previously 
received an echinocandin, and it has been changed to an alternative antifungal 
treatment (i.e., an azole or a polyene), he/she will be eligible for the study as long as 
there is a minimum of 5-day washout of the echinocandin, before the administration of 
rezafungin 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 35 of 86 
• 
Complete physical examination: A complete physical examination will include, at a 
minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and central 
and peripheral neurological system 
• 
Vital signs: Vital signs will be taken after subject is sitting or supine for at least 5 minutes 
and will include temperature, pulse rate, respiratory rate, and blood pressure 
(Appendix 5) 
• 
Clinical laboratory tests: haematology, biochemistry, and urinalysis (see Appendix 2 for 
details) 
• 
Urine pregnancy test (for postmenarchal females) 
• 
12-lead ECG 
The Screening assessments will be considered as baseline assessments. 
5.1.4 Dosing on Day 1 and Subsequent Pharmacokinetic Assessments 
Subjects with suspected or confirmed fungal infection, or subjects who require prophylactic 
systemic antifungals who meet the eligibility criteria will receive a single IV infusion of rezafungin 
on Day 1 at a dose of 3 mg/kg (Group 1: 12 to <18 years) or 4 mg/kg (Group 2 and Group 3: 
2 to <12 years) up to a maximum total dose of 200 mg, or 5 mg/kg (Group 4). The doses for 
Groups 2, 3, and 4 may be adjusted as appropriate after interim reviews of PK and safety data. 
Subjects will be continuously monitored (vital signs and continuous ECG monitoring) for the 
duration of infusion administration up to the end of the rezafungin infusion.  
Assessments performed on Day 1 include: 
• 
Record concomitant medications 
• 
Brief targeted physical examination: A brief targeted physical examination will include, at 
a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and central 
and peripheral neurological system, driven by the subject’s symptoms and signs  
• 
Vital signs: Vital signs will be taken after subject is sitting or supine for at least 5 minutes 
and will include temperature, pulse rate, respiratory rate, and blood pressure (predose, 
15 to 30 minutes after the start of drug administration, and 30 to 60 minutes after 
completion of the infusion) 
• 
12-lead ECG: at any time between 3 and 4 hours after start of IP infusion on Day 1 for 
Groups 1, 2, and 3. For Group 4, postdose ECG will be performed at 24 ± 4 hours after 
start of IP infusion (Day 2). 
• 
Continuous vital sign and ECG monitoring: during infusion 
• 
Blood sampling for PK measurement at end-of-infusion ± 15 minutes, then between 
3 and 4 hours after start of infusion, and between 6 and 8 hours after start of infusion (for 
Groups 1, 2, and 3). PK sampling for Group 4 will be performed at the end-of-infusion 
(± 15 minutes). 
• 
Record TEAEs/SAEs (including infusion-related reactions)  

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 36 of 86 
In addition to the above PK sampling timepoints, blood samples for PK measurement will also 
be collected at 48 hours (± 4 hours) after start of infusion (Day 3) and at 168 hours ± 12 hours 
(Day 8) after the start of rezafungin IV infusion for Groups 1, 2, and 3, and at 24 hours 
(± 4 hours) after start of infusion (Day 2), and at 168 hours (± 12 hours) after start of infusion 
(Day 8) for Group 4. The exact date and time of the PK samples must be recorded. 
5.1.5 Follow-up or Early Termination 
The Follow-up assessments will be performed on Day 30 (± 5 days) for all subjects. In case of 
subjects who withdraw consent before the Follow-up visit, or are discontinued early (for safety 
reasons) from the study, early termination (ET) assessments can be performed at the time of 
discontinuation. The reason for ET must be recorded in the eCRF. In cases where a subject is 
discontinued before all PK samples have been collected, a last PK sample can be collected if 
the subject and/or his/her parent(s)/LAR consents. The exact date and time of the PK sample 
must be recorded. 
The following assessments will be performed at Follow-up or ET: 
• 
Record concomitant medication use (includes medications that are ongoing or started 
after Day 1) 
• 
Complete physical examination: A complete physical examination will include, at a 
minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and central 
and peripheral neurological system 
• 
Vital signs: Vital signs will be taken after subject is sitting or supine for at least 5 minutes 
and will include temperature, pulse rate, respiratory rate, and blood pressure 
• 
Clinical laboratory tests: haematology, biochemistry and urinalysis (see Appendix 2 for 
details) 
• 
Urine pregnancy test (for postmenarchal females) 
• 
Record TEAEs/SAEs (see Appendix 3) 
• 
For ET, in addition to the above, reason for early termination must be recorded in the 
eCRF 
 
 Scientific Rationale for Study Design 
This is the first study investigating the use of rezafungin in paediatric subjects. 
The PK of a drug in the paediatric population usually cannot be precisely predicted from that in 
adults. Therefore, PK studies are needed to determine the appropriate paediatric dosing 
regimen. 
This study has been designed to investigate the PK and safety of a single IV dose of rezafungin 
in paediatric subjects from birth to <18 years in combination with a polyene or an azole (use of 
concomitant echinocandins is not allowed) used as standard-of-care for treatment of suspected 
or confirmed fungal infection or as prophylaxis for IFD. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 37 of 86 
Given the age of the study participants a sparse PK sampling schedule has been selected to 
reduce the number of blood samples required by the subjects in the study. The plasma 
concentration data obtained from these samples will be used to develop a population PK model 
for paediatric subjects, to predict the exposure in children and confirm the dosing regimen for 
this population.  
The study will be staggered to dose the 12 to <18 year olds first, followed by the 2 to <12-years 
age group, followed by birth to <2-years age group, respectively. Enrolment to Part 2, and 
subsequently to Part 3 of the study (i.e., the <12-years age groups) will start only after a review 
of the safety, tolerability and PK data of the preceding study Part(s) by the DSMB. This will 
enable confirmation of the dose and PK sampling timepoints planned for subjects <12 years old. 
The primary objective of this study is to define the safety, tolerability and PK of rezafungin, as 
opposed to efficacy; therefore, the subjects in this study will also be receiving standard-of-care 
antifungal treatment. To aid recruitment into this study a decision was made to include subjects 
receiving systemic antifungals prophylactically as well as subjects receiving systemic 
antifungals to treat a suspected or confirmed fungal infection. 
Non-adverse Schwann cell phospholipidosis was observed in peripheral nerves in rats and 
monkeys. Therefore, a series of juvenile animal toxicity studies will be conducted in parallel with 
this PK study to investigate the condition and effects of phospholipidosis on the growing and 
developing nervous system. Enrolment for Group 4 (from birth to <2 years) will not start until the 
juvenile animal toxicity studies are completed and the safety data have been reviewed. 
 
 Justification for Dose 
The doses selected for this study are based on the output of population PK modelling and 
simulation. A population model has been developed for rezafungin using data obtained from 
healthy and hepatically impaired adult subjects from Phase 1 studies, and adult patients with 
candidemia and/or IC from the Phase 2 (STRIVE), and Phase 3 (ReSTORE) studies. The 
population model is a 3-compartment model with first-order elimination, and body surface area 
(BSA) and albumin concentrations were identified as two of the statistically significant covariates 
of rezafungin exposure (Data on file). Weight-based dosing (mg/kg) was selected for dose 
normalisation for the paediatric population. To simulate the exposure in the different paediatric 
age groups, for a range of weight-based dosing regimens (mg/kg), the adult model was used, 
along with estimates of BSA from the National Healthy and Nutritional Examination Survey 
(NHANES) data base, produced by the Centers for Disease Control and Prevention (CDC) in 
the US. In addition, the albumin distribution in adult patients from STRIVE and ReSTORE was 
used and values were sampled at random from this population.  
The adult dosing regimen for commercialisation is an initial dose of 400 mg on Day 1 followed 
by a 200 mg dose on Day 8, and once weekly thereafter. The doses of rezafungin used in this 
study have been chosen to be similar to the single 200-mg adult dose on the basis of predicted 
plasma exposure. As this is a single-dose PK study and not an efficacy trial it is not necessary 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 38 of 86 
to select an efficacious dose, but rather to ensure that the dose will be sufficient to enable PK 
assessment in the paediatric population. 
Rezafungin will be administered as an IV infusion over a period of 2 hours. Using the paediatric 
population PK model, the dose for subjects aged 12 to <18 years has been selected as 3 mg/kg 
(not to exceed a total dose of 200 mg), and the dose for subjects aged 2 to <12 years is 
4 mg/kg (not to exceed a total dose of 200 mg). The dose administered to Group 2 and Group 3 
(children aged 2 to <12 years) will be confirmed after an interim review of the safety and PK 
data of Part 1 by the DSMB (DSMB review 1). Based on this review, the dose and PK sampling 
timepoints for Part 2 (Groups 2 and 3) may be adjusted as appropriate. The planned dose for 
subjects from birth to <2 years (Group 4) is 5 mg/kg. However, the dose and PK sampling 
timepoints for Group 4 may be adjusted as appropriate after assessment of the PK and safety 
data of Part 1 and Part 2 (DSMB review 3). 
The formulation to be used for dosing Group 1 (12 to <18 year olds) is the formulation used in 
adult clinical trials. This formulation, however, contains PS80, which is known to cause toxicity 
in younger paediatric populations. To minimise the PS80 effects, in parallel to this study a 
formulation development programme is being undertaken to attempt to identify a lower strength 
paediatric specific formulation with an appropriate PS80 level for use in children <12 years of 
age. Once the paediatric formulation is available for use and after completing dosing Group 1 
subjects, the study will be paused and a substantial amendment will be submitted to enable the 
paediatric formulation to be dosed to subjects in Groups 2, 3, and 4.  
 
 End-of-Study Definition 
The end-of-study is defined as the last visit of the last subject in the study. 
For an individual subject, the subject is considered to have completed the study if he/she has 
completed all visits per the SoA, including the Follow-up visit (see Table 1 and Table 2). 
 
