Clinical trial NCT03605212
Conditions: Tumor Lysis Syndrome
Keywords: TLS FLO-02 Hematological Malignancies
Sponsor: Menarini Group
Start date: 2017-02-27; Completion date: 2018-07-25
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the exposure of febuxostat in pediatric patients (≥6\<18 years of age) and in adults suffering from hematological malignancies at intermediate to high risk of TLS and to compare the effect in terms of serum uric acid levels.

Detailed description:
In the FLORET study it is planned to enroll 3 groups of patients in order to receive oral administration (film-coated tablets) of two different dose levels of febuxostat: children (from 6 to less than 12 years of age) will receive two different dose levels respectively; adolescents (from 12 to less than 18 years of age) will receive 80 and 120 mg/day respectively and adults (equal or major than 18 years of age) will receive 120 mg/day. The two dose levels for children and adolescents groups were to be sequentially administered, whereas the groups that will receive the first dose levels will simultaneously start the treatment at the study beginning. The individual treatment duration will be of 7 to 9 days, according to chemotherapy duration, as per Investigator's judgement.

Arms: arm 1: Febuxostat film-coated tablets 2x20 mg/QD for 7-9 days arm 2: Febuxostat film-coated tablets 3x20 mg/QD for 7-9 days arm 3: Febuxostat film-coated tablets 1x80 mg/QD for 7-9 days (Adenuric® 80 mg) arm 4: Febuxostat film-coated tablets 1x120 mg/QD for 7-9 days (Adenuric® 120 mg) arm 5: Febuxostat film-coated tablets 120 mg/QD for 7-9 days (Adenuric® 120 mg)
Interventions: intervention 1: Febuxostat
Intervention descriptions: intervention 1: Intervention is orally administered to patients in this arm.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Trial Protocol 
EudraCT No.: 2016-001445-61 
 
Study Code FLO-02
Final Version 1.0, 12 April 2016
 
 
 
 
Confidential 
Menarini Ricerche S.p.A 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
FINAL VERSION 1.0, 12 APR 2016  
OPEN LABEL, MULTI-CENTRE, PARALLEL GROUP STUDY TO COMPARE THE 
PHARMACOKINETICS (PK), PHARMACODYNAMICS (PD)  
AND SAFETY OF FEBUXOSTAT BETWEEN  
PEDIATRIC PATIENTS (≥6<18 YEARS OF AGE) AND ADULTS 
 
Study code 
FLO-02 
Study Nick Name/ Acronym 
FLORET 
EudraCT-Number 
 
2016-001445-61 
Investigational Medicinal Product 
febuxostat 
Development phase of study 
Phase I/II 
 
SPONSOR
CO-ORDINATING  
INVESTIGATOR 
CRO 
Menarini Ricerche S.p.A. 
Clinical Research 
Via Sette Santi, 1 
50131 Florence - Italy  
Phone: +39 05556809990 
     
 
 
 
STATEMENT OF CONFIDENTIALITY 
 
The information in this document contains trade secrets and proprietary commercial information of Menarini Group 
that is privileged or confidential and may not be disclosed unless such disclosure is required by law. In any case, 
persons to whom the information is disclosed must be informed that the information is privileged or confidential and 
may not be further disclosed without written authorisation by Menarini Group. 


Clinical Trial Protocol
EudraCT No." 2016-001445-61
FL@RET
Study Code FLO-02
Final Version 1.0, 12 Aprii 2016
1. SIGNATURES
The signatories have read the clinical trial protocol titled "Open label, multicentre, parallel
group study to compare the pharmacokinetics (PK), phat'macodynamics (PD) attd safety of
febuxostat between pediatrtÿpdttet'ents ÿ_6<18 years of age) and adults" - Final Version 1.0, 12
Apr 2016> - earefidly and agree to adhere to its provisions. Changes to the protocol have to be
stated by the Sponsor in amendments to the clinical trial protocol which, if they are substantial,
bave to be authorized by the Competent Authorities and Ethics Committees before translating
them into action.
Sponsor's Representative
Signature                    Date
Signature
Co-ordinating Investigator
Date
Confidential
Menarini Ricerche S.p.A
Page 2 of 124


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
PRINCIPAL INVESTIGA
 
a) Clinical Statement 
My signature below documents m
“Open label, multi-centre, pa
pharmacodynamics (PD) and saf
and adults” - Final Version  1.0
the required documentation/data 
entirety and with the ICH guideli
 
b) Anti-Corruption Statement 
I agree to - I will and I will caus
with the principles of any intern
Combating Bribery of Foreign P
Act and US Foreign Corrupt P
particular, along the performance
not to - directly or indirectly offe
gift of any money or thing of v
decisions or to induce such offi
relevant government body or any
writing in case of violations of o
the study and I acknowledge a
compliance with the above durin
accept that a violation of any 
research activities of the site I wo
 
Principal Investigator  
....................................................
 (printed name) 
 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
ATOR’S STATEMENT 
my agreement with the contents of this clinic
arallel group study to compare the pha
afety of febuxostat between pediatric patients
0 dated 12 Apr 2016 - with regard to the exec
collection. I agree to comply with this clinic
ines for Good Clinical Practice (GCP). 
se any of my collaborators to - perform any 
national anti-corruption legislations, such as O
ublic Officials in International Business Tran
Practices Act, including Italian Legislative 
e of the study, I will not - and I will cause an
fer, pay, give, or promise to pay or give or re
value to or from any government officer to 
icer to use its influence to effect or influenc
y other decision maker. I accept to promptly 
or deviations from any of the above prescript
and accept Sponsor’s rights to conduct aud
ng or in connection with the performance of 
of the above prescriptions may result in th
ork in and/or the entire study. 
Signature 
.......... ...........................................................
 
Study Code FLO-02
Version 1.0, 12 April 2016
Page 3 of 124 
cal trial protocol titled 
armacokinetics (PK), 
s (≥6<18 years of age) 
cution of the study and 
cal trial protocol in its 
activity in accordance 
OECD Convention on 
nsactions, UK Bribery 
Decree 231/2001. In 
ny of my collaborators 
eceive any payment or 
influence any acts or 
ce the decision of the 
inform the Sponsor in 
tions in the conduct of 
dits in order to verify 
the study. I agree and 
he termination of the 
Date 
.. ..............................
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
2. PROTOCOL SYNO
 
Study Title  
 
 
 
 
Sponsor Code 
 
Nick name/Acronym 
Phase 
Indication 
No. of sites  
Investigational Medicinal 
Product 
Treatment regimen 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
OPSIS 
Open label, multi-centre, parallel group 
pharmacokinetics (PK), pharmacodynam
febuxostat between pediatric patients (≥6
adults. 
 
FLO-02 
 
FLORET 
Phase I/II 
Tumor Lysis Syndrome (TLS) 
Approximately 40 sites. 
Febuxostat film-coated tablets. 
 
Eligible patients will receive oral a
following dose of febuxostat per age grou
- 
Children (from 6 to less than 12 years
Cohort 1: 40 mg once daily; 
Cohort 2: 60 mg once daily. 
- 
Adolescents (from 12 to less than 18 y
Cohort 3: 80 mg once daily; 
Cohort 4: 120 mg once daily. 
- 
Adults (equal or major than 18 years o
120 mg once daily. 
The two dose levels for children and adol
administered sequentially (Cohort 2 after
4 after Cohort 3), whereas Cohort 1, 
treatments will start simultaneously at the
The minimum treatment duration will be
treatment may be prolonged up to 9
chemotherapy duration, as per Investigato
Study Code FLO-02
Version 1.0, 12 April 2016
Page 4 of 124 
study to compare the 
mics (PD) and safety of 
6<18 years of age) and 
administration of the 
up: 
s of age)[1] 
years of age)[1] 
of age) 
lescents groups will be 
r Cohort 1, and Cohort 
Cohort 3 and adults 
e study beginning. 
e of 7 days. However, 
9 days according to 
or’s judgment.  


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
Design 
Primary objectives 
Secondary objectives 
Study duration 
Inclusion criteria 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
Open label, multi-centre, parallel group st
The primary objectives of this study are:
 To assess the pharmacokinetics (P
pediatric patients (≥6<18 years of
suffering from hematological malign
to high risk of TLS. 
 To compare the febuxostat exposure
(≥6<18 years of age) with the on
administered with a dose of 120 mg/Q
 To compare the pharmacodynamics
between pediatric patients (≥6<18 yea
  To evaluate and compare the PK
febuxostat in pediatric patients (≥6<
adults. 
 To evaluate the safety of febuxos
patients (≥6<18 years of age) and adu
 To evaluate the occurrence of Labora
Clinical TLS (CTLS) according t
Criteria (see Appendix I: Definition o
 To assess the age-appropriate formu
children.  
Individual study period: approximately 3 
Screening should occur up to 1 week 
timeframe window) prior to the Start o
Febuxostat treatment will start 2 days bef
continue for 7-9 days (Day 7 to Day 9). 
occur at Day 14 (±2 days of accepted tim
Patients meeting ALL the following crite
enter the study: 
male and female children of 6 to les
adolescents of 12 to less than 18 yea
a. 
scheduled for first cytotoxic
regardless of the line of t
Study Code FLO-02
Version 1.0, 12 April 2016
Page 5 of 124 
tudy. 
PK) of febuxostat in 
f age) and in adults 
nancies at intermediate 
e in pediatric patients 
ne achieved in adults 
QD.  
s (PD) of febuxostat 
ars of age) and adults. 
K/PD relationship of 
<18 years of age) and 
tat between pediatric 
ults. 
atory TLS (LTLS) and 
o Cairo and Bishop 
of LTLS and CTLS). 
ulation acceptability in 
weeks. 
(+2 days of accepted 
of Treatment (Day 1). 
fore chemotherapy and 
A follow-up visit will 
eframe window). 
eria will be eligible to 
s than 12 years of age, 
ars of age, and adults: 
c chemotherapy cycle, 
treatment, because of 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
hematologic malignancies, a
b. 
at intermediate or high risk 
c. 
with serum uric acid (sUA)
Visit 1 (Day 1), and 
d. 
 with no access to rasburica
 
Study Code FLO-02
Version 1.0, 12 April 2016
Page 6 of 124 
and  
for TLS, and 
) levels < 10 mg/dL at 
se; 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
Exclusion criteria 
Study procedures and PK/PD, 
Clinical and Safety assessments
(see also Flow Chart) 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
Patients will not be eligible to participa
meet ANY of the following exclusion crite
1. patients known to be hypersensitiv
any components of the formulation;
6. patients with severe renal insufficien
7. patients with severe hepatic insuffic
8. patients with diagnosis of Labora
Clinical TLS (CTLS) at Visit 1 (Day
 
s 
Written informed consent shall be provid
by parents (one or both, according to lo
legal guardian for children and adolesce
study procedures. 
 
Screening Visit (Day -9 to Day 1): 
 assessment of inclusion/exclusion cr
 demographic data collection; 
 medical and medication history; 
 physical examination and vital sign
Study Code FLO-02
Version 1.0, 12 April 2016
Page 7 of 124 
ate in the study if they 
eria: 
ve to febuxostat or to 
ncy; 
iency; 
atory TLS (LTLS) or 
y 1). 
ded by adult patients or 
cal regulations) or the 
ents prior to start any 
riteria; 
ns (i.e. blood pressure 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
[BP], heart rate [HR], breathin
temperature [T]); 
 performance status (PS) evaluation;
 12 lead ECG; 
 blood sampling and urine collection
tests, including pregnancy test (if ap
 record of adverse events. 
 
NOTE-1: Study procedures under Scree
also on more than one day. 
NOTE-2: Results of safety laboratory
hematology, coagulation, urinalysis and 
appropriate) and ECG, which have be
context of the standard patient’s managem
in the e-CRF under Screening Visit proc
they have been done within 24 hours p
Visit. 
NOTE-3: 
Re-screening 
is 
allow
sponsor/medical monitor’s approval. A p
be re-screened once. 
Visit 1, Start of Treatment (Day 1:
chemotherapy): 
Prior to study drug administration: 
 record of adverse events and ch
medications. 
 re-check of inclusion/exclusion crit
of patient’s eligibility; 
 physical examination and vital signs
 PS evaluation; 
 blood sampling and urine collection
tests (NOTE: safety laboratory tests
hours prior to Day 1 are accepted a
repeated on Visit 1); 
 blood sampling for centralized labor
Study Code FLO-02
Version 1.0, 12 April 2016
Page 8 of 124 
ng rate [BR], body 
n for safety laboratory 
pplicable); 
ening Visit may occur 
y tests (biochemistry, 
pregnancy test, when 
een performed in the 
ment, can be recorded 
cedures, provided that 
prior to the Screening 
wed 
but 
requires 
patient may maximally 
: two days prior to 
hange in concomitant 
teria and confirmation 
s; 
n for safety laboratory 
s performed within 24 
and do not need to be 
ratory test (sUA); 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
 assessment of LTLS/CTLS; 
 allocation of investigational medi
treatment box as per IxRS assignme
Study drug administration: 
 administration of febuxostat. 
After study drug administration: 
 assessment 
of 
the 
age-appr
acceptability only for children. 
NOTE: Screening Visit and Visit 1 (Day
same day. Common assessments will be p
 
Visit 2 (Day 2): 
 record of adverse events and ch
medications; 
 vital signs; 
 PS evaluation; 
 pre-dose PK blood sampling; 
 blood sampling for safety labora
centralized laboratory test (sUA); 
 study drug administration; 
 assessment 
of 
the 
age-appr
acceptability (only for children). 
 
Visit 3 (Day 3): 
 record of adverse events and ch
medications; 
 vital signs; 
 PS evaluation; 
 12 lead ECG; 
 pre-dose PK blood sampling; 
 blood sampling for safety labora
centralized laboratory test (sUA); 
 study drug administration; 
 assessment 
of 
the 
age-appr
Study Code FLO-02
Version 1.0, 12 April 2016
Page 9 of 124 
icinal product (IMP) 
nt. 
ropriate 
formulation 
y 1) may occur on the 
performed only once. 
hange in concomitant 
atory tests, including 
ropriate 
formulation 
hange in concomitant 
atory tests, including 
ropriate 
formulation 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
acceptability (only for children);  
 assessment of LTLS/CTLS; 
 starting of chemotherapy regimen. 
 
Visit 4-7 (Day 4-7): 
On each day from Day 4 to Day 7, the f
will be performed: 
 record of adverse events and ch
medications; 
 vital signs; 
 PS evaluation; 
 pre-dose PK blood sampling; 
 blood sampling for safety labora
centralized laboratory test (sUA); 
 study drug administration; 
 assessment 
of 
the 
age-appr
acceptability (only for children); 
 4 additional post-dose PK blood sam
7 (Day 7) at the assigned sampling
hours, 2-4 hours, 4-6 hours and 6-8 h
 urine collection for safety laborator
4 (Day 4); 
 assessment of LTLS/CTLS. 
 
Visit 8, Evaluation Visit (Day 8): 
On Day 8, at treatment Evaluation 
assessments will be performed: 
 record of adverse events and ch
medications; 
 physical examination and vital signs
 PS evaluation; 
 12 lead ECG; 
 PK blood sampling (pre-dose PK 
scheduled to prolong hypouricemic t
 blood sampling for safety labora
Study Code FLO-02
Version 1.0, 12 April 2016
Page 10 of 124 
following assessments 
hange in concomitant 
atory tests, including 
ropriate 
formulation 
mplings ONLY at Visit 
g time intervals: 0.5-2 
hours; 
ry tests ONLY at Visit 
Visit, the following 
hange in concomitant 
s; 
sampling for patients 
treatment); 
atory tests, including 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
centralized laboratory test (sUA); 
 urine collection for safety laboratory
 assessment of LTLS/CTLS. 
ONLY for patients scheduled to pr
treatment: 
 study drug administration; 
 assessment 
of 
the 
age-appr
acceptability (only for children). 
 
Visit 9 (Day 9): 
To be performed ONLY for patients s
hypouricemic treatment: 
 record of adverse events and ch
medications; 
 vital signs; 
 PS evaluation; 
 study drug administration; 
 assessment 
of 
the 
age-appr
acceptability (only for children); 
 blood sampling for safety laboratory
 
Visit 10, Follow-up/End of Study Visit 
A final safety Follow-up/End of Study V
at Day 14 (±2): 
 record of adverse events and ch
medications; 
 physical examination and vital signs
 PS evaluation; 
 12 lead ECG; 
 blood sampling and urine collection
tests. 
 
 
NOTE: 
Blood safety laboratory tests will be p
Study Code FLO-02
Version 1.0, 12 April 2016
Page 11 of 124 
y tests; 
rolong hypouricemic 
ropriate 
formulation 
scheduled to prolong 
hange in concomitant 
ropriate 
formulation 
y tests. 
(Day 14±2): 
Visit will be performed 
hange in concomitant 
s; 
n for safety laboratory 
performed at the Local 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
Primary endpoints 
 
Secondary endpoints 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
Laboratory and will include: albumin, 
amylase, 
alanine 
aminotransferase 
aminotransferase (AST), blood urea n
serum creatinine, serum uric acid (sUA
potassium, phosphorus, calcium, tot
bilirubin, gamma-glutamyl transpeptid
lactate dehydrogenase (LDH), total p
time/prothrombin activity, internation
(INR), platelets, red blood cells 
hematocrit and white blood cells (WBC) 
(absolute and %), and beta human chori
HCG) if applicable. 
Urinalysis will be performed at the Loca
include: pH, density, proteins, glucose, 
WBC, epithelial cells, casts, bacteria, yea
Blood samples for centralized laborato
PK tests will be collected and ana
Laboratory. 
Pharmacokinetic endpoints derived from 
 Primary PK parameters: CL/F, Vd/F
 Derived PK parameters: AUC and C
 Pharmacodynamic endpoint: 
− Area under the curve of sUA fr
Day 1) to the Evaluation Visit (Visit 
1-8) based on central laboratory results
 PK/PD endpoint: 
− The PK/PD relationship will be
sUA levels and febuxostat exposure.
 Clinical endpoints: 
− Incidence of Laboratory TLS (
Chemotherapy (Visit 3, Day 3) to 
Study Code FLO-02
Version 1.0, 12 April 2016
Page 12 of 124 
alkaline phosphatase, 
(ALT), 
aspartate 
nitrogen (BUN)/urea, 
A), sodium, chloride, 
tal bilirubin, direct 
ase (GGT), glucose, 
proteins, prothrombin 
nal normalized ratio 
(RBC), hemoglobin, 
with differential count 
ionic gonadotropin (β-
al Laboratory and will 
ketones, nitrite, RBC, 
asts and crystals. 
ory test (sUA) and for 
alyzed in a Central 
the study will include: 
F and Ka. 
Cmax. 
rom baseline (Visit 1, 
8, Day 8) (AUC sUA 
s. 
e evaluated based on 
LTLS) from Start of 
the Evaluation Visit 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
Sample size 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
(Visit 8, Day 8), based on local labora
− Incidence and grading of Clinic
Start of Chemotherapy (Visit 3, Day
Visit (Visit 8, Day 8) based on local l
 Safety endpoints: 
− Incidence, 
severity
Mild/Moderate/Severe scale and 
seriousness and treatment causality o
Signs and Symptoms (TESS). 
NOTE: An AE is considered as ‘Treatme
Symptoms (TESS)’ if it occurs for the fir
in terms of seriousness or severity after the
(Visit 1, Day 1).  
− Frequency of clinically signific
physical examination, safety laborat
and 12 Lead ECG. 
− Change in PS according to Karnof
 Assessment 
of 
the 
age-appr
acceptability (only for children). 
A sample size of approximately 24 patien
the Pharmacokinetic population for each
(pediatric cohorts 1-4 and adults).  
Assuming a 10% screening failure rate
should be screened in order to enroll 
Study Code FLO-02
Version 1.0, 12 April 2016
Page 13 of 124 
atory results. 
cal TLS (CTLS) from 
y 3) to the Evaluation 
aboratory results. 
(both 
through 
NCI-CTCAE grade), 
of Treatment-Emergent 
nt-Emergent Signs and 
rst time or if it worsens 
e first study drug intake  
cant abnormalities in 
tory tests, vital signs 
fsky/Lansky scales. 
ropriate 
formulation 
nts will be included in 
h age and dose group 
, around 135 patients 
approximately a total 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
Analysis populations 
Statistical analyses 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
number of 120 patients. 
 Safety population: all patients who
dose of study drug. 
 Pharmacokinetic (PK) populatio
received at least one dose of stu
reliable drug plasma concentration 
for the pharmacokinetic parameter o
 Intention to Treat (ITT) pop
allocated to a treatment box. 
 Per Protocol (PP) population: al
population excluding those who
protocol violation(s). 
 Per Protocol PK (PP-PK) populat
PK population who do not have
violation(s) relevant for PK analyses
Primary analyses: 
All pharmacokinetic results (e.g., PK 
concentrations) will be summarized by
using appropriate graphs and descriptive 
of patients (n), mean, standard deviat
mean, 95% confidence intervals, coe
(CV%), median, minimum, and maximum
Relevant PK parameters (e.g., AUC, C
adolescents will be descriptively compare
demonstrate 
sufficient 
similarity
pharmacokinetics. 
The pharmacokinetic analyses will be 
population and for exploratory reas
population. 
Secondary analyses: 
 Pharmacodynamics: treatment effic
by AUC sUA analyzed by Central L
Study Code FLO-02
Version 1.0, 12 April 2016
Page 14 of 124 
o received at least one 
on: all patients who 
udy drug and have a 
measurement relevant 
of interest. 
ulation: all patients 
ll patients of the ITT 
o experienced major 
tion: all patients from 
e any major protocol 
s.  
variables and plasma 
y dose and age group 
statistics [i.e., number 
tion (SD), geometric 
efficient of variation 
m].  
Cmax) in children and 
ed to those in adults to 
y 
of 
febuxostat 
conducted on the PK 
sons on the PP-PK 
cacy will be assessed 
Laboratory from Day 1 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
to Day 8 (AUC sUA1-8). Compa
between febuxostat doses among 
carried out on ITT and PK populatio
 PK/PD: observed exposure-respo
descriptively and graphically sum
dose group. 
 
 
 
 
 
 
 
 
  
The aim of this analysis is to suppo
comparable 
PK/PD 
relationship
patients (≥6<18 years of age) and ad
potential deviations in PK are cli
analysis will be conducted on PK po
 Clinical: incidence of LTLS a
summarized through descriptive st
dose and age group and their statis
be performed using a Chi Square t
analyses will be run on ITT 
exploratory reasons on PP-populatio
 Safety: 
− adverse events will be coded 
dictionary. The incidence, sever
causality of each TESS will be su
organ class, preferred term by feb
group; 
− reasons for early termination wi
febuxostat dose and age group;  
− laboratory findings and changes i
by febuxostat dose and age group. 
All safety analyses will be run on th
 
Assessment 
of 
the 
age-appr
Study Code FLO-02
Version 1.0, 12 April 2016
Page 15 of 124 
arisons will be made 
the age groups and 
on. 
onse data will be 
mmarized by age and 
 
 
 
 
 
 
 
 
ort the assumption of a 
p 
between 
pediatric 
dults and to evaluate if 
inically relevant. This 
opulation. 
and CTLS will be 
tatistics by febuxostat 
stical comparison will 
test. Clinical endpoint 
population and for 
on.  
using the MedDRA 
rity, seriousness and 
ummarized by system 
buxostat dose and age 
ill be summarized by 
in PS will be reported 
he safety population. 
ropriate 
formulation 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61 
 
 
 
         Final 
 
Confidential 
Menarini Ricerche S.p.A 
acceptability will be evaluated throu
summarized by means of desc
febuxostat dose in children. Th
conducted on the safety population.
Study Code FLO-02
Version 1.0, 12 April 2016
Page 16 of 124 
ugh a patient diary and 
criptive statistics by 
he analysis will be 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61     
 
 
 
 
2.1 SCHEMATIC STUDY DES
 
 
 
 
 
 
 
 
FEB
ADULTS 
CHILDREN 
ADOLESCENTS 
 
NOTE: ≈24 adults will receive oral adm
in children and adolescents will be adm
receive the doses of 40 mg and 80 m
administered to the following ≈24 child
for adolescents.  
 