6 
STUDY POPULATION 
 Inclusion Criteria 
To be eligible for enrolment, a subject must fulfil all of the following inclusion criteria: 
 Male or female subjects from birth to <18 years of age 
 Provide written parental (or LAR) informed consent and/or age-appropriate informed 
consent/assent (per national regulations/guidance) prior to any study-related procedure 
 Subject has sufficient central or peripheral venous access to permit administration of 
study medication, collection of PK samples and monitoring of laboratory safety variables 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 39 of 86 
 For subjects ≥2 years of age, having a BMI (weight in kilograms divided by height in 
metres, squared) between the 2nd and 98th percentiles, inclusive (Appendix 6) 
 For a female subject who has undergone menarche and is considered to be of 
childbearing potential:  
o True abstinence OR utilises one of the following for at least 1 month prior to 
Screening: hormonal contraceptives (injectable, oral, patch, or vaginal ring), 
intrauterine device, or barrier method (diaphragm). This method must be used in 
combination with a barrier method of contraception for their male partner 
(condom). Subjects must be willing to practice these methods for at least 30 days 
after study drug administration (until Follow-up) 
Note: a female subject is considered to be of childbearing potential if the subject is 
fertile, following menarche and until becoming post-menopausal unless permanently 
sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, 
and bilateral oophorectomy. 
 For male subjects who are sexually active with female partners who have undergone 
menarche: subject must be using and willing to continue using medically acceptable 
forms of contraception (male condom for subjects plus an additional method of 
contraception for their female partners) from Screening and for at least 3 months after 
study drug administration 
 Currently receiving systemic antifungals (oral or IV) as clinically indicated either: 
o for suspected or confirmed fungal infection, OR  
o as prophylaxis for IFI 
Note: In subjects who are receiving systemic antifungals for the treatment of suspected 
or confirmed fungal infection or as prophylaxis for IFI, rezafungin will be administered in 
addition to standard-of-care as per institutional, national, or international guidelines, as 
long as it involves a non-echinocandin agent (an azole or a polyene; subjects can 
receive only either an azole or polyene, not both). If a subject has previously received an 
echinocandin, and it has been changed to an alternative antifungal treatment (i.e., an 
azole or a polyene), he/she will be eligible for the study as long as there is a minimum of 
5-day washout of the echinocandin, before the administration of rezafungin. 
 Subjects and parent(s)/LAR are willing and able to comply with the study instructions. 
 
 Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
1. History of anaphylaxis, hypersensitivity, or any serious reaction to the echinocandin 
class of antifungals and/or excipients of this formulation, including, but not limited to, 
hereditary sugar disorders (e.g., fructose intolerance, sucrase-isomaltase deficiency), or 
echinocandin-induced exfoliative skin disorders (e.g., Stevens-Johnson syndrome or 
toxic epidermal necrolysis) 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 40 of 86 
2. Subject has a concurrent medical condition that in the opinion of the Investigator and/or 
medical monitor precludes enrolment into the study 
3. Evidence of impaired hepatic or renal functions, as defined by aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of 
normal (ULN), conjugated bilirubin >24 μmol/L (1.4 mg/dL), serum creatinine 
>177 μmol/L (2 mg/dL), or receiving renal replacement therapy 
4. The Investigator anticipates the subject becoming anaemic and not tolerating blood 
draws during the study period 
5. Subjects have intestinal hypoxia, ischaemia, necrosis, or necrotising enterocolitis 
6. Neonates with hyperbilirubinaemia and requiring phototherapy 
7. History of severe ataxia, persistent tremors (e.g., due to persistent hypoglycaemia, 
persistent hypocalcaemia, encephalopathy, etc.), intracranial haemorrhage, or 
neuropathy, or a diagnosis of epilepsy, multiple sclerosis, or a movement disorder 
(including, but not limited to, cerebral palsy and muscular dystrophy), any of which is of 
Grade 2 or higher, based on the Division of Acquired Immunodeficiency Syndrome 
(DAIDS) criteria, Version 2.1 
8. Planned or ongoing therapy at Screening or during the course of the study with a known 
severe neurotoxic medication (see Appendix 4) or CNS irradiation, or with a known 
moderate neurotoxic medication in a subject with ataxia, persistent tremors, intracranial 
haemorrhage, motor neuropathy, or sensory neuropathy, any of which is of Grade 1 or 
higher, based on the DAIDS criteria, Version 2.1 (see Appendix 3) 
a. Coadministration of vincristine (maximum: 2 mg/dose) with a dosing interval of every 
21 days or less frequent is permitted in subjects without a history of ataxia, persistent 
tremors, intracranial haemorrhage, motor neuropathy, or sensory neuropathy AND 
not receiving concomitant azole therapy during the course of the study (from signing 
the informed consent to the follow-up visit on Day 30 ± 5). 
9. Subject status is unstable (e.g., with sepsis or disseminated intravascular coagulation) 
and unlikely to complete required study procedures 
10. Subject is currently receiving an echinocandin (or has received an echinocandin within 
5 days before administration of rezafungin) 
11. Previous participation in this study or any previous rezafungin study 
12. Participation in another interventional treatment trial with an unapproved investigational 
agent or presence of an unapproved investigational device at the time of informed 
consent or within 28 days preceding study entry (informed consent) 
Note: Participation in investigational trials involving approved chemotherapeutic or 
immunological regimens, investigational radiotherapy trials, and observational trials are 
allowed. 
13. Pregnant or lactating females 
14. The Investigator is of the opinion the subject should not participate in the study 
15. Subjects/LARs dependent on the Sponsor, Investigator or study site 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 41 of 86 
16. Unable to give his/her own informed consent if a subject reaches the age of consent 
during the study 
17. Committed to an institution in accordance with an order issued either by the judicial or 
the administrative authorities 
18. Tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by a 
nucleic acid amplification test or antigen test within 7 days prior to dosing of rezafungin 
(note, SARS-CoV-2 testing is not a protocol requirement and should be performed 
according to the institutional policy and clinical need) 
 
 Lifestyle Considerations 
It is expected that all the subjects will receive rezafungin IV infusion in a hospital setting; 
subjects may be permitted to complete PK assessments on an outpatient basis if deemed 
appropriate by the Investigator. 
 
 Screen Failures 
After signing the informed consent, subjects who drop out or withdraw from the study for any 
reason without completing all Screening evaluations, or subjects who do not meet the eligibility 
criteria will be considered screen failures. 
Subjects who do not meet the criteria for participation may be rescreened. Subjects are only 
allowed to be rescreened once; the entire screening process must be repeated. Rescreened 
subjects will be assigned a new subject number for every screening/rescreening event.  
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 42 of 86 
7 
STUDY TREATMENT 
The details of the study treatment (IV rezafungin) are provided in Table 3. 
 Study Treatment Administered 
This is an open-label study and all subjects will receive a single IV infusion of rezafungin over 
2 hours (± 5 minutes). 
Part 1 (Group 1 – 12 to <18 years of age) 
The IP formulation used for Group 1 will be same as the one used in the adult clinical trials. 
Dose for Group 1 will be 3 mg/kg (not to exceed a total dose of 200 mg). 
Part 2 (Group 2 – 6 to <12 years and Group 3 – 2 to <6 years of age) and Part 3 (Group 4 – 
from birth to <2 years of age) 
In parallel to this clinical study, a formulation development programme is being undertaken to 
identify a lower strength paediatric specific formulation with an appropriate PS80 level for use in 
subjects <12 years of age. When an adequate paediatric formulation is identified, after the 
completion of Group 1, the study will be paused and a substantial amendment will be submitted 
to enable the paediatric formulation to be used in the subjects in Groups 2, 3, and 4. 
The planned dose for Group 2 and Group 3 is 4 mg/kg (not to exceed a total dose of 200 mg) 
and the planned dose for Group 4 is 5 mg/kg; however, the doses will be confirmed after 
assessment of the interim PK and safety data. The doses may be adjusted as appropriate. 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 43 of 86 
Table 3 
Study Treatment Administered 
Study Treatment 
Test Product 
Study Treatment Name 
Rezafungin acetate (MR907) 
Treatment Description 
Part 1: Rezafungin is a sterile product of lyophilised powder for 
reconstitution with sterile water for injection prior to dilution into infusion 
bags containing normal saline, half-normal saline, or 5% dextrose. 
Each single-dose vial contains rezafungin acetate (200 mg of active 
rezafungin) and excipients, including polysorbate 80 (450 mg), mannitol 
(500 mg), and histidine (47 mg).  
The formulation may contain hydrochloric acid and/or sodium hydroxide 
as needed for pH adjustment.  
After reconstitution of the lyophilised powder with water for injection, the 
reconstituted solution should be immediately diluted into infusion bags 
containing normal saline, half-normal saline or 5% dextrose. 
Part 2 and Part 3: Formulation information will be included when 
available. 
Formulation 
Powder for concentration for solution for infusion (for Part 1). 
Formulation for Part 2 and Part 3 will be included when available. 
Unit Dose Strength 
200 mg/vial (for Part 1) 
Dose(s) 
Age-appropriate doses (as a single dose) 
• 
3 mg/kg (not to exceed a total dose of 200 mg) for 12 to <18 years 
(Group 1) 
• 
4 mg/kg (not to exceed a total dose of 200 mg) for 2 to <12 years 
(Group 2 and Group 3) 
• 
5 mg/kg for subjects from birth to <2 years (Group 4) 
Route of Administration 
Intravenous infusion over 2 hours (± 5 minutes) 
Packaging and Labelling 
Labelling and packaging of study medication will be as per applicable 
regulatory requirements. 
Study medication must be stored in a secure, limited access area, and 
may be dispensed only by specifically authorised personnel. 
Refer to the Pharmacy Manual for further details on packaging, 
labelling, and storage. 
Manufacturer 
Patheon, Monza, Italy 
 
 Administration 
Subjects will receive a single IV dose of rezafungin as a 2-hour (± 5 minutes) IV infusion.  
For Group 1, rezafungin will be reconstituted with water for injection. The reconstituted solution 
should be immediately diluted into infusion bags containing normal saline, half-normal saline or 
5% dextrose. Age-appropriate volumes (based on body weight) will be used to dilute 
reconstituted rezafungin with final concentrations between 0.8 and 1.6 mg/mL. Infusion rates will 
differ based on the volume of each dose in each subject, and will between 0.9375 and 
1.875 mL/kg/hour. The PS80 infusion rate will be 0.0563 mg/kg/min. Please refer to the 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 44 of 86 
Pharmacy Manual for the detailed directions for preparation and administration of rezafungin 
intravenous solution. 
Once the paediatric formulation for Groups 2, 3, and 4 is available, the method of administration 
will be determined and included in the protocol via a substantial amendment. 
 
 Preparation/Handling/Storage/Accountability 
The study treatment will be supplied to the Investigator or designee by the Sponsor, either 
directly or via a local warehouse contracted by the Sponsor. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received, and any discrepancies are reported 
and resolved before use of the study treatment. 
Only subjects enrolled in the study may receive study treatment, and only authorised site staff 
may supply or administer study treatment. All study treatment must be stored in the packaging 
to protect from light, in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to the 
Investigator and authorised site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Unused study treatments including empty containers, are to be returned to the Sponsor or 
Sponsor-designated warehouse at the conclusion of the study, unless provision is made by the 
Sponsor for destruction of supplies and containers at the investigational site. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual.  
 
 Measures to Minimise Bias: Randomisation and Blinding 
Not applicable as this is an open-label, single-arm study. 
 
 Treatment Compliance 
The IP (rezafungin) will be administered at the site (hospital). Subjects will receive the infusion 
from the Investigator or designee, under medical supervision. The date and time of the infusion 
and dose administered will be recorded in the source documents. The dose of IP and subject 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study treatment.  

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 45 of 86 
Compliance will be documented in the source documents and relevant medical and pharmacy 
records. Deviation(s) from the prescribed dose regimen (e.g., dose, infusion volume, and 
infusion duration) should be recorded. 
 
 Dose Modification 
If any mild local infusion-related reaction occurs, the Investigator may temporarily slow or 
discontinue the infusion, or re-site the infusion. If any systemic or moderate/severe local 
infusion-related reaction occurs, the Investigator may stop the infusion and inform the 
Sponsor/medical monitor. 
7.6.1 Treatment Overdose 
For this study, any dose of rezafungin greater than the stipulated dose will be considered an 
overdose. 
In the event of an overdose, the Investigator should: 
• 
Contact the medical monitor immediately. 
• 
Closely monitor the subject for any AE/SAE and laboratory abnormalities until resolution, 
stabilisation of the event, the event is otherwise explained, or the subject is lost to 
follow-up. 
• 
Obtain an additional blood sample for PK analysis if requested by the medical monitor 
(to be determined on a case-to-case basis). 
• 
Document the quantity of the excess dose as well as the duration of the overdose. 
 
 Concomitant Therapy 
Any medication taken by the subject or administered to the subject other than the IP specified in 
the protocol (including medication administered for treatment of AEs) is considered concomitant 
medication. Information about concomitant medications will be recorded in the eCRF from the 
Screening visit until Follow-up (Day 30 ± 5 days).  
Administration of any other antifungal medication classified as an azole or polyene (as 
standard-of-care), will be allowed. 
Using a concomitant echinocandin as the standard-of-care, or having received an echinocandin 
within 5 days before planned dosing with rezafungin, is not permitted in the study. However, if 
following dosing with rezafungin, a subject requires the administration of another echinocandin 
due to medical needs judged by the Investigator, it will be allowed after at least 7 full days after 
dosing with rezafungin. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 46 of 86 
Medications that are ongoing at study entry (after the informed consent) and any medication 
given to the subjects during the study (after the informed consent) through the last study 
evaluation (Follow-up [Day 30 ± 5 days]) must be recorded on the source documents and 
appropriate section of the eCRF. The use of any concomitant medication must relate to an AE 
or the subject’s medical history. The medication must be recorded with: 
Reason for use 
Dates of administration including start and end dates 
Dosage information including dose, frequency, and route of administration 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
7.7.1 Rescue Medication 
For the purpose of this study, there is no specific rescue medication. 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 47 of 86 
8 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT DISCONTINUATION/
 
WITHDRAWAL 
 Discontinuation of Study Treatment 
This is a single-dose study. All subjects enrolled will receive a single infusion of IP (rezafungin). 
Stopping Rules 
Stopping Criteria for an Individual Subject 
• 
In case of any systemic reaction (i.e., cytokine release syndrome, including nausea, 
headache, tachycardia, hypotension, rash, and/or shortness of breath) or local 
infusion-related reaction (i.e., injection site pain or tenderness, erythema or redness, 
induration or swelling, or pruritis) with a severity of Grade 2 or higher (according to the 
DAIDS criteria, Version 2.1), the infusion will be immediately stopped and not restarted, 
and treatment provided as appropriate. The date and time of discontinuation must be 
recorded in the eCRF. The Sponsor/medical monitor must be informed immediately (no 
later than 24 hours of Principal Investigator’s knowledge of the event). Where feasible, 
the PK assessment will continue if the subject is well enough and willing to continue. 
Note: in case of Grade 1 local reactions, the investigator may slow down the infusion or 
temporarily discontinue the infusion (see Section 7.6).  
• 
A subject becomes pregnant. 
Criteria for Pausing or Stopping the Study 
The study would be paused in cases where: 
• 
One subject experiences a serious unexpected adverse event that is considered at least 
possibly related to rezafungin. The event will be investigated and the causality 
established before dosing the next available subject. 
The study would be stopped in cases where any of the following occurs:  
• 
A study drug-related significant adverse reaction (i.e., a serious AE considered at least 
possibly related to the IP administration) leading to treatment discontinuation in 
2 subjects 
• 
Two or more subjects have experienced a Grade ≥4 AE considered to be related to 
rezafungin 
• 
The Investigator and the Sponsor both agree that the tolerability profile is unacceptable, 
based on the frequency and intensity of observed AEs (including serious and related 
AEs) 
• 
At the request of the DSMB, based on a safety concern during the review of the safety 
and tolerability data 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 48 of 86 
• 
Additional data from other clinical trials or toxicological studies become available that 
negatively influence the risk/benefit assessment 
• 
At a specific site/in a specific region: if the local regulatory authority or Independent 
Ethics Committee (IEC) withdraws approval of the study 
 
 Subject Discontinuation/Withdrawal from the Study 
Participation in the study is strictly voluntary. 
• 
A subject has the right to withdraw from the study at any time for any reason. 
• 
The subject’s parent(s)/LAR (as applicable) may choose to withdraw the subject from the 
study at any time or the subject may be withdrawn at any time at the discretion of the 
Investigator for safety (due to AEs or SAEs), or compliance reasons.  
• 
At the time of discontinuation from the study, if possible, an ET visit should be 
conducted, as shown in the SoA. For data to be collected at the time of study 
discontinuation see SoA (Table 1 and Table 2). The subject will be permanently 
discontinued from the study treatment and the study at that time. 
• 
If the subject or subject’s parent(s)/LAR withdraws consent for disclosure of future 
information, the Sponsor may retain and continue to use any data collected before such 
a withdrawal of consent. 
• 
If a subject withdraws from the study, he/she or the subject’s parent(s)/LAR may request 
destruction of any samples taken and not tested, and the Investigator must document 
this in the source documents and relevant medical records. Samples not yet tested at 
the time of destruction request will be destroyed. 
• 
The reason for withdrawal will be recorded in the eCRF. 
 
 Lost to Follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for the 
scheduled Follow-up visit and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:  
• 
The site must attempt to contact the subject or the subject’s parent(s)/LAR and ascertain 
whether the subject wishes to and/or should continue in the study. 
• 
Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject or the subject’s parent(s)/LAR (where 
possible, 3 telephone calls, and if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 49 of 86 
• 
Should the subject or the subject’s parent(s)/LAR continue to be unreachable, he/she 
will be considered to have withdrawn from the study. 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 50 of 86 
9 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timings are summarised in Table 1 and Table 2. 
Any safety concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the subject should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a Screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screen failure, as applicable. 
Investigations conducted as part of the subject’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilised for Screening or baseline purposes 
provided the investigations meet the protocol-specified criteria and were performed within 
Day -3 to Day -1. 
Blood samples for plasma PK determination (rezafungin plasma levels) will be collected in all 
subjects.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
The blood volume for PK and other laboratory tests will not exceed the volume limits 
recommended by the EU paediatric guidance21 (up to approximately 3% of total weight [2.4 mL 
blood/kg body weight], with no more than 1% [0.8 mL blood/kg body weight] at any single time). 
For subjects <2 years of age (Group 4), a maximum total of 1 mL of blood will be taken for PK 
sampling. 
 
 Efficacy and/or Immunogenicity Assessments 
Not applicable. 
 