Screening
V1 
V2 
Day -9–1 
Day 1
Day 2
D
Start of 
Treatment 
St
Chem
    Final Ver
 
Confidential 
Menarini Ricerche S.p.A 
SIGN 
UXOSTAT TREATMENT REGIMEN 
≈24 patients: febuxostat 120 mg/QD
first ≈24 patients 
(40 mg/QD) 
futher 
(60
first ≈24 patients 
(80 mg/QD) 
futher 
(120
ministration of febuxostat 120 mg once daily. The two
ministered sequentially: the first ≈24 children and the
mg once daily, respectively. Afterwards, the higher
dren and ≈24 adolescents: 60 mg once daily for childr
STUDY VISITS 
Treatment Period 
V3 
V4 
V5 
V6 
V7 
V8 
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
tart of 
motherapy 
Evaluatio
Study Code FLO-02
rsion 1.0, 12 April 2016
Page 17 of 124 
End of Study 
≈24 patients 
0 mg/QD) 
≈24 patients 
0 mg/QD) 
o dose levels per age group 
e first ≈24 adolescents will 
r febuxostat doses will be 
ren and 120 mg once daily 
 
 
V9 
V10 
Day 9
Day 14±2
on 
End of Study 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61     
 
 
 
 
 
2.2 STUDY FLOW-CHART 
a= Performance status evaluation according to Karnofsky performance status 
Guideline CIBMTR 2009. 
b= Safety lab tests, Urinalysis and Pregnancy test (if applicable) will be perfo
c= Blood sampling for centralized lab test (sUA) is collected in conjunction w
d= One daily pre-dose sampling at all visits from Day 2 to Day 8. 
e= Four additional post-dose PK samples to collect on Day 7 at the following
f= The two dose levels per age group will be sequentially administered in chi
daily. Higher doses will be subsequently administered: 60 mg once daily to ch
g= To be performed ONLY for patients scheduled to prolong hypouricemic tr
h = Chemotherapy shall be started on Day 3 (Visit 3) and will continue as per
PROCEDURE 
Prior to 
any study 
procedures 
Screening  
Visit  
Day -9 to Day 1 
Informed consent  
X 
 
Inclusion/exclusion 
criteria 
 
X 
Demographics  
 
X 
Medical history 
 
X 
Prior and concomitant 
medication 
 
X 
Physical examination 
 
X 
PS evaluationa 
 
X 
Vital signs  
 
X 
12-Lead ECG 
 
X 
Safety Lab Testsb 
 
X 
Centralized Lab Testc 
 
 
PK blood samplingd 
 
 
Pregnancy Testb 
 
X 
Urinalysisb 
 
X 
LTLS/CTLS 
 
 
Study drug allocation 
through IxRS 
 
 
Study drug 
administrationf 
 
 
Assessment of the age-
appropriate formulation  
acceptability  
 
 
Adverse events 
 
X 
Start of Chemotherapyh 
 
 
 
Confidential 
Menarini Ricerche S.p.A 
(KPS) scale for patients aged 16 years and older and  Lansky Play performance status (LPS) sc
ormed locally to guarantee the management of the patient. 
with safety lab tests, whenever possible .  
g time intervals: 0.5-2 hours, 2-4 hours, 4-6 hours and 6-8 hours. 
ldren and adolescents. The first 24 children will receive the lower dose of 40 mg once daily, and
hildren and 120 mg once daily to adolescents.  
reatment. 
r Investigator’s judgment. 
STUDY VISITS 
Treatment Period 
Visit 1 
Day 1 
Visit 2 
Day 2 
Visit 3 
Day 3 
Visit 4 
Day 4 
Visit 5 
Day 5 
Visit 6 
Day 6 
Visit 7 
Day 7 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Xe 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
Study Code FLO-02 
Final Version 1.0, 12 April 2016 
Page 18 of 124 
 
cale for patients aged less than 16 years, as per 
d the first 24 adolescents the dose of 80 mg once 
Evaluation  
Visit 8 
Day 8 
 
Visit 9g  
Day 9 
End of Study 
Visit 10 
Day 14±2 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
Xg 
X 
 
Xg 
X 
 
X 
X 
X 
 
 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
3. INVESTIGATOR(
 
Co-ordinating Investigator 
 
Sponsor 
 
 
Corporate Director of Clinical Researc
Sponsor’s Representative 
 
Head of Corporate Therapeutic Areas  
Oncology, Immunology & Antinfective
Clinical Research Physician  
Study Manager  
Head of Corporate Biostatistic and Dat
Management 
Biostatistician 
Data Manager   
Senior Corporate Pharmacokineticist 
  
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
(S) AND STUDY ADMINISTRATIV
 
 
 
 
 
 
Menarini Ricerche S.p.A. 
Clinical Research 
Via Sette Santi, 1 
50131 Florence, Italy 
h / 
 
 
  
 
        
 
e   
 
 
    
 
        
 
 
 
    
 
       
 
 
  
 
        
ta 
 
 
        
 
 
 
  
 
      
 
 
 
  
 
      
 
 
 
    
 
        
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 19 of 124 
VE STRUCTURE 
 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Sponsor’s Pharmaceutical Manufact
the IMP 
Head of the Department of Pharmaceut
Development 
Packaging, Labelling, and Distribution
of the IMP 
 
Sponsor’s Pharmacovigilance Unit 
Drug Safety Manager 
 
 
Quality Assurance 
Head of Quality Assurance & GXP com
 
CRO  
 
 
 
 
Central Laboratory Pharmacokineti
Central Lab Project Manager
Central Laboratory 
Final Versi
Confidential 
Menarini Ricerche S.p.A
turer of 
A. Menarini Research & Business Service
Pharmaceutical Development Departmen
Glienicker Weg 125 
12489 Berlin, Germany
tical 
 
 
 
      
 
n 
  
 
 
      
 
Laboratorios Menarini S.A. -Menarini G
Clinical Research 
C/ Alfons XII, 587 
08918, Badalona, Spain 
 
 
 
      
 
 
  
mpliance
 
 
  
      
 
  
 
 
 
ic 
Menarini Ricerche,  
Clinical Laboratory 
Via Tito Speri, 10 
00071 Pomezia, Roma (Italy) 
 
 
 
      
 
R.T.C. Research Toxicology Centre S.p.A
Clinical Laboratory 
Via Tito Speri, 12/14 
00071 Pomezia, Rome, Italy  
Study Code FLO-02
ion 1.0, 12 April 2016
Page 20 of 124 
e GmbH  
nt 
Group 
 
 
 
A. 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Scientific Responsible of the Service/S
Central Lab and Logistics
 
 
 
 
IxRS 
Final Versi
Confidential 
Menarini Ricerche S.p.A
Study
  
 
 
      
 
 
 
 
      
 
 
 
  