 Safety Assessments 
Safety will be assessed through incidence of TEAEs, including infusion-related and local 
infusion-site reactions, electrocardiograms (ECGs), clinical laboratory evaluations (including 
haematology, blood chemistry and urinalysis), vital signs, and physical examination findings. 
Any clinically significant observations, as determined by the Investigator, in results of clinical 
laboratory, 12-lead ECGs, vital signs, or physical examinations will be recorded as AEs. 
Planned timepoints for all safety assessments are provided in the SoA (see Table 1 and 
Table 2). 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 51 of 86 
9.2.1 Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and serious AEs (SAEs) can be found in Appendix 3. 
The subject/subject’s parent(s)/LAR, or a caregiver will be asked in general terms about any 
AEs at regular intervals during the study. In addition, all AEs reported spontaneously by the 
subject/subject’s parent(s)/LAR, or a caregiver during the course of the study will be recorded. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up until resolution, all AEs that are serious, considered related to the study treatment or that 
caused the subject to discontinue the study treatment. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
9.2.2 Time Period and Frequency for Collecting AE and SAE Information 
All AEs/SAEs will be collected from the start of IV infusion until the Follow-up visit at the 
timepoints specified in the SoA (see Table 1 and Table 2). 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded as medical history/current medical conditions, not as AEs. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from the time of awareness, as indicated in 
Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 24 hours 
of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the Investigator must promptly 
notify the Sponsor. 
9.2.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow up each subject. 
All SAEs and AEs of special interest (as defined in Section 9.2.6) will be followed up until 
resolution, stabilisation, the event is otherwise explained, or the subject is lost to follow-up. 
Further information on follow-up procedures is provided in Appendix 3. 
9.2.4 Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects 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 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 52 of 86 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IECs, and Investigators. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file it 
along with the study documents and will notify the IEC, if appropriate according to local 
requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
All confirmed (laboratory-tested positive result) and suspected cases of COVID-19 that occur 
from the signing of informed consent through the Follow-up visit, whether symptomatic or not, 
will be reported as AEs. 
9.2.5 Pregnancy 
Details of all pregnancies in female subjects and, if indicated, female partners of male subjects 
will be collected after the start of study treatment and until the time period for reporting 
pregnancies (should align with the time period for post-treatment contraception determined in 
Section 6.1). 
If a pregnancy is reported, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the female subject or female 
partner of a male subject (after obtaining the necessary signed informed consent from the 
female partner) pregnancy. All pregnancies will be followed up for the outcome of pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
9.2.6 Adverse Event of Special Interest 
In addition to SAEs, the following are considered an adverse event of special interest (AESI) 
and should be promptly reported to the Sponsor within 24 hours of awareness through the 
Reporting of SAEs process as defined in Appendix 3, even if the nature of the AE is deemed 
non-serious according to the usual regulatory criteria.  
Infusion-related reactions 
Events that, in the opinion of the Investigator, may represent intolerance of the IV infusion of the 
IP. In general, these events would be temporally associated with the IV infusion of the 
Sponsor’s IP. 
Phototoxicity 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 53 of 86 
Due to results from a nonclinical phototoxicity study in rats and a Phase 1 clinical trial indicating 
that rezafungin causes an increased risk for phototoxicity, classified as mild, subjects should be 
advised to avoid sun and other UV light exposure without adequate protection from Day 1 to 
Day 8 (i.e., including 7 days after the administration of rezafungin). Investigators should report 
any AE potentially related to or suspicion of phototoxicity to the Sponsor. 
Neurological manifestations (such as ataxia, tremor and neuropathy) 
In a rezafungin 3-month toxicity study in monkeys, there were observations of tremors, and 
histology with Schwann cell hypertrophy/hyperplasia (reversible) and phospholipidosis in the 
dorsal root ganglia first appearing at Week 6 of dosing and at 9.2-fold the exposure to the 
dosing regimen of rezafungin used in the Phase 3 pivotal study. Ataxia, axonal neuropathy, 
hypoesthesia, hyperesthesia, paraesthesia, peripheral neuropathy (motor, sensory, or 
sensorimotor), polyneuropathy, toxic neuropathy, and tremors will be considered AESIs. 
9.2.7 Physical Examination 
A complete physical examination is to be performed at Screening and Follow-up. At all other 
time points, a brief targeted examination is to be performed as clinically indicated, driven by the 
subject’s symptoms and signs. A complete and brief targeted physical examination will include, 
at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and central and 
peripheral neurological systems. 
9.2.8 Vital Signs 
Vital signs will be measured in a sitting or supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse, and respiratory rate. 
9.2.9 Electrocardiograms 
Single 12-lead ECG(s) will be obtained as outlined in the SoA (see Table 1 and Table 2) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals. ECGs will be judged by the Investigator for clinical significance. 
9.2.10 Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and see Table 1 and 
Table 2 for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
subject’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation in 
the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or medical monitor. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 54 of 86 
• 
If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the aetiology should be identified, and the 
Sponsor notified. 
• 
All protocol-required laboratory tests, as defined in Appendix 2, must be conducted in 
accordance with the Laboratory Manual and the SoA (Table 1 and Table 2). 
• 
If laboratory values from non-protocol-specified laboratory tests performed require a 
change in subject management or are considered clinically significant by the Investigator 
then the results must be recorded. 
 
 Pharmacokinetic Assessment 
9.3.1 Collection of Blood Samples for Pharmacokinetic Assessment 
At the time points defined in the SoA (Table 1), blood samples of 1 mL each will be collected for 
the analysis of rezafungin plasma concentration. For subjects from birth to <2 years of age 
(Group 4; Table 2), a maximum total of 1 mL of blood will be taken for PK sampling. The blood 
samples will be taken via an indwelling IV catheter or arterial line or by direct venepuncture. The 
exact times of blood sampling will be recorded in the eCRF.  
The method of PK blood draws is at the discretion of the Investigator (e.g., via indwelling central 
venous catheter, port-a-cath, arterial line, or peripheral phlebotomies). However, it is advised to 
avoid taking PK samples from the same catheter used for rezafungin administration, especially 
for the end-of-infusion timepoint. In subjects with an indwelling central venous catheter or port-
a-cath, it is recommended to administer rezafungin via an alternative line (e.g., a peripheral line) 
and obtain all PK samples via the central venous catheter or port-a-cath. For procedures for 
taking PK samples from an indwelling catheter, follow the site’s standard of care to prevent 
contamination of PK samples from the dose administered. 
Samples collected for analyses of rezafungin plasma concentration may also be used to 
evaluate safety aspects related to concerns arising during the study. 
Details on sample collection, handling, storage, and shipping will be described in the Laboratory 
Manual. 
9.3.2 Pharmacokinetic Assessments for Part 1 and Part 2 
Subjects enrolled in Part 1 (aged 12 to <18 years) and Part 2 (aged 2 to <12 years) will undergo 
PK sampling as described below: 
Blood samples will be collected for measurement of plasma rezafungin concentrations at the 
following 5 timepoints: at end-of-infusion ± 15 minutes, then between 3 and 4 hours after start of 
infusion, between 6 and 8 hours after start of infusion, at 48 hours (± 4 hours) after start of 
infusion, and at 168 hours (± 12 hours) after start of infusion. The exact time and date of the PK 
samples must be recorded. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 55 of 86 
Approximately 5 mL of blood (5 samples, 1 mL each) will be taken from each subject for the 
measurement of rezafungin concentrations.  
9.3.3 Pharmacokinetic Assessments for Part 3 
In Part 3, blood samples for measurement of plasma rezafungin concentrations will be collected 
at the following 3 timepoints: at end-of-infusion ± 15 minutes, at 24 hours (± 4 hours) after start 
of infusion, and at 168 hours (± 12 hours) after start of infusion. The exact date and time of the 
PK samples must be recorded. 
A maximum total of 1 mL of blood (3 samples) will be taken from each of the 8 subjects for the 
measurement of rezafungin concentrations. 
 
 Genetics OR Pharmacogenomics 
Genetics are not evaluated in this study. 
 
 Biomarkers 
Biomarkers are not evaluated in this study. 
 
 Immunogenicity Assessment 
Not applicable. 
 
 Health Economics OR Medical Resource Utilisation and Health Economics 
Health economics OR medical resource utilisation and health economics parameters are not 
evaluated in this study. 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 56 of 86 
10 
STATISTICAL CONSIDERATIONS 
The Statistical Analysis Plan will be finalised prior to database lock. It will include a more 
technical and detailed description of the statistical analyses described in this section. 
 Sample Size Determination 
No formal sample size calculation was performed. It is estimated that at least 8 subjects per age 
range will enable estimation of rezafungin PK in subjects from birth to <18 years of age. 
 
 Statistical Hypotheses 
No statistical hypotheses are planned for the study. 
 
 Analysis Sets 
The following populations will be used 
Table 4 
Definition of Analysis Populations 
Populations Analysis Set 
Description 
Enrolled set 
All subjects who sign the ICF 
Safety analysis set 
All subjects who receive any amount of the rezafungin infusion 
PK analysis set 
All subjects who receive the single IV infusion of rezafungin and 
provide at least one blood sample for measurement of rezafungin 
plasma concentration 
ICF=Informed Consent Form; IV=intravenous; PK=pharmacokinetic 
 
 Statistical Analyses 
10.4.1 General Considerations 
In general, continuous data will be summarised by group using descriptive statistics. Categorical 
data will be summarised by group as the number and percentage of subjects in each category. 
Baseline is defined as the last value prior to IV infusion of rezafungin (Screening). 
10.4.2 Demographic and Baseline Characteristics 
Demographics (including age [chronological age], sex, and race) and baseline characteristics 
(including height, weight, and disease characteristics) will be presented descriptively, overall 
and by group. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 57 of 86 
10.4.3 Primary Endpoints Analyses  
For Parts 1 and 2, PK parameters are primary endpoints for this study. The following PK 
parameters will be determined: Cmax, Tmax, AUC0-t, AUC0-∞, CL, Vss, Vz, and t1/2.  
For Part 3, as only three plasma concentrations will be determined from each subject, there will 
not be sufficient data to determine PK parameters. Therefore, the plasma concentrations will be 
listed and summarised using descriptive statistics. 
For details see Section 10.5. 
10.4.4 Secondary Endpoints Analyses 
Safety will be assessed through treatment-emergent AEs (TEAEs), SAEs, AESIs, clinical 
laboratory tests, vital signs, 12-lead ECGs, and physical examination. 
The Safety Analysis Set will be used for the analysis of safety data. 
10.4.5 Adverse Events 
Adverse events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding system to give a SOC and Preferred Term (PT) for each AE. 
A treatment-emergent AE (TEAE) is defined as any event not present prior to the administration 
of the IP infusion or any event already present that worsens in either severity or frequency 
following exposure to the IP. 
Only treatment-emergent AEs will be summarised. 
The number and percentage of subjects experiencing TEAEs will be summarised by group, 
severity, and relation to IP. TEAEs will be summarised by MedDRA SOC and PT. All AEs will be 
listed by subject. The number and percentage of subjects reporting at least one TEAE will be 
summarised by PT nested within SOC for each group (Groups 1, 2, 3, and 4), and overall, for 
each of the following AE types: 
• 
Any TEAE 
• 
Any related TEAE 
• 
Any severe TEAE 
• 
Any related severe TEAE 
• 
Any SAE 
• 
Any related SAE 
• 
Any SAE leading to death 
• 
Any AE leading to discontinuation 
• 
Any AE requiring additional therapy 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 58 of 86 
The number and percentage of subjects with any AE will be summarised by the DAIDS grades 
as follows: 
• 
Mild (Grade 1): Mild symptoms causing no or minimal interference with usual social 
& functional activities with intervention not indicated 
• 
Moderate (Grade 2): Moderate symptoms causing greater than minimal interference 
with usual social & functional activities with intervention indicated 
• 
Severe (Grade 3): Severe symptoms causing inability to perform usual social & 
functional activities with intervention or hospitalization indicated 
• 
Life-threatening (Grade 4): Potentially life-threatening symptoms causing inability to 
perform basic self-care functions with intervention indicated to prevent permanent 
impairment, persistent disability, or death 
• 
Death (Grade 5): all deaths related to an AE 
10.4.6 Laboratory Values 
All laboratory data will be converted to International System of Units for reporting and 
processing purposes. 
Clinical laboratory data to be summarised include haematology, blood chemistry, and urinalysis. 
The clinical laboratory parameters to be assessed are listed in Appendix 2. 
Clinical laboratory parameters at each timepoint and change from baseline to each 
post-baseline timepoint will be summarised using descriptive summary statistics for each 
parameter by group. Clinical laboratory values for each parameter will be assigned an LNH 
classification according to whether the value is lower (L), within (N) or higher (H) than the 
reference range for that parameter. The values will be summarised using shift tables from 
baseline to worst on study result with respect to reference range values (low, normal, high) for 
each parameter by group. Clinical significance of the laboratory value change will be stated. 
10.4.7 Vital Signs, Electrocardiogram, and Physical Examination 
Vital signs and ECG parameters will be listed and presented descriptively, where applicable.  
Vital signs include temperature, pulse rate, respiratory rate, and blood pressure (systolic blood 
pressure and diastolic blood pressure). Vital sign parameters at each timepoint, and change 
from baseline to worst on study result will be summarised using descriptive summary statistics 
for each parameter by group. The normal ranges of vital signs are listed in Appendix 5. 
The 12-lead ECG data will be summarised by group and listed by patient. ECGs will be judged 
by the Investigator as clinically significant (yes/no). The number and percentage of subjects with 
clinically significant ECG findings will be summarised by group for each timepoint. Any abnormal 
findings in the continuous ECG monitoring will listed. 
Abnormal physical examination findings will be described and listed by group and scheduled 
timepoint. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 59 of 86 
 Pharmacokinetic Measurements and Analyses 
10.5.1 Drug Concentration Measurements and Analysis 
Individual and mean plasma concentrations at each sampling timepoint for rezafungin will be 
presented by listings and descriptive statistics including: n, mean, standard deviation (SD), 
standard error (SE), geometric mean, coefficient of variation expressed as percent (CV%), 
median, minimum and maximum, as well as quartiles (Q1 and Q3).  
10.5.2 Pharmacokinetic Parameters 
For Parts 1 and 2, the following PK parameters will be determined from the rezafungin 
concentration-time data using non-compartmental methods (Phoenix WinNonlin®, Build 
8.0.0.3176 or higher, Certara USA, Inc., Princeton, New Jersey, US) and actual sampling times: 
Cmax 
 
Maximum observed plasma concentration 
tmax 
 
Time at which the maximum plasma concentration was observed 
AUC0-t 
Area under the plasma concentration-time curve from time 0 to the time of the 
last quantifiable concentration  
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 extrapolated to 
infinity 
t1/2 
 
Terminal elimination half-life 
λz 
 
Terminal elimination rate constant 
CL 
 
Total clearance 
Vss 
 
Volume of distribution at steady-state 
Vz 
 
Apparent volume of distribution during the terminal phase 
10.5.3 Pharmacokinetic Evaluation 
Summary statistics of PK parameters including means, geometric means, medians, ranges, 
SDs, and CVs around the arithmetic and geometric means will be presented by group. 
All PK parameters will be calculated by non-compartmental analysis. 
 
 Interim Analysis 
No formal interim analysis is planned for this study.  
A DSMB has been appointed for this study. Three interim reviews by the DSMB are planned 
during this study: one after completion of Part 1, the second review after 50% of data from 
Groups 2 and 3 (Part 2) are available, and a third interim review after completion of Part 2. For 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 60 of 86 
the third DSMB review, PK and safety data from both Part 1 and Part 2 will be included for 
review. 
Part 1: The first interim review will be performed after completion of Group 1. Review of safety 
and PK data by the DSMB will be performed after all subjects in Group 1 have completed the 
Follow-up visit. Recruitment for Group 2 and Group 3 will be started only after DSMB completes 
the review and confirms the safety. The dose and PK sampling timepoints for Part 2 may be 
adjusted as appropriate after assessment of the PK and safety data of Part 1. 
Part 2: After the review of data from Group 1 by the DSMB and a decision to proceed to Part 2, 
enrolment in Group 2 and Group 3 will be started in parallel. A second interim review by DSMB 
is planned when data from 50% of the subjects enrolled in Part 2 are available. The second 
interim review of the safety and PK data will be performed to ensure that the exposure achieved 
in subjects from this age group is safe and well tolerated, and inform whether adjustments to the 
dose and PK sampling timepoints are required for the remaining subjects. Recruitment/dosing in 
Group 2 and Group 3 will not be paused during DSMB review 2. 
Part 3: A third DSMB review will be performed when Part 2 is completed. Enrolment for Group 4 
will not start until the juvenile animal toxicity studies are completed, the animal safety data have 
been reviewed, and the safety and tolerability from the preceding Parts have been confirmed by 
the DSMB. The dose and sampling time points may be adjusted as appropriate after 
assessment of the PK and safety data of Part 1 and Part 2. 
 
 Population PK Modelling 
The PK data from all groups may also be analysed using nonlinear mixed-effects modelling. Any 
PK modelling will be subject to a separate analysis plan and will be reported separately from the 
clinical study report for this study. 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 61 of 86 
11 
APPENDICES FOR SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the CSP and in accordance with the following: 
• 
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organisations of Medical Sciences (CIOMS) 
international ethical guidelines. 
• 
Applicable ICH GCP guidelines. 
• 
Applicable local laws and regulations. 
The CSP, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
will be submitted to an IEC by the Investigator for review and approval prior to the eligibility 
screening.  
Any amendments to the CSP will require IEC approval before implementation of changes made 
to the study design, except for changes necessary to eliminate an immediate hazard to study 
subjects. 
CSPs and any substantial amendments to the CSP will require health authority approval prior to 
initiation except for changes necessary to eliminate an immediate hazard to study subjects. 
The Investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IEC annually or more frequently 
in accordance with the requirements, policies, and procedures established by the IEC. 
• 
Notifying the IEC of SAEs or other significant safety findings as required by IEC procedures. 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements of 
Code of Federal Regulations Title 21 (21 CFR), ICH guidelines, the IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Informed Consent Process 
Informed consent and assent should be obtained by means of a Subject/Patient Information 
Sheet and ICF, prepared in accordance with ICH E6 and applicable local regulations, written in 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 62 of 86 
non-technical, age-appropriate language. The Investigator or his/her representative will explain 
the nature of the study, including the risks and benefits, to the subject or their LAR (an individual 
or juridical or other body authorised under applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial) and answer all questions regarding the 
study. 
• 
Subjects must be informed that their participation is voluntary. Subjects or their 
parent(s)/LAR will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50 (Protection of Human Subjects), local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the IEC or 
study centre. 
• 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF. 
• 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the subject or their LAR. 
Subjects who are rescreened are required to sign a new ICF. 
Data Protection 
In this trial processing of personal data will be carried out on behalf of the Sponsor by the 
CRO/the data processor, governed by a contract and strictly according and subject to the 
General Data Protection Regulation (GDPR) and any applicable data protection rules and 
regulations. As such, the Sponsor will treat data according to personal data Regulation (EU) 
2016/679, and any other applicable national and international regulation. The Sponsor and the 
CRO/data processor will implement appropriate technical and organisational measures to 
ensure a level of security appropriate to the risk, taking into account the state of the art, the 
costs of implementation and the nature, scope, context and purposes of processing as well as 
the risk of varying likelihood and severity for the rights and freedoms of natural persons. Quality 
control will occur at each stage of data handling to ensure that all data are reliable and have 
been processed correctly. The Sponsor will ensure oversight of any trial-related duties and 
functions carried out on its behalf, including trial-related duties and functions that are 
subcontracted to another party by the CRO. 
• 
All information generated in this trial is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the trial unless prior written 
consent is gained from the Sponsor. However, authorized regulatory officials, IEC 
personnel, the Sponsor and its authorised representatives are allowed full access to the 
records. All personal details will be treated as confidential by the Investigator and staff at the 
CRO. Prior to the processing, the Sponsor will perform an assessment of the impact of the 
envisaged processing operations on the protection of personal data (according to Article 35 
of the GDPR). In the event of a data breach being identified, the Sponsor commits to 
notifying the relevant data protection supervisory authority and the individuals affected. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 63 of 86 
• 
Subjects and/or his/her LAR will be assigned a unique identifier by the Sponsor. Any subject 
records or datasets that are transferred to the Sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred. 
All personal identifiers according to applicable regulations (e.g., name, phone number) must 
be redacted permanently by the site personnel and replaced with the subject’s unique 
identification number in all records and data before transfer to the Sponsor (or designee). 
• 
The subject and/or his/her LAR must be informed that his/her personal study-related data 
will be used by the Sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the subject and/or his/her LAR who will be required to 
give consent for their data to be used as described in the informed consent. 
• 
The subject and/or his/her LAR must be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors or other authorised personnel appointed by 
the Sponsor, by appropriate IEC members, and by inspectors from regulatory authorities. 
Committees Structure 
Data Safety Monitoring Board  
Subject safety will be monitored by the DSMB during the study. Details for composition of the 
DSMB will be included in the DSMB charter. 
All safety data collected will be summarised and reviewed by the DSMB for agreement of next 
steps. 
In particular, data will be reviewed by the Sponsor for identification of the events that would 
potentially contribute to a requirement to pause/stop the study. 
Enrolment will be paused during the first and third DSMB reviews. If a pausing/stopping rule is 
met, a decision will be made, based on the review, as to whether enrolment in the study will be 
allowed to resume. 
Data Quality Assurance 
All subject data relating to the study will be recorded on eCRFs unless transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF. 
Guidance on completion of eCRFs will be provided in the CRF completion guidelines. 
The Investigator must permit study-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 64 of 86 
The Sponsor or designee is responsible for the data management of this study, including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
Source Documents 
• 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved CSP and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Publication Policy 
• 
The Sponsor will determine the identity of the Co-ordinating Investigator for the study who 
will review and sign off the clinical study report. This decision will be based on involvement 
in the study including, but not limited to, study design, subject recruitment and interpretation 
of study data. 
• 
Clinical studies will be registered in public databases and summary results released / 
disseminated via publicly available clinical study databases according to the Sponsor’s 
standard operating procedures and local requirements. As a general rule, both Phase 1 
Healthy Volunteer studies and studies using a medicinal product in the normal course of 
medical practice (for example Non-Interventional Studies and Post Marketing Surveillance 
studies), are excluded from the above public registration and reporting requirements. If such 
studies do require public registration and/or reporting, this will be undertaken according to 
local requirements. 
• 
The Sponsor registers clinical studies and posts the summary results as follows: 
o For clinical studies carried out exclusively within the European Union, through the 
EU Clinical Trial Register (EudraCT) www.clinicaltrialsregister.eu; 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 65 of 86 
o Following the end of the clinical study, the summary results should be made 
publicly available according to accepted timelines and requirements, usually 
within 12 months of study completion. Special note should be taken to ensure 
timelines for the release of paediatric study results are met, which may be 
6 months from study completion. 
o For multi-site studies, it is mandatory that the first publication be based on data 
obtained from all analysed subjects; therefore, Investigators participating in multi-
site studies must not present data gathered individually or by a subgroup of sites 
prior to the full, initial publication, unless this has been agreed to by all other 
Investigators and the Sponsor. Publication of clinical study results may include 
the presentation of such work at national and international congresses, 
symposia, professional meetings, peer-reviewed journals, and via other 
appropriate channels. Named authors and contributors to such publications shall 
be determined by the Sponsor in accordance with both the Company Publication 
Policy (which can be found at: http://www.mundipharma-rd.eu/research-
areas/publications.html) and the generally accepted criteria for authorship as 
outlined by the International Committee of Medical Journal Editors authorship 
guidelines. The data associated with any publication will be and shall remain the 
sole property of the Sponsor; the copyright of the document may be transferred 
to the scientific peer-reviewed journal prior to and as part of the publication 
process, as appropriate. 
o Subject to the paragraph above, the site may publish or present the results of the 
clinical study subject to the protection of the Sponsor or its nominee(s) 
intellectual property rights, know-how, and its proprietary information. The 
Sponsor must be furnished with a copy of any proposed publication or 
presentation at least 60 days prior to submission for review and comment. Upon 
notice by the Sponsor, however, that the Sponsor intends to secure its 
intellectual property rights (for example, file a patent application relating to the 
study) or that Sponsor requires for its know-how or proprietary information to be 
removed prior to such publication, such publication may be delayed for a further 
6 months or until its intellectual property rights have been secured, whichever is 
the later. The site further agrees that Sponsor’s reasonable comments in relation 
to the proposed publication will be incorporated into the publication. 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 66 of 86 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 5 will be performed by the local laboratory. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in Section 6 of 
the CSP. Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
 