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 21 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
4. TABLE OF CONT
1. 
SIGNATURES ................................
2. 
PROTOCOL SYNOPSIS ...................
2.1 
SCHEMATIC STUDY DESIGN ............
2.2 
STUDY FLOW-CHART ....................
3. 
INVESTIGATOR(S) AND STUDY AD
4. 
TABLE OF CONTENTS ....................
4.1 
GLOSSARY ..............................
5. 
ETHICAL AND LEGAL ASPECTS ......
5.1 
GENERAL ASPECTS ......................
5.2 
INDEPENDENT ETHICS COMMITTEE 
5.3 
PATIENT INFORMATION AND DECLA
5.4 
PATIENT INSURANCE ....................
5.5 
DOCUMENTATION OF STUDY-RELAT
5.6 
CONFIDENTIALITY ........................
5.7 
PROTOCOL MODIFICATIONS ..........
5.8 
STUDY COMMENCEMENT .............
5.9 
PATIENT’S SAFETY .......................
5.10 
DATA PROPERTY/PUBLICATION PO
5.11 
DATA PROTECTION......................
5.11.1 
General Principles on Pe
5.11.2 
Data Controllers and Da
5.11.3 
Duties of the Parties invo
5.11.4 
Information notice on pe
6. 
BACKGROUND INFORMATION .....
6.1 
DISEASE AND STUDY RATIONALE ....
6.2 
INVESTIGATIONAL MEDICINAL PROD
6.2.1 
Non-clinical data ...........
6.2.2 
Clinical experience ........
6.3 
RISK-BENEFIT ASSESSMENT ..........
7. 
STUDY OBJECTIVES ......................
7.1 
PRIMARY OBJECTIVE ....................
7.2 
SECONDARY OBJECTIVES ...............
8. 
INVESTIGATIONAL PLAN ..............
8.1 
OVERALL STUDY DESIGN AND PLAN
8.2 
DISCUSSION OF STUDY DESIGN, INC
8.3 
SELECTION OF STUDY POPULATION
8.3.1 
Inclusion criteria ...........
8.3.2 
Exclusion criteria ...........
8.3.3 
Withdrawal of patients fr
8.4 
IDENTITY OF THE INVESTIGATIONAL 
8.4.1 
Description of Investigat
8.4.2 
Packaging, labeling, and
8.4.3 
Drug accountability .......
8.4.4 
Destruction of surplus m
8.5 
TREATMENTS .............................
Final Versi
Confidential 
Menarini Ricerche S.p.A
TENTS 
..................................................................................
..................................................................................
......................................................................................
......................................................................................
DMINISTRATIVE STRUCTURE ......................................
..................................................................................
......................................................................................
..................................................................................
......................................................................................
AND LEGAL REQUIREMENTS ................................................
ARATION OF CONSENT ........................................................
......................................................................................
TED DATA AND RECORD RETENTION ......................................
......................................................................................
......................................................................................
......................................................................................
......................................................................................
LICY ................................................................................
......................................................................................
ersonal Data Compliance ............................................
ata Processors ..............................................................
olved in the performance of the study ..........................
ersonal data protection and pseudo-anonymisation .....
..................................................................................
......................................................................................
DUCT: FEBUXOSTAT ............................................................
......................................................................................
......................................................................................
......................................................................................
..................................................................................
......................................................................................
......................................................................................
..................................................................................
N DESCRIPTION ..................................................................
CLUDING THE CHOICE OF CONTROL GROUP .............................
.....................................................................................
......................................................................................
......................................................................................
from therapy or assessment ...........................................
PRODUCT ........................................................................
tional Medicinal Product ..............................................
d storage .......................................................................
......................................................................................
medication ......................................................................
......................................................................................
Study Code FLO-02
ion 1.0, 12 April 2016
Page 22 of 124 
....................................... 2 
....................................... 4 
................................. 17 
................................. 18 
..................................... 19 
..................................... 22 
................................. 25 
..................................... 28 
................................. 28 
................................. 28 
................................. 28 
................................. 29 
................................. 29 
................................. 30 
................................. 30 
................................. 31 
................................. 31 
................................. 31 
................................. 32 
...................................... 32 
...................................... 32 
...................................... 32 
...................................... 34 
..................................... 36 
................................. 36 
................................. 38 
...................................... 39 
...................................... 40 
................................. 42 
..................................... 44 
................................. 44 
................................. 44 
..................................... 45 
................................. 45 
................................. 46 
................................. 48 
...................................... 48 
...................................... 49 
...................................... 49 
................................. 50 
...................................... 50 
...................................... 51 
...................................... 52 
...................................... 52 
................................. 52 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.5.1 
Treatment Allocation .....
8.5.2 
Treatment administration
8.5.3 
Treatment compliance ...
8.5.4 
Dosage modification ......
8.5.5 
Concomitant Medication
8.6 
STUDY PROCEDURES AND ASSESSM
8.6.1 
Study Schedule ...............
8.6.1.1 
Screening Visit (Day -9 t
8.6.1.2 
Visit 1, Start of Treatmen
8.6.1.3 
Visit 2 (Day 2) ................
8.6.1.4 
Visit 3 (Day 3) ................
8.6.1.5 
Visits 4-7 (Days 4-7) ......
8.6.1.6 
Visit 8 (Day 8) ................
8.6.1.7 
Visit 9 (Day 9) ................
8.6.1.8 
Visit 10, Follow-up/End 
8.6.2 
Assessment of Pharmaco
8.6.2.1 
Pharmacokinetic parame
8.6.2.2 
Sampling and handling o
8.6.2.2.1 Drug assay .....................
8.6.2.2.2 Analytical methods .........
8.6.2.3 
Centralized Laboratory E
8.6.3 
Assessment of Safety ......
8.6.3.1 
Medical History .............
8.6.3.2 
Physical Examinations a
8.6.3.3 
Safety Laboratory Evalu
8.6.3.4 
12 Lead ECG .................
8.6.3.5 
Performance Status eval
8.6.4 
LTLS and CTLS Assessm
8.6.5 
Assessment of the age-ap
8.7 
ADVERSE EVENT DEFINITIONS, MO
8.7.1 
Definitions .....................
8.7.1.1 
Adverse Event (AE) ........
8.7.1.2 
Drug Relationship ..........
8.7.1.3 
Adverse Drug Reactions 
8.7.1.4 
Seriousness ....................
8.7.1.5 
Adverse Event (AE)/Adve
8.7.1.6 
Adverse Event (AE)/Adve
8.7.1.7 
Serious Unexpected Adve
8.7.2 
Monitoring and Recordin
8.7.3 
Management of Serious A
8.7.3.1 
Reporting Duties of the I
8.7.3.2 
Reporting Duties of the S
8.7.4 
Management of Non-Ser
8.7.5 
Management of Pregnan
8.7.6 
Annual Safety Reporting
8.7.7 
Breaking of the Randomi
8.7.8 
Serious and Non-serious
8.8 
PHARMACOKINETIC/PHARMACODY
8.8.1 
Primary Endpoints .........
8.8.2 
Secondary Endpoints .....
9. 
STATISTICAL METHODS AND DETE
9.1 
DETERMINATION OF SAMPLE SIZE ..
9.2 
ANALYSIS POPULATIONS ...............
9.3 
STATISTICAL ANALYSIS .................
9.3.1 
Descriptive statistics ......
Final Versi
Confidential 
Menarini Ricerche S.p.A
......................................................................................
n - frequency and duration of application ....................
......................................................................................
......................................................................................
n.....................................................................................
MENTS ..............................................................................
......................................................................................
to Day 1) .......................................................................
nt (Day 1)......................................................................
......................................................................................
......................................................................................
......................................................................................
......................................................................................
......................................................................................
of Study (Day 14 ± 2) ...................................................
okinetics/Pharmacodynamics ........................................
eters ..............................................................................
of blood samples for drug assays ..................................
......................................................................................
......................................................................................
Evaluation for Pharmacodynamic Parameter .............
......................................................................................
......................................................................................
and Vital signs ...............................................................
ation .............................................................................
......................................................................................
luation ...........................................................................
ment ...............................................................................
ppropriate formulation acceptability ............................
NITORING/ RECORDING AND MANAGEMENT ..........................
......................................................................................
......................................................................................
......................................................................................
(ADRs) ........................................................................
......................................................................................
erse Drug Reaction (ADR) Intensity ............................
erse Drug Reaction (ADR) Expectedness .....................
erse Drug Reaction (SUSAR) .......................................
ng of Adverse Events ....................................................
Adverse Events (SAEs) .................................................
Investigator ...................................................................
Sponsor .........................................................................
rious Adverse Events (NSAEs) and/or laboratory abnor
ncy Exposure Cases .......................................................
g .....................................................................................
ization Code .................................................................
s Adverse Events Follow-up ..........................................
YNAMIC AND SAFETY ENDPOINTS ...........................................
......................................................................................
......................................................................................
ERMINATION OF SAMPLE SIZE ...................................
......................................................................................
......................................................................................
......................................................................................
......................................................................................
Study Code FLO-02
ion 1.0, 12 April 2016
Page 23 of 124 
...................................... 52 
...................................... 53 
...................................... 53 
...................................... 53 
...................................... 54 
................................. 54 
...................................... 54 
...................................... 55 
...................................... 55 
...................................... 56 
...................................... 57 
...................................... 57 
...................................... 57 
...................................... 58 
...................................... 58 
...................................... 59 
...................................... 59 
...................................... 59 
...................................... 59 
...................................... 60 
...................................... 60 
...................................... 61 
...................................... 61 
...................................... 61 
...................................... 62 
...................................... 63 
...................................... 63 
...................................... 63 
...................................... 63 
................................. 64 
...................................... 64 
...................................... 64 
...................................... 64 
...................................... 65 
...................................... 65 
...................................... 66 
...................................... 67 
...................................... 67 
...................................... 67 
...................................... 67 
...................................... 67 
...................................... 69 
rmalities ........................ 70 
...................................... 70 
...................................... 71 
...................................... 71 
...................................... 71 
................................. 71 
...................................... 71 
...................................... 71 
..................................... 73 
................................. 73 
................................. 73 
................................. 73 
...................................... 73 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
9.3.2 
Population Pharmacokin
9.3.3 
Primary analysis ............
9.3.4 
Secondary analysis ........
9.3.5 
Subgroup analysis ..........
9.3.6 
Safety analysis ...............
9.3.7 
Data imputations ...........
9.4 
PROTOCOL VIOLATIONS AND DATA 
9.5 
STATISTICAL ANALYSIS PLAN .........
9.6 
DATA ANALYSIS PLAN ..................
10. DATA QUALITY MANAGEMENT ....
10.1 
DATA COLLECTION ......................
10.1.1 
Case Report Forms ........
10.1.2 
IxRS ................................
10.1.3 
Patient diary ..................
10.1.4 
Central Laboratory/Exam
10.1.5 
Data capture systems ver
10.2 
CLINICAL DATA MANAGEMENT .....
10.3 
SOURCE DATA ............................
10.4 
QUALITY CONTROL/QUALITY ASSU
10.4.1 
Study Monitoring ...........
10.4.2 
Quality Assurance ..........
11. PREMATURE TERMINATION OF TH
12. END OF CLINICAL TRIAL AND ARCH
12.1 
ARCHIVING OF ELECTRONIC DOCUM
13. APPENDIX ....................................
13.1 
APPENDIX I: DEFINITION OF LTLS A
13.2 
APPENDIX II: EU SMPCS FOR ADEN
13.3 
APPENDIX III: TLS RISK ASSESSMEN
13.4 
APPENDIX IV: KARNOFSKY AND LAN
13.5 
APPENDIX V: COMMON TERMINOL
4.03: JUNE 14, 2010). U.S.DEPARTMENT 
INSTITUTE .............................................
14. REFERENCES .................................
Final Versi
Confidential 
Menarini Ricerche S.p.A
netic (Pop-PK) analysis ................................................
......................................................................................
......................................................................................
......................................................................................
......................................................................................
......................................................................................
REVIEW MEETING ............................................................
......................................................................................
......................................................................................
..................................................................................
......................................................................................
......................................................................................
......................................................................................
......................................................................................
mination data ...............................................................
rsions and validation documentation ...........................
......................................................................................
......................................................................................
RANCE ............................................................................
......................................................................................
......................................................................................
HE WHOLE STUDY .....................................................
HIVING ......................................................................
MENTATION/DATA .............................................................
..................................................................................
AND CTLS ........................................................................
NURIC® ............................................................................
NT...................................................................................
NSKY PLAY PERFORMANCE STATUS SCALES ..............................
LOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) VERSION 4.0. PU
OF HEALTH AND HUMAN SERVICES – NATIONAL INSTITUTE OF H
......................................................................................
..................................................................................
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 24 of 124 
...................................... 74 
...................................... 75 
...................................... 75 
...................................... 78 
...................................... 78 
...................................... 78 
................................. 78 
................................. 79 
................................. 79 
..................................... 80 
................................. 80 
...................................... 80 
...................................... 80 
...................................... 81 
...................................... 81 
...................................... 81 
................................. 81 
................................. 82 
................................. 82 
...................................... 82 
...................................... 83 
..................................... 84 
..................................... 85 
................................. 85 
..................................... 86 
................................. 86 
................................. 87 
............................... 116 
............................... 119 
UBLISHED: MAY 28, 2009 (V 
HEALTH – NATIONAL CANCER 
............................... 120 
................................... 121 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
4.1 GLOSSARY 
ADR 
Advers
AE 
Advers
ALCL 
Anapla
ALL 
Acute L
ALT 
Alanin
AML 
Acute M
APEX 
Allopu
AST 
Asparta
ATL 
Adult T
AUC 
Area U
BL 
Burkitt
BP 
Blood 
BR 
Breath 
BUN 
Blood 
CA 
Compe
CBER 
Center 
CDER 
Center 
CI 
Confid
CL 
Clearan
CLcr 
Creatin
CL/F  
Appare
CLL 
Chroni
Cmax 
Maxim
CML 
Chroni
CONFIRMS 
CONfi
CRF 
Case R
CRO 
Contra
CTCAE 
Comm
CTLS 
Clinica
CV 
Coeffic
CYP 
Cytoch
 
DLBCL 
Diffuse
DSM 
Drug S
DSUR 
Develo
EC 
Europe
ECG 
Electro
eCRF 
electro
EMA 
Europe
ER 
Exposu
EU 
Europe
EXCEL 
fEbuXo
FACT 
Febuxo
FEB 
FEBux
FL 
Follucu
FOCE 
First-O
FOCUS  
Febuxo
GCP 
Good C
GGT 
Gamm
GLP 
Good L
ß-HCG 
Beta-H
HL 
Hodgk
HR 
Heart R
Final Versi
Confidential 
Menarini Ricerche S.p.A
se Drug Reaction 
se Event 
astic Large Cell Lymphoma 
Lymphoblastic Leukemia 
ne Aminotransferase 
Myelogenous Leukemia 
urinol-Placebo-controlled Efficacy study of febuXostat
ate Aminotransferase 
T-cell Lymphoma 
Under Curve 
t Lymphoma/Leukaemia 
Pressure 
Rate 
Urea Nitrogen 
etent Authority 
for Biologics Evaluation and Research 
for Drug Evaluation and Research 
dence Interval 
nce 
nine Clearance 
ent clearance 
ic Lymphocytic Leukemia 
mum plasma Concentration 
ic Myeloid Leukemia 
rmation of Febuxostat In Reducing and Maintaining S
Report Form 
act Research Organization 
mon Terminology Criteria for Adverse Events 
al Tumor Lysis Syndrome 
cient of Variation 
hromeP450 
 
e Large B-Cell Lymphoma 
Safety Manager 
opment Safety Update Report 
ean Commission  
ocardiogram 
nic Case Report Form 
ean Medicines Agency 
ure Response 
ean Union 
ostat Comparative Extension Long-term study 
ostat versus Allopurinol Controlled Trial 
xostat 
ular Lymphoma 
Order Conditional Estimation 
ostat Open-label Clinical trial of Urate-lowering effica
Clinical Practice 
ma-Glutamyl Transpeptidase 
Laboratory Practice 
Human Chorionic Gonadotropine 
kin Lymphoma 
Rate 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 25 of 124 
t 
Serum urate 
acy and Safety 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
HRD 
High R
IB 
Investi
ICF 
Inform
ICH 
Interna
ID 
Identifi
IMP 
Investi
INR 
Interna
IRB/IEC 
Institut
IRD 
Interme
ITT 
Intent-t
IxRS 
Interac
Ka  
Absorp
KPS 
Karnof
LC-MS/MS 
Liquid 
LDH 
Lactate
LL 
Lymph
LOCF 
Last Ob
LPS 
Lansky
LRD 
Low R
LTLS 
Labora
MALT 
Mucos
MCL 
Mantel
NCI 
Nation
NHL 
Non-H
NSADR 
Non-se
NSAE 
Non-se
OBJF 
OBJect
PCTFE  
PolyCh
PD 
Pharma
PIP 
Pediatr
PK 
Pharma
PP 
Per-pro
PS 
Perform
PT 
Preferr
PTCL 
Periphe
PVC 
PolyVi
QA 
Quality
QD 
Quaque
RBC 
Red Bl
RTC 
Resear
SADR 
Serious
SAE 
Serious
 
sC 
serum 
SD 
Standa
SIV 
Site Ini
SmPC 
Summa
SOC 
System
SOP 
Standa
SST 
Serum-
sUA 
serum U
SUSAR 
Suspec
T 
Body t
TESS 
Treatm
Final Versi
Confidential 
Menarini Ricerche S.p.A
Risk Disease 
gator’s Brochure 
med Consent Form 
ational Conference on Harmonisation 
fication number 
gational Medicinal Product 
ational Normalized Ratio 
tional Review Board/Independent Ethics Committees
ediate Risk Disease 
to-treat 
ctive Voice / Web Response System 
ption rate constant   
fsky Performance Status 
Chromatography-tandem Mass Spectrometry 
e DeHydrogenase 
hoblastic Lymphoma 
bservation Carried Forward 
y Play Performance Status 
Risk Disease 
atory Tumor Lysis Syndrome 
a-Associated Lymphoma Tissue 
l Cell Lymphoma 
nal Cancer Institute 
Hodgkin Lymphoma 
erious Adverse Drug Reaction 
erious Adverse Event 
tive Function 
hloroTriFluoroEthylene 
acodynamic 
ric Investigational Plan 
acokinetics 
otocol 
mance Status 
red Term 
eral T-Cell Lymphoma 
inyl Chloride 
y Assurance 
e Die (once day) 
lood Cell 
rch Toxicology Center 
s Adverse Drug Reaction 
s Adverse Event 
 