Table 5 
Safety Laboratory Tests 
Laboratory 
Tests 
Parameters  
Haematology 
Complete blood count (platelet count, RBC, haemoglobin, haematocrit, RBC indices: 
MCV, MCH, % reticulocytes, WBC with differential: neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) 
Clinical 
chemistry 
Alkaline phosphatase (ALP), BUN, ALT/SGPT, AST/SGOT, total and conjugated 
bilirubin, creatinine, total protein and albumin, glucose (fasting or non-fasting), 
potassium, sodium, calcium 
Routine 
urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
testing 
Urine pregnancy test (for postmenarchal females) 
Abbreviations: ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea 
nitrogen; MCH: Mean corpuscular haemoglobin; MCV: Mean corpuscular volume; RBC: Red blood cell 
count; SGOT: serum glutamic-oxaloacetic transaminase; SGPT: serum glutamic-pyruvic transaminase; 
WBC: White blood cell. 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 67 of 86 
Appendix 3: AEs and SAEs: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study subject, temporally associated 
with the use of study treatment, whether or not considered related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study treatment. 
Definition of Unsolicited and Solicited AE 
• 
An unsolicited AEs is an AE that was not solicited using a subject diary and that is 
communicated by a subject/subject’s parent(s)/legally authorised representative (LAR) who 
has signed the informed consent. Unsolicited AEs include serious and non-serious AEs. 
• 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses requiring a 
hospitalisation, emergency room visit, or visit to/by a healthcare provider). The 
subject/subject’s parent(s)/LAR(s) will be instructed to contact the site as soon as possible to 
report medically attended event(s), as well as any events that, though not medically attended, 
are of subject/subject’s parent(s)/LAR(s) concern. Detailed information about reported 
unsolicited AEs will be collected by qualified site personnel and documented in the subject’s 
records. 
• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
subject/subject’s parent(s)/LAR(s) will be collected during an interview with the 
subject/subject’s parent(s)/LAR(s) and by review of available medical records at the next visit. 
• 
Solicited AEs are predefined local at the injection site and systemic events for which the 
subject is specifically questioned. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital sign measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgement of the Investigator (i.e., 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 condition 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 treatment-intervention 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. 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 68 of 86 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the subject’s condition 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition 
• 
Medical or surgical procedure (e.g., 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 
Adverse Events of Special Interest 
• 
In addition to SAEs, the following AESIs should be promptly reported to the Sponsor within 
24 hours of awareness through the SAE reporting process even if the nature of the AE is 
deemed non-serious according to the usual regulatory criteria 
• 
The AESIs for this study are infusion-related reactions, phototoxicity, adverse events 
suggestive of neurotoxicity (e.g., ataxia, neuropathy, and tremors) 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 69 of 86 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of 
the criteria listed: 
a. 
Results in death 
b. 
Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the subject was at 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. 
c. 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
In general, hospitalisation signifies that the subject has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event is serious. When in doubt as to 
whether hospitalisation occurred or was necessary, the AE should be considered serious. 
• 
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental 
trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations 
• 
Medical or scientific judgement should be exercised by the Investigator in deciding whether 
SAE reporting is appropriate in other situations such as significant medical events that may 
jeopardise the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be considered 
serious. 
o 
Examples of such events include invasive or malignant cancers, intensive treatment for 
allergic bronchospasm, blood dyscrasias, convulsions or development of intervention 
dependency or intervention abuse. 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 70 of 86 
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the 
event. 
• 
The Investigator will then record all relevant AE/SAE information. 
• 
For all AEs, the Investigator must obtain adequate information about the event, severity, time 
of occurrence (including whether the AE onset was before, during, or after the IP 
administration if the AE started on the dosing day), duration, and any action, e.g., 
treatment/follow-up tests. The outcome of the event should be provided along with the 
Investigator’s assessment of the relationship to the IP. The Investigator must also assess 
whether the event meets the criteria for classification as an SAE. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The terms serious and severe are not synonymous. The general term “severe” is often used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is usually 
associated with events that pose a threat to a patient’s life or ability to function.  
Investigators will grade all AEs by severity using DAIDS (Version 2.1). If an AE is not listed in the 
DAIDS criteria, a corresponding grading is to be performed by the Investigator based on his/her best 
medical judgement as follows: 
• 
Mild (Grade 1): Mild symptoms causing no or minimal interference with usual social & 
functional activities with intervention not indicated 
• 
Moderate (Grade 2): Moderate symptoms causing greater than minimal interference with 
usual social & functional activities with intervention indicated 
• 
Severe (Grade 3): Severe symptoms causing inability to perform usual social & functional 
activities with intervention or hospitalization indicated 
• 
Life-threatening (Grade 4): Potentially life-threatening symptoms causing inability to perform 
basic self-care functions with intervention indicated to prevent permanent impairment, 
persistent disability, or death 
• 
Death (Grade 5): all deaths related to an AE 
 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 71 of 86 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. The Investigator will use clinical judgement to determine the 
relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
• 
Causality: 
Related 
o 
Related: The AE follows a reasonable temporal sequence to IP administration, and it is 
a known reaction to the drug under study or a related chemical group or is predicted by 
known pharmacology 
o 
Possibly related: There is a clinically plausible time sequence between onset of the AE 
and study treatment administration, but the AE could also have been caused by the 
concurrent/underlying illness, other drugs, or procedures. Information regarding study 
treatment withdrawal may be lacking or unclear. “Possible” should be used when study 
treatment administration is one of several biologically plausible causes of the AE.  
o 
Unlikely related: The AE is most likely due to a non-study-treatment-related cause. 
However, association with the study treatment cannot be completely ruled out. 
Not related 
o 
Unrelated: Another cause of the AE is most plausible, and a clinically plausible 
temporal sequence is inconsistent with the onset of the AE and study treatment 
administration and/or a causal relationship is considered biologically implausible. 
Follow-up of AEs and SAEs 
• 
During the study (and after the follow-up visit), all AEs and SAEs should be followed 
proactively by the Investigator until the event resolves or the condition stabilises to a level 
acceptable to the Investigator, until the event is otherwise explained, or until the subject is lost 
to follow-up. At the time the subject’s study participation ends, all ongoing AEs and SAEs 
should be evaluated for resolution. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt 
of the information. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 72 of 86 
Reporting of SAEs 
SAE Reporting to ICON safety team via Paper Data Collection Tool 
• 
The primary mechanism for reporting an SAE to ICON safety team will be the paper data 
collection tool. 
• 
Email of the SAE paper data collection tool is the preferred method to transmit this information 
to ICON safety team. 
• 
In rare circumstances and in the absence of email, notification by fax of a copy of the SAE 
data collection tool is acceptable. 
• 
For safety reports received via fax, the receipt date and time (initial or follow-up) are recorded 
electronically by the ICON PVS fax system and are sent from ICON’s fax server system to 
ICON’s mhgsafety@iconplc.com email inbox. Then this will be distributed to ICON safety 
team for processing. 
• 
Contacts for SAE reporting can be found below. 
Drug Safety and PV 
Email: MHGSafety@iconplc.com 
Fax: +44 1792 525 720 
 