Creatinine 
ard Deviation 
itiation Visit 
ary of Product Characteristics 
m Organ Class 
ard Operating Procedure 
-Separating Tube 
Uric Acid 
cted Unexpected Serious Adverse Reaction 
emperature 
ment Emergent Sign and Symptoms 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 26 of 124 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
TLS 
Tumor
TMF 
Trial M
Tmax 
Time to
UA 
Uric A
UGT 
Uridine
ULN 
Upper 
US 
United
Vd/F  
Appare
VPC 
Visual 
WBC 
White 
WHO 
World 
WNL 
Within
XDH 
Xanthi
XO 
Xanthi
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
r Lysis Syndrome 
Master File 
o Cmax 
Acid 
e Diphosphate Glucuronosyltransferase  
Limit of Normal 
d States 
ent volume of distribution 
Predictive Check 
Blood Cell 
Health Organisation 
n Normal Limit 
ne Dehydrogenase  
ne Oxidase 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 27 of 124 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
5. ETHICAL AND LE
5.1 GENERAL ASPECTS 
This study will be carried out 
biomedical research on human s
Harmonization -Good Clinical P
2001, and national requirements o
Furthermore, the study will be
Organisation’s (CRO’s) Standard
SOPs are listed in the project man
All clinical work conducted 
audits/inspections by the Sponso
Health Authority representatives 
the study site, facilities, and of stu
the Sponsor, and/or its delegate
concerning personal data protectio
5.2 INDEPENDENT ETHICS 
Before starting the study in a stud
to and approved by the Institution
Competent Authorities (CAs) of th
In addition, all local national legal
prior to the start of the study. Th
about  any changes in the study p
appropriate and within the request
5.3 PATIENT INFORMATION
Before any study-related procedu
patient (adult) or by patient’s pa
(child and adolescent), by means o
The Informed Consent Form (IC
accordance with local laws and re
parents/legal guardian.  
In the information leaflet, patient
Final Versi
Confidential 
Menarini Ricerche S.p.A
EGAL ASPECTS 
in compliance with the study protocol, the
ubjects of the Declaration of Helsinki, Intern
Practice (ICH-GCP) Guidelines, EU-Directiv
of the participating country(ies). 
e conducted in agreement with Sponsor’s 
d Operating Procedures’ (SOP) requirements 
nagement plan and monitoring plan of the study
under this protocol is subject to GCP 
or and/or its delegate (e.g. CRO), and/or by
at any time. All Investigators must agree to t
udy-related records by the Health Authority re
es, which must be performed in accordanc
on. 
COMMITTEE AND LEGAL REQUIREME
dy site, study protocol and relevant documenta
nal Review Board/Independent Ethics Commit
he participating countries. 
l requirements for the conduct of a clinical stu
e CAs and IRB/IECs of the participating cou
protocol, the end of the study, or the prematu
ted time period.  
N AND DECLARATION OF CONSENT 
ures may be performed, informed consent mus
arents (one or both, according to local regula
of a signed declaration. 
CF) must be approved in the corresponding 
egulations by the IRB/IEC prior to be submitt
ts and/or parents/legal guardian will be given
Study Code FLO-02
ion 1.0, 12 April 2016
Page 28 of 124 
e recommendations on 
national Conference of 
ve 2001/20 of April 4, 
or Contract Research 
as agreed. The agreed 
y.  
rules. This includes 
y national/international 
the audits/inspection of 
epresentatives and/or by 
ce with national laws 
ENTS 
ation must be submitted 
ttees (IRB/IEC) and the 
udy have to be followed 
untries will be informed 
ure study termination as 
st be obtained from the 
ation) or legal guardian 
local language and in 
ted to the patient and/or 
n information and fully 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
comprehensive explanation in ea
benefits, restrictions, discomforts, 
the properties of the Investigation
and any medically accepted and re
Patients and/or parents/legal guard
their minor confidentiality accordi
After being duly informed and in
freely has to date and sign an IC
undergoing any study procedure.
Investigator’s File, and the patien
process of obtaining the ICF has to
If a protocol amendment would a
change and submitted to IRB/IEC
is signed by all patients or by the p
and those currently in the study, be
5.4 PATIENT INSURANCE 
For patients participating in the st
accordance with local regulatory r
Details on the insurance compan
patients in the ICF and/or provided
A copy of the insurance certific
Investigator’s File at the sites and 
5.5 DOCUMENTATION OF S
It is the responsibility of the Inve
report form (CRF). For this stud
guarantee the accuracy of the docu
In addition to the eCRF the Inv
participation of the patient in the
documentation). Details on the sou
ICH-GCP guidelines, the Investig
two years after the last approval o
or contemplated marketing applic
Final Versi
Confidential 
Menarini Ricerche S.p.A
asily understandable terms of the study pro
and risks for themselves or for their minor in t
nal Medicinal Product (IMP), the method of as
eadily available treatment other than the IMP. 
dian will also be informed about the measures 
ing to the pertinent legislation.  
nterviewed by the Investigator, the patient or
CF before their or their minor enrolment into
. The Investigator must store the original of 
nt or parents/legal guardian will be provided 
o be documented in the source documents. 
affect the terms of the ICF, it will be revised
C for approval. The Investigator will ensure that
parents/legal guardian of all minors subsequen
efore the changes take effect on their participat
tudy, Menarini Ricerche S.p.A. has stipulated
requirements. 
ny, the insurance number and conditions will
d as a separate document, in accordance with n
cate will be provided to each Investigator an
in the study’s Trial Master File (TMF). 
STUDY-RELATED DATA AND RECORD R
estigator to document all study-related data for
dy, an electronic CRF (eCRF) will be used. T
umented data and has to comment any missing
vestigator will maintain adequate records th
e clinical study including the study assessmen
urce data documentation are provided in sectio
gator will keep patients’ records and essential d
f a marketing application in an ICH region; un
cations in an ICH region, or at least two years
Study Code FLO-02
ion 1.0, 12 April 2016
Page 29 of 124 
ocedures, regarding the 
taking part in the study, 
signment to treatments, 
taken to ensure their or 
r parents/legal guardian 
o the study and before 
f the signed ICF in the 
with a copy of it. The 
d to reflect the protocol 
t this new consent form 
ntly entered in the study 
tion in the trial. 
d an insurance policy in 
l be made available to 
national requirements. 
nd will be filed in the 
RETENTION  
r each patient in a case 
The Investigator has to 
g or spurious data. 
hat fully document the 
nts (patient source data 
on 10.3. As required by 
documents until at least 
ntil there are no pending 
 have elapsed since the 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
formal discontinuation of clinical 
Patients’ data (e.g.: eCRFs, labor
documents should be retained fo
requirements or by an agreement w
No study documents should be 
Investigator. Should the Investiga
notify the Sponsor in writing.  
5.6 CONFIDENTIALITY 
By signing the study protocol, th
will be maintained in confidence, 
under an appropriate understandin
In order to maintain the patient’s 
pseudonymously in the eCRF. P
Investigator agrees that withi
representatives of the Sponsor, 
documents in order to verify data
reviewed by the study monitor to
of eCRFs. The review will be con
professional standards of confiden
5.7 PROTOCOL MODIFICAT
The protocol must be read thorou
instructions must be exactly follow
Changes in the study protocol wi
upon and approved in writing by 
likely to have an impact on the s
documents in support of the condu
the CAs in the participating countr
Changes which have no significan
will be agreed upon and approved
notified of this protocol amendme
Any substantial amendments of 
Principal Investigator must ensure
Final Versi
Confidential 
Menarini Ricerche S.p.A
development of the IMP.  
ratory data) have to be archived for the same
r a longer period however, if required by th
with the Sponsor.  
destroyed without prior written agreement 
ator wish moving the study record to another
e Investigator affirms that any information pr
and that such information will be divulged to 
ng of confidentiality with such a committee or i
confidentiality, all data collected by the Invest
Patient’s data will be identified by a unique
in national regulatory restrictions and e
any regulatory agency, and IRB/IEC may
a in the eCRF. Patient medical records pertine
o assure adequate source documentation, accur
nducted in accordance with relevant SOPs and 
ntiality, GCP, and the relevant data protection l
TIONS 
ughly by everybody whom the information th
wed. 
ill require a protocol amendment. Such amen
all signatories of the protocol. If amendments
safety of the patients, or to change the interpr
uct of the study, or if they are otherwise signifi
ries have to approve these amendments before 
nt impact on patient safety medical or scientif
d in writing by all signatories of the protocol a
ent. 
the protocol will be integrated in an update
e full compliance with the updated study protoc
Study Code FLO-02
ion 1.0, 12 April 2016
Page 30 of 124 
e period of time. These 
e applicable regulatory 
between Sponsor and 
r location, he/she must 
rovided by the Sponsor 
IRB/IECs or CAs only 
institution. 
tigator will be recorded 
e patient number. The 
ethical considerations, 
y consult study source 
ent to the study will be 
racy, and completeness 
with strict adherence to 
legislation. 
herein concerns and the 
ndments will be agreed 
s are substantial, i.e. are 
retation of the scientific 
icant, the IRB/IECs and 
implementation.  
fic validity of the study 
and the IRB/IEC will be 
ed study protocol. The 
col. 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
5.8 STUDY COMMENCEMEN
The study can commence in an in
to ICH/GCP guidelines, any local 
5.9 PATIENT’S SAFETY 
If any event(s) related to the cond
the study participants, the Sponso
protect the patients against any im
about these new events and the me
5.10 DATA PROPERTY/PUBL
All data generated in the study (e.
results of the statistical evaluation
are the property of Menarini Ricer
It is intended that study design
In addition, the results of the stud
in submissions to CAs and IRB/I
confidential commercial informati
All information concerning febuxo
basic scientific data, or formulat
S.p.A. and not previously publish
remain the sole property of Mena
purposes without written consent f
Menarini Ricerche S.p.A. will use
development of febuxostat and the
European Union or abroad. In ord
the Investigator has an obligation t
data recorded during this study. 
Prior to submitting the results of 
Menarini Ricerche S.p.A. at lea
manuscript. Menarini Ricerche S.
60 days before publishing to th
recognized principles of scientifi
personnel will be discussed and
publisher. 
Final Versi
Confidential 
Menarini Ricerche S.p.A
NT 
ndividual study site only after all prerequisites
regulatory requirements, and the Sponsor/CRO
duct of the study or the development of the IM
or and the Investigator will take appropriate urg
mmediate hazard. The CAs and IRB/IECs will
easures taken. 
LICATION POLICY 
g. eCRFs, the structured data files in the clinic
n, and medical interpretation as well as the fin
rche S.p.A. 
n and main results will be published on 
dy may be published as scientific literature. Re
IECs. The conditions mentioned below are in
ion (patents, etc.), and not to restrict publicatio
ostat (such as patent applications, formulae, m
tion information supplied to the Investigator 
hed) is considered confidential by Menarini R
arini Ricerche S.p.A. The Investigator agrees
from Menarini Ricerche S.p.A. 
e the information obtained in this clinical study
erefore may disclose it to other Investigators o
der to allow for the use of information derived f
to provide Menarini Ricerche S.p.A. with com
this study for publication or presentation, the 
ast 60 days time to review and comment 
.p.A. will provide any manuscript of the resul
he authors for a complete review. In acco
fic collaboration, co-authorship with any Me
d mutually agreed upon before submission 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 31 of 124 
s are fulfilled according 
O’s SOPs. 
MP affects the safety of 
gent safety measures to 
l be informed forthwith 
cal database system, the 
nal clinical study report) 
www.clinicaltrials.gov.  
esults may also be used 
ntended only to protect 
n. 
manufacturing processes, 
by Menarini Ricerche 
Ricerche S.p.A. and will 
s not to use it for other 
y in connection with the 
or concerned CAs in the 
from this clinical study, 
mplete test results and all 
Investigator will allow 
upon the publication 
lts of this study at least 
ordance with generally 
enarini Ricerche S.p.A. 
of a manuscript to a 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
It is agreed, that the results of 
exhibition, or publication by the I
and agreed to any publication. 
5.11 DATA PROTECTION  
5.11.1 General Principles on
The site, the Principal Investigato
and service providers acknowledg
(a) the performance of the study
(b) personal data processing is r
where the study is conducted
hereby acknowledged that b
to mandatorily comply with
cooperate with the Sponsor 
doubt, it is hereby clarified t
legal provisions on data prot
(c) strict compliance with the a
their employees who take pa
for the appointment of the c
CRO, etc. 
5.11.2 Data Controllers and
The parties acknowledge that acc
independent data controllers whi
will act as data processors resp
beginning of the study, the sites w
processors (and by signing this p
Data Processor by their respectiv
5.11.3 Duties of the Parties 
Collection and use of patients’ pe
will be carried out in full respe
freedoms and dignity of data su
adequate measures to warrant th
privacy laws. 
Final Versi
Confidential 
Menarini Ricerche S.p.A
the study will not be submitted for presen
Investigator until Menarini Ricerche S.p.A. ha
n Personal Data Compliance 
or, the Central Laboratory, the CRO as well a
ge that:  
y will imply processing of sensitive personal d
regulated by the applicable local laws (i.e. th
d) as well as by the Sponsor’s national legisla
being the Sponsor a company incorporated un
h Italian legal provisions on data protection
to allow the fulfilment of such obligations.
that only the Sponsor and its service provider
ection; 
applicable data protection laws and instructio
art to the study, is deemed by the Sponsor as
collaboration with the research site, the Prin
d Data Processors  
cording to the applicable privacy laws, Spons
ile CRO, the Centralised Laboratory and the
pectively of the Sponsor and of their respe
will appoint in writing their respective Princip
protocol, the latter undertakes to ensure that 
ve sites before the start of the study). 
involved in the performance of the s
ersonal data (i.e. subjects’ data), including th
ect of the information notices duties, privac
ubjects. All the parties involved in this stud
hat data will always be processed securely an
Study Code FLO-02
ion 1.0, 12 April 2016
Page 32 of 124 
ntation, abstract, poster 
as reviewed/commented 
as their appointed staff 
data; 
he laws of the country 
ation. In particular, it is 
nder Italian law, it has 
n: therefore they shall 
. For the avoidance of 
rs are bound by Italian 
ons by any parties and 
s an essential condition 
ncipal Investigator, the 
sor and sites will act as 
e Principal Investigator 
ective site. Before the 
pal Investigator as data 
he/she is appointed as 
study 
heir biological samples, 
cy rights, fundamental 
dy undertake to adopt 
nd in compliance with 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
The site, the Principal Investigato
their appointed staff and service p
limits of their specific role in th
logical, organizational, technical
data of the patients involved in th
(i) DATA SAFETY. The site 
measures to prevent or minimiz
illegal/unauthorized access to pa
this extent, before the beginning 
that the actual measures they h
particular: 
- 
in order to minimise the risk
personal data are stored sha
individuals who need to re
professional purposes; the sa
- 
any electronic database conta
password and it must be ofte
every three months) and tha
include, for example, file sy
which renders data unintellig
- 
security measures are imple
match the patients’ personal
(as defined at point (iv) below
The site shall, upon request from
about the measures listed above. 
The CRO shall ensure that the 
measures.  
(ii) TRANSMISSION OF DAT
centralised database(s) used to
implement secure protocols bas
unauthorized individuals. 
(iii) SECURITY OF THE CEN
Sponsor shall have the following 
Final Versi
Confidential 
Menarini Ricerche S.p.A
or, the Sponsor, the CRO and the Centralised
providers, each in its respective field of com
he study, shall implement the following safe
, electronic, I.T. etc) to ensure adequate pro
he study. In particular, 
and/or the Principal Investigator shall ad
ze the risks of theft, partial or total loss, ac
atient’s data or Sponsor’s proprietary confid
of the study, the sites and/or the Principal In
have implemented are fit-for-purpose and l
k of unauthorized access and theft, the hardw
all be placed in a restricted-access area, ac
etrieve the patients’ personal data included
ame safeguards shall be put in place for non-e
aining the patients’ personal data is password
en updated (e.g.: it is at least 8 character lon
at adequate cryptographic protection measur
stem or database cryptography, or any other 
gible to those who are not authorised to acces
emented also on the files or databases which
l data (i.e. name, surname, etc.) with their re
w).  
m the Sponsor and/or the CRO, provide detail
 
selected sites for the study have impleme
TA. All the parties that transfer data through
o process study’s data or to generate sta
ed on cryptographic standards which make
NTRALISED DATA BASE. The centralised
safeguards in place:  
Study Code FLO-02
ion 1.0, 12 April 2016
Page 33 of 124 
d Laboratory as well as 
mpetence and within the 
ty measures (physical, 
tection of the personal 
dopt all the necessary 
ccidental disclosure or 
dential information; to 
nvestigator shall ensure 
law-compliant, and in 
ware on which patients’ 
ccessible only to those 
d in the database for 
electronic databases; 
d-protected, by a strong 
ng and updated at least 
res are in place (these 
equivalent IT measure 
s them);  
h contain the “key” to 
espective “Patient IDs” 
led written information 
ented the above listed 
h internet and/or to the 
tistical analyses shall 
e data unintelligible to 
d database held by the 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
- 
appropriate authentication m
their respective roles so as t
exclusively to those for who
the study; 
- 
appropriate measures to ensu
password change); 
 (iv) PSEUDO ANONYMISAT
involved in the study shall be a
(“pseudo-anonymisation” proces
identification data of patients f
alphanumerical code (“Patient ID
Sponsor, the Centralised Laborat
 
Site/Principal Investigator shall 
identification code, together wit
measures as defined above. The P
for the longest period of time allo
further communication from the S
 