 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 73 of 86 
Appendix 4: List of Prohibited Concomitant Neurotoxic Medications 
LIST OF PROHIBITED NEUROTOXIC CONCOMITANT MEDICATIONS a 
Definite High Risk 
vinca alkaloids (Vincristine) with a dosing interval more frequent than every 21 days 
taxols (paclitaxel, docetaxel, cabazitaxel) 
Moderate Risk 
amiodarone (Cordarone) 
arsenic trioxide (Trisenox) 
bortezomib (Velcade) 
brentuximab vedotin (Adcetris) 
cetuximab (Erbitux) 
cisplatin & oxaliplatin 
colchicine (extended use) 
dapsone b 
didanosine (ddI, Videx) 
dichloroacetate 
disulfiram (Antabuse) 
eribulin (Halaven) 
gold salts 
ipilimumab (Yervoy) 
ixabepilone (Ixempra) 
leflunomide (Arava) 
lenalidomide (Revlimid) 
metronidazole/misonidazole (extended use) 
nitrofurantoin (Macrodantin, Furadantin, Macrobid) 
nitrous oxide 
nivolumab (Opdivo) 
pembrolizumab (Keytruda) 
perhexiline (not used in the United States) 
pomalidomide (Pomalyst) 
stavudine (d4T, Zerit) 
suramin 
thalidomide 
vinca alkaloids (Vincristine) with a dosing interval 
of every 21 days or less frequent c 
zalcitabine (ddC, Hivid) 
a. Adapted from the Charcot Marie Tooth Association list of neurotoxic medications. 
b. Dapsone is prohibited as a concomitant medication with rezafungin in this study.  
c. Maximum dose of vincristine is 2 mg/dose. Subjects who receive vincristine should not receive 
concomitant azole therapy during the course of the study (from signing the informed consent to the 
follow-up visit on Day 30 ± 5). 
 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 74 of 86 
Appendix 5: Reference Ranges for Vital Signs 
Normal Vital Signs by Age 
Age 
Heart Rate 
(beats/min) 
Systolic/Diastolic 
Blood Pressure (mmHg) 
Respiratory Rate 
(breaths/min) 
Premature 
120 – 170 
55–75 / 35–45 
40 – 70 
0 – 3 months 
110 – 160 
65–85 / 45–55 
30 – 60 
3 – 6 months 
100 – 150 
70–90 / 50–65 
30 – 45 
6 – 12 months 
90 – 130 
80–100 / 55–65 
25 – 40 
1 – 3 years 
80 – 125 
90–105 / 55–70 
20 – 30 
3 – 6 years 
70 – 115 
95–110 / 60–75 
20 – 25 
6 – 12 years 
60 – 100 
100–120 / 60–75 
14 – 22 
>12 years 
60 – 100 
100–120 / 70–80 
12 – 18 
Source: The Harriet Lane Handbook (Johns Hopkins Hospital). 22nd Edition.22 
 
 
Normal Temperature Ranges 
Measurement Method 
Normal Temperature Range 
Rectal 
36.6°C to 38°C (97.9°F to 100.4°F) 
Ear 
35.8°C to 38°C (96.4°F to 100.4°F) 
Oral 
35.5°C to 37.5°C (95.9°F to 99.5°F) 
Axillary 
34.7°C to 37.3°C (94.5°F to 99.1°F) 
Source: Temperature measurement in paediatrics23 
 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 75 of 86 
Appendix 6: BMI Charts 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 76 of 86 
 
Source: Royal College of Paediatrics and Child Health24 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 77 of 86 
Appendix 7: Paediatric Index of Mortality 2 (PIM2) 
Variable 
1. Systolic blood pressure (SBP), mmHg. If the patient is in cardiac arrest, record SBP=0; if the 
patient is shocked and the blood pressure is so low that it cannot be measured, record SBP=30; if 
unknown, record SBP=120. 
2. Pupillary reactions to bright light (>3 mm and both fixed=1, other or unknown=0). Do not record 
an abnormal finding if this is due to drugs, toxins or local eye injury. 
3. PaO2, mmHg (unknown=0), and FiO2 at the time of PaO2 if oxygen via ETT or headbox 
(unknown=0) 
4. Base excess in arterial or capillary blood, mmol/L (unknown=0) 
5. Mechanical ventilation at any time during the first hour in ICU (no=0, yes=1), including mask or 
nasal CPAP or BiPAP or negative pressure ventilation 
6. Elective admission to ICU (no=0, yes=1), including admission after elective surgery or admission 
for an elective procedure (e.g., insertion of a central line), or elective monitoring, or review of 
home ventilation. An ICU admission or an operation is considered elective if it could be postponed 
for >6 hours without adverse effect. 
7. Recovery from surgery or a procedure is the main reason for ICU admission (no=0, yes=1), 
including a radiology procedure or cardiac catheter. Do not include patients admitted from the 
operating theatre where recovery from surgery is not the main reason for ICU admission (e.g., a 
patient with a head injury who is admitted from theatre after insertion of an ICP monitor; in this 
patient the main reason for ICU admission is the head injury). 
8. Admitted following cardiac bypass (no=0, yes=1). These patients must also be coded as recovery 
from surgery. 
9. High-risk diagnosis. Record the number in brackets. If in doubt record 0. 
[0] None 
[1] Cardiac arrest preceding ICU admission, including both in-hospital and out-of-hospital 
arrests, requiring either documented absent pulse or external cardiac compression. Do not 
include past history of cardiac arrest. 
[2] Severe combined immune deficiency 
[3] Leukaemia or lymphoma after first induction 
[4] Spontaneous cerebral haemorrhage (e.g., from aneurysm or AV malformation). Do not 
include traumatic cerebral haemorrhage or intracranial haemorrhage that is not intracerebral 
(e.g., subdural haemorrhage). 
[5] Cardiomyopathy or myocarditis 
[6] Hypoplastic left heart syndrome; includes only cases where a Norwood procedure or 
equivalent is or was required in the neonatal period to sustain life 
[7] HIV infection 
[8] Liver failure is the main reason for ICU admission, either acute or chronic, including patients 
admitted for recovery following liver transplantation for acute or chronic liver failure 
[9] Neuro-degenerative disorder, requiring a history of progressive loss of milestones or a 
diagnosis where this will inevitably occur 
10. Low risk diagnosis. Record the number in brackets. If in doubt record 0. 
[0] None 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 78 of 86 
Variable 
[1] Asthma is the main reason for ICU admission 
[2] Bronchiolitis is the main reason for ICU admission, including children who present either with 
respiratory distress or central apnoea where the clinical diagnosis is bronchiolitis 
[3] Croup is the main reason for ICU admission 
[4] Obstructive sleep apnoea is the main reason for ICU admission, including patients admitted 
following adenoidectomy and/or tonsillectomy in whom obstructive sleep apnoea is the main 
reason for ICU admission (and code as recovery from surgery). 
[5] Diabetic keto-acidosis is the main reason for ICU admission 
Source: PIM2: a revised version of the Paediatric Index of Mortality25 
Abbreviation: AV=Arteriovenous; BiPAP=Bilevel positive airway pressure; CPAP=Continuous positive airway 
pressure; ETT=Endotracheal tube; FiO2=Fraction of inspired oxygen; HIV=Human immunodeficiency virus; 
ICP=Intracranial pressure; ICU=Intensive care unit; PaO2=Arterial oxygen partial pressure; SBP=Systolic blood 
pressure 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 79 of 86 
Appendix 8: Abbreviations 
ACM 
All-cause mortality 
ADL 
Activities of Daily Living 
AE 
Adverse events 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organisations of Medical Sciences 
CNS 
Central nervous system 
CRO 
Contract Research Organisation 
CSP 
Clinical Study Protocol 
CV 
Coefficient of variation 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
ET 
Early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GLP 
Good Laboratory Practice 
IB 
Investigator's Brochure 
IC 
Invasive candidiasis 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFD 
Invasive fungal disease 
IFI 
Invasive fungal infection 
INR 
International normalised ratio 
IP 
Investigational product 
IV 
Intravenous 
LAR 
Legally authorised representative 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
mITT 
Microbiological intent-to-treat 
NOAEL 
No observed adverse effect level 
PI 
Principal Investigator 
PS80 
Polysorbate 80 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SE 
Standard error 
SD 
Standard deviation 
SoA 
Schedule of Assessments 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 80 of 86 
SOC 
System organ class 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
UV 
Ultraviolet 
 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 81 of 86 
Appendix 9: Protocol Amendment History 
Amendment 3 (18 Jul 2023) 
Overall Rationale for the Amendment: This amendment is to clarify the neurotoxicity risk of 
vinca alkaloids (one of the prohibited neurotoxic concomitant medications). 
Section # and Name 
Description of Change 
Brief Rationale 
6.2 Exclusion Criteria; 
Appendix 4: List of 
Prohibited 
Concomitant 
Neurotoxic 
Medications 
Addition of the dosing frequency of 
vinca alkaloids to define the risk level 
of neurotoxicity; addition of the 
maximum dose of vincristine 
To clarify the neurotoxicity 
risk of vinca alkaloids 
 
Amendment 2 (26 May 2023) 
Overall Rationale for the Amendment: This amendment is to incorporate the updates requested 
by the European Medicines Agency (EMA) and UK Medicines and Healthcare products 
Regulatory Agency (MHRA) to have a global protocol and to update the safety reporting 
processes. 
Section # and Name 
Description of Change 
Brief Rationale 
Table 1: Schedule of 
Assessments for Part 
1 and Part 2 
Addition of vital sign assessments to 
all visits on Day 1; clarification of PK 
sampling procedure in withdrawn 
subjects in the footnote 
To align with study 
procedure 
6.2 Exclusion Criteria 
Clarification of criterion #12 
To clarify the criterion  
6.2 Exclusion Criteria 
and 10.4.5 Adverse 
Events 
Changed adverse event grading from 
CTCAE to DAIDS 
The DAIDS grading 
system has age-specific 
definitions 
3.3 Benefit and Risk 
Evaluation,  
9.2.6 Adverse Event 
of Special Interest 
and Appendix 3 AEs 
and SAEs: Definition 
and Procedures for 
Recording, 
Evaluating, Follow-up, 
and Reporting 
Updated safety reporting process to 
delete EDC and to change preferred 
method; specified the duration 
required for protection from 
phototoxicity 
To align with the study’s 
Safety Management Plan; 
to clarify the duration for 
phototoxicity 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 82 of 86 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Editorial changes 
Minor editorial changes 
associated with text added 
or removed based on the 
above changes and 
correcting typographical 
errors in referencing. 
 