Biological samples and any othe
case will they bear other inform
patient.  
(v) TRAINING. The parties sha
proper training on data protection
All actions related to the implem
Sponsor and/or the CRO to the 
Ethics Committees if and whe
implementation of the afore me
protection of the patients’ person
overcome such remarks to assure
5.11.4 Information notice o
Prior to patients’ enrolment in th
personnel) shall provide each 
consent forms to process person
separate, specific form) provided
Final Versi
Confidential 
Menarini Ricerche S.p.A
methods, which differentiate between differe
to ensure that access to a specific set of subj
om access to such data is essential in the con
ure that the authentication credentials are per
TION. All personal data that may allow identi
adequately dissociated from the other data p
ss). The Principal Investigator shall adeq
from the data pertaining to the study by li
D”) so as to ensure that only anonymous data
ory and/or the CRO. 
securely store a separate list (e.g. identif
th all signed informed consents, in accorda
Principal Investigator and/or the site will mai
owed by the applicable laws and this protoco
Sponsor. 
er examination (e.g. X-ray, ECG) shall bear
mation that may lead to the direct or indirec
all ensure that any personnel involved in th
n issues. 
mentation of the afore mentioned measures sh
competent authorities (including data prote
en requested. If such authorities or the 
entioned measures insufficient to guarantee
nal data, the parties undertake to adopt all the
e the full compliance with the data protection 
n personal data protection and pseud
he study, the Principal Investigator and/or th
patient with adequate, law-compliant “inf
al data” as included in the ICF (or, as the c
d by the Sponsor or delegated CRO and shall
Study Code FLO-02
ion 1.0, 12 April 2016
Page 34 of 124 
ent users according to 
jects' data is permitted 
ntext of their work for 
riodically updated (i.e. 
ification of the patients 
pertaining to the study 
quately dissociate the 
inking results to a an 
a are transmitted to the 
fication log) with the 
ance with the security 
intain these documents 
ol, and in any case until 
r Patient ID, and in no 
ct identification of the 
he study have received 
hall be provided by the 
ection authorities) and 
Sponsor consider the 
e an adequate level of 
e necessary activities to 
laws.  
do-anonymisation 
he site (including their 
formation notices and 
case may be, through a 
l collect his/her written 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
consent to the processing of pers
the study is carried out. 
The ICF (or the separate form) sh
the processing of personal data i
study they may ask that their per
that in this last case the results of
remain in the database. The IC
transferred abroad including cou
protection as that of the patient. 
Final Versi
Confidential 
Menarini Ricerche S.p.A
sonal data according to the actual performanc
hall inform patients/parent of minors/legal gu
is required to take part in the study, that if th
rsonal data be deleted and their samples dest
f tests that have already been performed will 
CF (or the separate form) shall also spec
untries whose laws do not ensure the same 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 35 of 124 
ce conditions in which 
uardian that consent to 
hey withdraw from the 
troyed and will specify 
not be deleted and will 
cify that data may be 
level of personal data 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
6. BACKGROUND IN
6.1 DISEASE AND STUDY RA
The Tumor Lysis Syndrome (TL
physicians caring for children o
possibly fatal complication result
most often after initial treatment
patients affected by hematol
chemotherapy.  
In this condition, the rapid releas
electrolyte balances, potentially 
hypocalcemia. The precipitation/
may then lead to impaired renal 
electrolytes imbalances. 
According to Coiffier et al. [3], 
acute renal impairment, is signif
those with lower levels. For ever
(p<0.0001), while the risk of ren
the importance of preventing/con
The potential severity of compli
prompt treatment. Recognition o
pharmacological interventions ar
An international TLS consens
pathophysiology, prophylaxis an
intermediate and high risk TLS c
Indeed, between adult and pediat
1) Clinical manifestations: clini
vomiting, lethargy, edema, fluid 
muscle cramps, tetany, syncope
present within 12-72 hours after c
2) Diagnosis: Laboratory TLS (L
potassium, phosphate or calcium
at least 25% from baseline (see
Final Versi
Confidential 
Menarini Ricerche S.p.A
NFORMATION 
ATIONALE  
LS) is the most common disease-related emer
or adults with hematologic cancers. TLS rep
ting from the rapid lyses of large numbers of
t with chemotherapy [2, 3]. It is estimated th
ogical malignancies have renal insuffic
se of intracellular metabolites can alter the no
leading to hyperuricemia, hyperkalemia, hy
/crystallization of uric acid or calcium phos
function/failure which in turn may further ex
the risk of developing TLS, or more simply 
ficantly increased in patients with higher lev
ry mg/dL increase in sUA, the risk of TLS 
nal events by a factor 2.21 (p=0.0012). This 
ntaining the uric acid increase during chemoth
ications resulting from TLS requires measur
of risk factors, close monitoring of at risk pa
e the keys for preventing/managing TLS. 
us panel of pediatric and adult oncolog
nd management, has recently developed a
classification and associated TLS prophylaxis
tric populations no major differences exist in 
ical symptoms both in adults and children
overload, congestive heart failure, cardiac d
e and possibly sudden death. Clinical man
cytotoxic therapy administration [5].  
LTLS) is diagnosed if levels of 2 or more seru
m are more or less than normal at presentation
Appendix I: Definition of LTLS and CTLS)
Study Code FLO-02
ion 1.0, 12 April 2016
Page 36 of 124 
rgency encountered by 
presents a critical and 
f tumor cells, observed 
hat from 5% to 30% of 
ciency during initial 
ormal homeostatic and 
yperphosphatemia and 
sphate in renal tubules 
xacerbate the degree of 
the risk of developing 
vels of uric acid versus 
raises by a factor 1.75 
observation underlines 
herapy.  
res for prevention and 
atients and appropriate 
gists, experts in TLS 
a final model of low, 
s recommendations [4]. 
terms of: 
n may include nausea, 
dysrhythmias, seizures, 
nifestations commonly 
um values of uric acid, 
n, or if they change by 
). The only significant 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
difference between adults and ch
an age-dependent way [5-7]. 
The diagnosis of Clinical TLS (C
requires the presence of one o
arrhythmia/sudden death or seiz
pathway is the same between ad
Finally, the same grading system
III: TLS Risk Assessment), using
3) Treatment: according to intern
TLS is prevention. In particular,
monitoring is considered appro
recommended in addition to hyd
along with hydration [3, 4]. 
Allopurinol is considered an effe
limitations with its use, i.e. the n
frequent condition in this patient p
serious side effects including hyp
target levels in some patients.  
Rasburicase is a recombinant fo
allantoin, an inactive and soluble 
some disadvantages, such as the i
and the formation of neutralizing 
strongly limit the use of rasburicas
On April 8th 2015 febuxostat 120
oxidase/xanthine dehydrogenase 
hyperuricemia in adult patients un
to high risk of TLS [8]. The appro
III pivotal study FLORENCE, wh
setting so far (see section 6.2.2). 
Febuxostat addresses an importan
treatments for the prevention a
chemotherapy for hematologic ma
The medical need of TLS manage
Final Versi
Confidential 
Menarini Ricerche S.p.A
hildren is the threshold of phosphate, which i
CTLS) is based on the same criteria both in c
or more between increased creatinine level
zure in addition to the diagnosis of LTLS.
dults and children, with a clarification abou
m for TLS can be applied both in adults and c
g the respective creatinine ULN.  
national guidelines and recommendations, th
 in patients at low risk, the “watch and wait
opriate; whereas, in patients at intermediat
dration; finally, in patients at high risk, rasbu
ctive and tolerated treatment for TLS; howev
need to reduce dose in patients with renal i
population, the potential for drug interactions
persensitivity reactions, and the inability to r
orm of urate-oxidase that catalyzes the oxida
metabolite. Rasburicase is more potent than al
ntravenous administration, possible severe hyp
antibodies. These issues, together with the hig
se in clinical practice.  
0 mg strength, an orally administered, non-pu
inhibitor, has been approved for the preven
ndergoing chemotherapy for hematologic malig
oval was based on the results of the randomiz
hich is moreover the largest randomized trial
nt unmet medical need and adds to the armam
and management of hyperuricemia in adul
alignancies.  
ement in the pediatric population can be consi
Study Code FLO-02
ion 1.0, 12 April 2016
Page 37 of 124 
is higher in children in 
children and adults and 
l ≥ 1.5 ULN, cardiac 
Again, the diagnostic 
ut the creatinine ULN. 
children (see Appendix 
he best management of 
t” approach with close 
te risk, allopurinol is 
uricase should be used 
ver, there may be some 
mpairment, which is a 
, the rare occurrence of 
each/maintain the sUA 
ation of uric acid into 
llopurinol, but it retains 
persensitivity reactions, 
gh cost of the treatment, 
urine, selective xanthine 
ntion and treatment of 
gnancies at intermediate 
zed, double blind, phase 
l performed in the TLS 
mentarium of available 
lt patients undergoing 
idered even higher than 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
in adults. In fact, age is an indepe
Leukemia (ALL), the most com
proliferation rate and high sensit
massive TLS with even fatal outco
patients miss an age-appropriate o
correct (weight-adjusted) TLS pro
considering the high cost and the 
appropriate febuxostat formulatio
alternative to the present therapy.
TLS usually develops in pati
Lymphoblastic Leukemia (ALL)
population, TLS is more frequent 
13]. An overall TLS incidence of
adolescents with NHL [11] and, o
B-cell ALL.  
As children and adolescents do n
treatment in respect of the adult p
that febuxostat could be of sign
assumption that the clinical cond
undergoing chemotherapy is simi
exposure-response (ER) relationsh
present study aims at showing tha
with the selected doses are similar
The proposed Pharmacodynamic 
primary efficacy parameter which
[8]. The Pharmacokinetic (PK) an
PD observed data in order to inv
Therefore, the efficacy and safety
will be bridged to the pediatric po
matching of febuxostat drug ex
populations. 
6.2 INVESTIGATIONAL MED
Febuxostat is an orally admin
dehydrogenase (XDH) inhibitor. 
Final Versi
Confidential 
Menarini Ricerche S.p.A
endent risk factor for TLS development [9] and
mmon pediatric hematologic malignancy, h
tiveness to chemotherapy, thus predisposing
omes. Treatment possibilities for the managem
oral formulation of allopurinol. Therefore, chil
ophylaxis only with an intravenous treatment w
limited access to rasburicase in some of the E
on certainly deserves clinical evaluation and 
ients with aggressive Non-Hodgkin Lymp
), or Acute Myelogenous Leukemia (AML) 
in B-cell ALL or in Burkitt’s lymphoma with 
f 4.4% was reported in two multicentre studie
f these, TLS occurred in 8.4% of patients with 
not show any major differences in TLS diag
population, the FLORENCE study results in 
nificant benefit also in children and adolesce
dition of hyperuricemia in patients with hema
ilar between adults and children, it is reasona
hip between the two populations could be sim
at the febuxostat exposure levels achieved in ch
r to those achieved in adults receiving 120 mg
(PD) assessment, namely AUC sUA Days 1
h was evaluated in the phase III pivotal study
nd PK/PD modeling and simulation analyses w
vestigate the relationship between PK/PD and
y data collected in the pivotal phase III study
opulation by solely PK, as well as by PK/PD a
xposure and exposure/response between th
DICINAL PRODUCT: FEBUXOSTAT 
nistered, non-purine, selective xanthine o
XO inhibitors reduce sUA levels by impeding
Study Code FLO-02
ion 1.0, 12 April 2016
Page 38 of 124 
d Acute Lymphoblastic 
has a particularly high 
children to a possible 
ment of TLS in pediatric 
dren can receive a fully 
with rasburicase. Hence, 
U 28 countries, an age-
may represent a valid 
phoma (NHL), Acute 
[10]. In the pediatric 
high tumor burden [11-
es of 1791 children and 
h Burkitt’s lymphoma or 
gnosis, management or 
adults strongly suggest 
ents. Starting from the 
atological malignancies 
able to assume that the 
milar. In this context, the 
hildren and adolescents 
g febuxostat once daily. 
1-8, corresponds to the 
y FLORENCE in adults 
will apply to the PK and 
age as main covariate. 
y FLORENCE in adults 
analyses, showing a full 
he adult and pediatric 
oxidase (XO)/xanthine 
g the transformation of 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
hypoxanthine to xanthine and of x
enzymes; the active sites of these 
in mammals. In the European Un
approval in April 2009 at doses 
hyperuricemia of conditions wh
presence of tophus and/or gouty a
40 mg and 80 mg /QD) received
hyperuricemia in patients with gou
with or without gout (FEBURIC®
Finally, on April 8th 2015 [8], the
marketing authorization for febux
and treatment of hyperuricemi
malignancies at intermediate to h
adenuric® ). 
6.2.1 Non-clinical data 
Following single- or multiple-do
maximum plasma concentration 
(AUC) is observed over the 10-2
Circulating febuxostat is substan
volume of distribution at steady
accumulation when febuxostat is a
half-life of febuxostat typically 
conjugation via uridine diphospha
oxidative metabolism via cytochro
In preclinical studies, febuxostat
sUA levels. In vitro, the drug con
derived from bovine milk, mou
compared with 1700, 380 and 10
humans in terms of purine metabo
and 72 hours with febuxostat by 5
5 mg/kg/day orally for 3 days [16]
A specific toxicology program h
development [17]. Effects in non-
maximum human exposure. In b
Final Versi
Confidential 
Menarini Ricerche S.p.A
xanthine to uric acid; both conversions are cata
enzymes are structurally equivalent and XDH 
nion (EU), febuxostat (trade name ADENURIC
of 80 mg or 120 mg once daily (QD) for th
ere urate deposition has already occurred (
arthritis). In the United States (US), febuxostat
d FDA approval in February 2009 for the c
ut, while in Japan it was approved for the treat
10 mg to 60 mg/QD).  
e European Commission (EC) has granted th
xostat 120 mg strength, adding the following
ia in adult patients undergoing chemothe
high risk of TLS (ADENURIC® SmPc, Appen
ose administration of febuxostat, dose-propor
(Cmax) and in the area under the plasma co
240 mg dose range. The time to Cmax (tmax) is
ntially bound to albumin (approximately 99
y state of approximately 0.7 L/kg [14]. Th
administered every 24 hours. The apparent me
ranges from 5 to 8 hours. Febuxostat is m
ate-glucuronosyltransferase (UGT) enzymes or
ome P450 (CYP) enzymes to form active meta
was more potent than allopurinol in inhibiti
ncentrations resulting in 50% inhibition of th
se liver or rat liver were 1.4, 1.8 and 2.2 
00 nmol/L for allopurinol [15]. In vivo, in c
olite levels and urate excretion), sUA levels we
6%, 70% and 74%, and with allopurinol by 28
]. 
has been run to fulfill the requirements of th
-clinical studies were generally observed at exp
both adult and juvenile rats, dose-limiting tox
Study Code FLO-02
ion 1.0, 12 April 2016
Page 39 of 124 
alyzed by XO and XDH 
readily converts to XO 
C®) received marketing 
he treatment of chronic 
(including a history or 
(trade name ULORIC®  
chronic management of 
tment of hyperuricemia 
he variation of previous 
g indication: prevention 
rapy for hematologic 
ndix II: EU SmPCs for 
rtional increases in the 
oncentration-time curve 
 approximately 1 hour. 
9%), with an apparent 
here is no appreciable 
ean terminal elimination 
metabolized mainly by 
r to a smaller extent by 
abolites.  
ing XO and decreasing 
he activity of XO/XDH 
nmol/L for febuxostat 
himpanzees (similar to 
ere reduced after 24, 48 
8%, 42% and 45%, each 
he febuxostat pediatric 
posures in excess of the 
xicities were associated 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
with obstructive nephropathies d
considered a consequence of sp
deemed of no relevance for th
nephrotoxic effects of XO inhibit
humans [18]. In fact, the rate of 
larger compared to rodents [19]. F
the same high levels reported in a
the formation of xanthine crystals
humans and neither for children an
Further details on non-clinical ph
adult toxicology can be found in
Brochure (IB). 
6.2.2 Clinical experience 
The pharmacodynamic effects of
dose-dependently reduced the mea
acid excretion by 46-66% relative
plateau at dosages  >120 mg/day
on the pharmacokinetics of oral, o
in studies in healthy volunteers [2
The anti-hyperuricemic efficacy o
gout and hyperuricemia in several
dose-response study [23] and thr
Allopurinol Controlled Trial), a
(Allopurinol-Placebo-controlled E
placebo-controlled study (n= 10
study), a long-term, non blind ext
and CONFIRMS (CONfirmation 
randomized, double-blind, allopur
trials excluded patients with a ser
moderate renal impairment (seru
efficacy and tolerability of febuxo
lowering efficacy and Safety) stu
response trial [28]. 
In the dose-response study [23], f
Final Versi
Confidential 
Menarini Ricerche S.p.A
due to the precipitation of xanthine in urin
pecies-specific purine metabolism and urine 
he clinical development. As already reporte
ors is species-related, being observed in roden
purine biosynthesis is slower in humans and 
For this reason, xanthine concentration in hum
animal toxicology studies following febuxosta
s is not expected at the febuxostat dose levels 
nd adolescents from 6 to 17 years of age. 
harmacology, pharmacokinetics (PK) also in s
n the EU Summary of Product Characteristic
f oral febuxostat have been examined in hea
an sUA levels from baseline by 25-70%, and t
e to placebo after 8 days of treatment. Both e
[20]. The effects of food intake, anti-acid con
once-daily febuxostat were not considered to b
1, 22]. 
of oral, once-daily febuxostat has been evaluate
l randomized, multicentre trials. One double-bl
ree trials with allopurinol as comparator: FA
a phase III, 52-week, double-blind study (
Efficacy study of febuXostat), a phase III, 2
67) [25]; EXCEL (fEbuXostat Comparative
tension study in patients completing FACT an
of Febuxostat In Reducing and Maintaining Se
rinol-controlled study (n= 2269) [27]. The do
rum creatinine level >1.5 mg/dL, while APEX
um creatinine level of 1.6-2.0 mg/dL). In a
ostat were assessed in the FOCUS (Febuxosta
udy (n= 116), a long-term, non comparative 
febuxostat was significantly more effective th
Study Code FLO-02
ion 1.0, 12 April 2016
Page 40 of 124 
ne. These findings are 
composition, and are 
ed for allopurinol, the 
nts and dogs, but not in 
the volume of urine is 
man urine does not reach 
at treatment. Therefore, 
recommended for adult 
pecial populations, and 
cs (SmPC)/Investigator 
althy subjects, where it 
the 24-hour urinary uric 
effects seemed to reach 
nsumption, age and sex 
be clinically significant 
ed in adult patients with 
lind, placebo-controlled 
ACT (Febuxostat versus 
(n= 760) [24]; APEX 
28-week, double-blind, 
e Extension Long-term 
d APEX (n= 735) [26]; 
erum urate), a phase III, 
ose-response and FACT 
X included patients with 
addition, the long-term 
at Open-label of Urate-
extension of the dose-
han placebo at reducing 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
sUA levels. After 4 weeks of trea
120 mg/day versus placebo had s
Furthermore, febuxostat had sign
FACT [24] and the APEX [25] tr
superiority of both the febuxostat
allopurinol 300/100 mg (22%) gro
(proportion of subjects with last 3
120 mg group was statistically sig
urate-lowering effect (all treatmen
throughout the course of treatme
patients with mild or moderate re
mild or moderate hepatic impairm
and its oxidative metabolites [29].
Febuxostat was generally well tol
related adverse events were of mil
phase III trials on 1043 patients, 
abnormalities (3.5%), diarrhea (2
nausea and vomiting were more fr
The safety and efficacy of febux
intermediate to high risk for TL
parallel-group, comparative phas
randomized to receive febuxosta
chemotherapy. Study treatment 
allopurinol 200/300/600 mg or fi
primary endpoints, sUA area und
from baseline to Day 8 through an
Secondary endpoints included tre
safety. Results of the FLORENCE
over allopurinol in terms of reduct
endpoint for TLS and renal im
malignancies at intermediate to hi
sUA reduction compared to allop
FLORENCE trial [30] provided e
target population. No safety conc
These results showed that febuxos
Final Versi
Confidential 
Menarini Ricerche S.p.A
atment, a greater proportion of patients receivin
sUA levels <6.0 mg/dL (56%, 76%, 94% ver
nificantly greater urate-lowering efficacy than 
rials. Indeed, in these phase III pivotal studies,
80 mg (51%) and 120 mg (63%) treatment gro
oup were demonstrated with respect to the pri
3 serum urate levels <6.0 mg/dL). The respons
gnificant greater compared to that in the febux
nt groups) was observed by week 2 of therap
ent [24, 26]. Dosage adjustment of febuxost
enal impairment, and there was no statisticall
ment on the pharmacokinetics of multiple-dose 
 