Amendment 1 (UK) (17 Apr 2023) 
Overall Rationale for the Amendment: This amendment is based on requests from the 
Medicines & Healthcare products Regulatory Agency (MHRA). 
This amendment is considered to be non-substantial based on the criteria set forth in the 
medicines for human use (clinical trials) regulation 2004 S.I. 2004/1031. 
Section # and Name 
Description of Change 
Brief Rationale 
6.1 Inclusion Criteria 
Removed ‘abstinence’ from criterion 
#6 
Based on a request for 
information from MHRA 
Amendment 1 (16 Mar 2023) 
Overall Rationale for the Amendment: This amendment is based on requests from the European 
Medicines Agency (EMA). 
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. 
Section # and Name 
Description of Change 
Brief Rationale 
Table 1: Schedule of 
Assessments for Part 
1 and Part 2; and 
5.1.5 Follow-up or 
Early Termination 
Addition of a pregnancy test at the 
follow-up visit. 
Based on a request for 
information from EMA 
3.3 Benefit and Risk 
Evaluation 
Addition of confirmation that pivotal 
nonclinical studies were conducted in 
accordance with all applicable laws 
and regulations. 
Based on a request for 
information from EMA 
3.3 Benefit and Risk 
Evaluation 
Addition of a description of the 
methods of analysis of nonclinical 
pharmacokinetic and toxicokinetic 
samples. 
Based on a request for 
information from EMA 
6.1 Inclusion Criteria 
Definition of woman of childbearing 
potential added to criterion #5. 
Based on a request for 
information from EMA 
6.2 Exclusion Criteria 
New criterion added: 
Based on a request for 
information from EMA 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 83 of 86 
Section # and Name 
Description of Change 
Brief Rationale 
• Subjects/LARs dependent on the 
Sponsor, Investigator or study site. 
6.2 Exclusion Criteria 
New criterion added: 
• Unable to give his/her own 
informed consent if a subject 
reaches the age of consent during 
the study. 
Based on a request for 
information from EMA 
6.2 Exclusion Criteria 
New criterion added: 
• Committed to an institution in 
accordance with an order issued 
either by the judicial or the 
administrative authorities. 
Based on a request for 
information from EMA 
6.2 Exclusion Criteria 
New criterion added: 
• Tested positive for severe acute 
respiratory syndrome coronavirus 
2 (SARS-CoV-2) by a nucleic acid 
amplification test or antigen test 
within 7 days prior to dosing of 
rezafungin (note, SARS-CoV-2 
testing is not a protocol 
requirement and should be 
performed according to the 
institutional policy and clinical 
need). 
Based on a request for 
information from EMA 
8.1 Discontinuation of 
Study Treatment 
Changed individual stopping criteria to 
be based on the DAIDS severity 
criteria and not the Investigator’s 
judgement. 
Based on a request for 
information from EMA 
8.1 Discontinuation of 
Study Treatment 
New individual stopping criterion 
added: 
• A subject becomes pregnant 
Based on a request for 
information from EMA 
8.1 Discontinuation of 
Study Treatment 
New study stopping criterion added: 
• Additional data from other clinical 
trials or toxicological studies 
become available that negatively 
influence the risk/benefit 
assessment 
Based on a request for 
information from EMA 
8.1 Discontinuation of 
Study Treatment 
New study stopping criterion added: 
• At a specific site/in a specific 
region: if the local regulatory 
authority or Independent Ethics 
Based on a request for 
information from EMA 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 84 of 86 
Section # and Name 
Description of Change 
Brief Rationale 
Committee (IEC) withdraws 
approval of the study 
Appendix 1 
Regulatory, Ethical, 
and Study Oversight 
Considerations 
Addition of description of processes to 
be followed to protect subjects’ data. 
Based on a request for 
information from EMA 
Throughout 
Editorial changes 
Minor editorial changes 
associated with text added 
or removed based on the 
above changes and 
correcting typographical 
errors in referencing. 
 
 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 85 of 86 
12 
REFERENCES  
1. Rezafungin Investigator’s Brochure; Edition10, dated 07Sep2021 
2. Maertens J, Marchetti O, Herbrecht R, Cornely OA, Flückiger U, Frêre P, et al.; Third 
European Conference on Infections in Leukemia. European guidelines for antifungal 
management in leukemia and hematopoietic stem cell transplant recipients: summary of 
the ECIL 3—2009 update. Bone Marrow Transpl. 2011; 46(5): 709–718 
3. Cortés, JA, Corrales, IF. Invasive Candidiasis: Epidemiology and Risk Factors. In: de 
Loreto, É.i., Tondolo, J. S. M, editors. Fungal Infection [Internet]. London: IntechOpen; 
2018 [Accessed 2022 May 04]. Accessed from: 
https://www.intechopen.com/chapters/64365 doi: 10.5772/intechopen.81813] 
4. Arendrup MC, Patterson TF. Multidrug-Resistant Candida: Epidemiology, Molecular 
Mechanisms, and Treatment. J Infect Dis. 2017 Aug 15;216(suppl_3):S445-S451 
5. Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al.; 
Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use 
Prevalence Survey Team. Multistate point-prevalence survey of health care-associated 
infections. N Engl J Med.2014; 370(13): 1198–1208 
6. Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, et al.; Mycoses Study 
Group. Impact of treatment strategy on outcomes in patients with candidemia and other 
forms of invasive candidiasis: a patient-level quantitative review of randomized trials. 
Clin Infect Dis. 2012; 54(8): 1110–1122 
7. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial 
bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective 
nationwide surveillance study. Clin Infect Dis. 2004; 39: 309–317 
8. Alexander BD, Johnson MD, Pfeiffer CD, Jiménez-Ortigosa C, Catania J, Booker R, et 
al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with 
presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect 
Dis. 2013;56(12): 1724–1732. Erratum in: Clin Infect Dis. 2014; 58(5): 754 
9. Arendrup MC, Dzajic E, Jensen RH, Johansen HK, Kjaeldgaard P, Knudsen JD, et al. 
Epidemiological changes with potential implication for antifungal prescription 
recommendations for fungaemia: data from a nationwide fungaemia surveillance 
programme. Clin Microbiol Infect. 2013;19(8): E343–353. Erratum in: Clin Microbiol 
Infect. 2013;19(8): E376 
10. Ostrosky-Zeichner L. Candida glabrata and FKS mutations: witnessing the emergence of 
the true multidrug-resistant Candida. Clin Infect Dis. 2013; 56: 1733–1734 
11. Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences 
for treatment. Am J Med. 2012a; 125: S3–13 
12. Pfaller MA, Castanheira M, Lockhart SR, Ahlquist AM, Messer SA, Jones RN. 
Frequency of decreased susceptibility and resistance to echinocandins among 
fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol. 2012b; 
50: 1199–1203. 

 
 
 
 
MR907-1501 
 
CONFIDENTIAL 
 
Page 86 of 86 
13. CDC 2013. Antibiotic resistance threats in the United States, 2013. Accessed at 
https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf on July13, 2022.  
14. CDC 2016. Clinical Alert to United States (US) Healthcare Facilities: Global emergence 
of invasive infections caused by the multidrug-resistant yeast Candida auris 2016. 
https://www.cdc.gov/fungal/diseases/candidiasis/candida-auris-alert.html. Accessed 
April 25, 2018 
15. Auriti C, Falcone M, Ronchetti MP, et al. High-Dose Micafungin for Preterm Neonates 
and Infants with Invasive and Central Nervous System Candidiasis. Antimicrob Agents 
Chemother. 2016;60(12):7333-7339 
16. Warris A, Pana ZD, Oletto A, et al. Etiology and Outcome of Candidemia in Neonates 
and Children in Europe: An 11-year Multinational Retrospective Study. Pediatr Infect Dis 
J. 2020,39(2):114-120 
17. Hope WW, Castagnola E, Groll AH, et al. (2012). ESCMID guideline for the diagnosis 
and management of Candida diseases 2012: prevention and management of invasive 
infections in neonates and children caused by Candida spp. Clin Microbiol Infect. 
18 (Suppl. 7): 38–52 
18. Breiden B, Sandhoff K. Emerging mechanisms of drug-induced phospholipidosis. 
Biological Chemistry. 2019;401(1): 31-46. 
19. Colacurcio DJ, Nixon RA. Disorders of lysosomal acidification-The emerging role of v-
ATPase in aging and neurodegenerative disease. Ageing Res Rev. 2016;32:75-88. 
20. Thompson GR, Soriano A, Skoutelis A, et al. Rezafungin Versus Caspofungin in a 
Phase 2, Randomized, Double-blind Study for the Treatment of Candidemia and 
Invasive Candidiasis: The STRIVE Trial [published correction appears in Clin Infect Dis. 
2021 Aug 2;73(3):561-562]. Clin Infect Dis. 2021;73(11):e3647-e3655 
21. Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the 
Paediatric Population (2008). Recommendations of the ad hoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to Good 
Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use 
22. The Harriet Lane Handbook (Johns Hopkins Hospital). 22nd Edition. Elsevier. April 22, 
2020. eBook ISBN: 9780323674096 
23. Temperature measurement in paediatrics. Paediatr Child Health. 2000;5(5):273-284. 
24. Royal College of Paediatrics and Child Health available at 
https://www.rcpch.ac.uk/resources/body-mass-index-bmi-chart accessed on July 13, 
2022. 
25. Slater A, Shann F, Pearson G; Paediatric Index of Mortality (PIM) Study Group. PIM2: a 
revised version of the Paediatric Index of Mortality. Intensive Care Med. 2003 
Feb;29(2):278-85