lerated in patients with gout and hyperuricem
ld to moderate severity. In a pooled analysis o
the most commonly reported adverse events w
2.7%), headache (1.8%), nausea (1.7%), and 
requent in patients treated concomitantly with c
xostat over allopurinol in patients with hemat
LS was investigated in the multicenter, doub
se III pivotal study FLORENCE [30]. Over
at or allopurinol for 7-9 days, starting 2 d
was blinded, while daily dose (low/sta
xed febuxostat 120 mg) depended on Investig
der curve (AUC sUA1-8) and serum creatinine 
nalysis of covariance with two-sided overall si
eatment responder rate, laboratory and clinic
E study [30] provided clear evidence of the su
tion of the exposure to sUA (p < 0.0001), a we
mpairment, in patients undergoing chemothe
igh risk of TLS. Noteworthy, febuxostat achiev
purinol since the first 24 hours of treatment. M
evidence that febuxostat is active in preservin
cerns raised from febuxostat in comparison to
stat is a more effective treatment alternative to
Study Code FLO-02
ion 1.0, 12 April 2016
Page 41 of 124 
ng febuxostat 40, 80 or 
rsus 0%; all p< 0.001). 
allopurinol in both the 
 the non-inferiority and 
oups compared with the 
imary efficacy endpoint 
se rate in the febuxostat 
ostat 80 mg group. The 
py and was maintained 
tat was not required in 
ly significant effects of 
febuxostat 80 mg daily 
mia and most treatment-
of the FACT and APEX 
were liver function test 
rash (1.5%). Diarrhea, 
colchicines. 
tologic malignancies at 
ble blind, randomized, 
rall, 346 patients were 
days prior to induction 
andard/high containing 
gator’s choice. The co-
change, were assessed 
ignificance level of 5%. 
cal TLS incidence, and 
uperiority of febuxostat 
ell established surrogate 
erapy for hematologic 
ved a significant higher 
Moreover, results of the 
ng renal function in the 
o allopurinol treatment. 
allopurinol in reducing 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
the risk of TLS and renal events i
of TLS, also providing the advant
in case of renal impairment. 
Globally the post-marketing expo
20 April 2015 was 1.781.064 p
marketing solicited sources were r
safety concerns, no changes in 
significant new information on
experiences in special patient grou
information that could alter the co
was collected [31]. 
6.3 RISK-BENEFIT ASSESSM
Febuxostat is approved in the Eur
mg once a day, while the 120 mg 
the prevention and treatment o
hematologic malignancies at int
participating to the present trial c
whereas the pediatric population w
into account the following evidenc
 1) TLS is a life-threatening co
malignancies are typically highly 
may be strongly effective for the
therefore essential to protect childr
worth noting that at the moment 
Europe. The present study is pa
Pediatric Committee of the EMA 
2) A specific toxicology program
development [17]. In both adul
obstructive nephropathies due to t
consequence of species-specific 
relevance for febuxostat clinical
expected at the febuxostat dose l
adolescents from 6 to 17 years of a
3) Febuxostat efficacy in the pr
Final Versi
Confidential 
Menarini Ricerche S.p.A
n patients with hematologic malignancies at in
tage of a fixed once daily dose without the nee
osure to febuxostat during the reporting period
patient-years. A total of 1.435 ADRs from 
reported. The review of interval and cumulativ
characteristics of ADRs or increase in re
n drug interactions, experiences during pr
ups, effects of long term treatment, or prescrip
onsolidated clinical benefit of febuxostat in th
MENT 
ropean Union for the treatment of gout at dos
strength has recently received marketing appr
of hyperuricemia in adult patients undergo
termediate to high risk of TLS. Therefore
can benefit from an early access to an effect
will be exposed to potential risk, which can be
ces: 
ndition that may occur rapidly in children. 
y proliferative and highly chemosensitive. Thu
em, it may also determine massive TLS wit
dren with the best available and more suitable th
an oral age-appropriate formulation of allopur
art of the febuxostat Pediatric Investigational
[32] and endorsed by the EMA [17].  
m has been run to fulfill the requirements of t
lt and juvenile rats, dose-limiting toxicities 
the precipitation of xanthine in urine. These fin
purine metabolism and urine composition, a
l development. Indeed, the formation of xa
levels recommended for adult humans and n
age. 
revention/treatment of hyperuricemia in adu
Study Code FLO-02
ion 1.0, 12 April 2016
Page 42 of 124 
ntermediate to high risk 
ed for dose adjustments 
d from 21 April 2014 to 
spontaneous and post-
ve data revealed no new 
eporting frequency, no 
regnancy or lactation, 
ption errors. Overall, no 
he approved indications 
ages of 80 mg and 120 
roval by the  EC [8] for 
oing chemotherapy for 
, the adult population 
ive and safe treatment, 
e considered low taking 
Children hematologic 
us, while chemotherapy 
th fatal outcomes. It is 
herapeutic strategy. It is 
rinol is not available in 
l Plan agreed with the 
the febuxostat pediatric 
were associated with 
ndings are considered a 
and are deemed of no 
anthine crystals is not 
neither for children and 
ult patients undergoing 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
chemotherapy for hematologic m
proven by the FLORENCE study
prevention and treatment of hyper
II: EU SmPCs for adenuric® ). 
4) Febuxostat safety profile in ad
the clinical development for the
febuxostat dose; more than 2500 
febuxostat 120 mg; and the m
approximately 350 and 400 days
doses of 80 mg, 120 mg and 240 
(ADRs) were mostly mild or m
confirmed the safety of febuxo
FLORENCE study [30] comparin
adult patients with hematologic m
exposed to febuxostat 120 mg fo
from febuxostat treatment. Adve
allopurinol (6.4%) and, noteworth
serious ADRs, nor study drug-rel
5) The pediatric febuxostat doses
were considered to be safe (i.e., 
dose in previous clinical studies), 
adults was effective in controlling 
6) In order to reduce any risk or di
a population PK design allowing t
Finally, the potential risk for the 
estimated low, also considering th
age group, while the expected ben
the TLS diagnosis and managem
reduction of sUA levels obtaine
expected to be confirmed in the p
explore the PK/PD profile of feb
possibly define the best dose, in
adolescents, while avoiding/minim
as per guideline CHMP/EWP/147
Final Versi
Confidential 
Menarini Ricerche S.p.A
malignancies at intermediate to high risk of
y [30] and febuxostat 120 mg strength was rec
ruricemia in this patient population (ADENU
dults has been broadly explored in the gout a
e gout indication, more than 4000 subjects
subjects were exposed to febuxostat 80 mg, 
mean duration of dosing in the 80 mg and
s, respectively. Febuxostat was safe and gene
mg (two times the maximum clinical dose). A
moderate in severity. The worldwide post-
ostat in the gout and adult TLS setting [
ng febuxostat to allopurinol for the preventio
malignancies at intermediate to high risk for T
or a mean time of approximately 7 days. No 
erse drug reactions (ADRs) occurred with t
hy, all febuxostat ADRs were mild or moder
lated deaths occurred.  
were selected based on predicted exposures (
exposure not greater than that observed in ad
and efficacious (i.e., febuxostat exposure follo
g sUA levels throughout the chemotherapy treat
iscomfort associated with blood sampling in ch
to minimize the number of blood samples has b
pediatric population associated with the partic
he sequential administration of the two differe
nefit is predicted to be quite relevant. In fact, n
ment are present between adults and child
ed by febuxostat in comparison to allopurin
pediatric population. The present PK/PD stud
buxostat in the pediatric population in compa
n terms of safety and efficacy, to be admini
mizing inappropriate exposure to non efficacio
7013/2004 [33].  
Study Code FLO-02
ion 1.0, 12 April 2016
Page 43 of 124 
f TLS was extensively 
cently approved for the 
URIC® SmPC Appendix 
and TLS experience. In 
 received at least one 
and more than 1000 to 
d 120 mg groups was 
erally well tolerated at 
Adverse drug reactions 
-marketing experience 
[31]. In the phase III 
on of hyperuricemia in 
TLS, 173 patients were 
safety concerns raised 
the same incidence of 
ate in severity. Neither 
(Cmax and AUC) which 
dults receiving 240 mg 
owing a 120 mg dose to 
tment period). 
hildren and adolescents, 
been adopted. 
cipation to this study is 
ent treatment doses per 
no major differences in 
dren, thus the superior 
nol in adults is highly 
dy has been designed to 
arison to adults, and to 
istered to children and 
ous/non safe treatment, 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
7. STUDY OBJECTIV
7.1 PRIMARY OBJECTIVE 
The primary objectives of this tria
 To assess the pharmacoki
and in adults suffering fro
 To compare the febuxosta
achieved in adults admini
7.2 SECONDARY OBJECTIV
The secondary objectives of this tr
 To compare the pharmac
years of age) and adults.
 To evaluate and compare
years of age) and adults.
 To evaluate the safety o
adults. 
 To evaluate the occurrenc
to Cairo and Bishop Crite
 To assess the age-appropr
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
VES  
al are: 
inetics (PK) of febuxostat in pediatric patient
om hematological malignancies at intermediat
at exposure in pediatric patients (≥6<18 year
istered with a dose of 120 mg/QD. 
VES 
rial are:  
codynamics (PD) of febuxostat between ped
e the PK/PD relationship of febuxostat in ped
f febuxostat between pediatric patients (≥6<
ce of Laboratory TLS (LTLS) and Clinical T
eria (see Appendix I: Definition of LTLS and 
riate formulation acceptability in children.  
Study Code FLO-02
ion 1.0, 12 April 2016
Page 44 of 124 
ts (≥6<18 years of age) 
te to high risk of TLS. 
rs of age) with the one 
diatric patients (≥6<18 
diatric patients (≥6<18 
<18 years of age) and 
TLS (CTLS) according 
CTLS). 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8. INVESTIGATION
8.1 OVERALL STUDY DESIG
This trial is designed as an op
approximately 40 sites. A total of
age-cohorts: 48 children (aged 6 t
[1] and 24 adults, suffering from h
no access to rasburicase, and sche
of line of treatment. The evaluati
Cairo and co-workers and publish
III: TLS Risk Assessment. 
Potential hematologic patients at i
Screening Visit, which should be 
the Start of Treatment (Day -9 to 
days prior to the planned start of 
coincide. 
After confirmation that all inclusi
receive oral administration of the
- 
Children  
Cohort 1: 40 mg once daily; 
Cohort 2: 60 mg once daily. 
- 
Adolescents  
Cohort 3: 80 mg once daily; 
Cohort 4: 120 mg once daily. 
- 
Adults  
120 mg once daily. 
The two dose levels per children
The first ≈24 children will receive
dose of 80 mg once daily. After
children, and 120 mg once daily 
simultaneously. The control group
parameters between the pediatric (
The final total number of patient
Final Versi
Confidential 
Menarini Ricerche S.p.A
NAL PLAN 
GN AND PLAN DESCRIPTION 
pen label, multi-centre, parallel group study
f 120 patients are expected to be treated in th
to less than 12 years), 48 adolescents (aged 12
hematological malignancies at intermediate to
eduled to receive the first cycle of cytotoxic ch
ion of TLS risk will be based on the classific
hed in the British Journal of Haematology [4], a
intermediate to high risk of  TLS will be asses
held up to 1 week (+2 days of accepted timef
Day 1). The Start of Treatment (Visit 1, Day
f first chemotherapy cycle; Screening Visit an
ion and none of the exclusion criteria are met
e following dose of febuxostat per age group:
n and adolescent groups will be sequentially a
e the lower dose of 40 mg once daily and the fi
rwards, the higher doses will be administered
y to adolescents. Cohort 1, Cohort 3 and adul
p of adult patients has been chosen to allow the
(≥6<18 years) and the adult populations.  
ts/patients distributed in each age/dose cohort
Study Code FLO-02
ion 1.0, 12 April 2016
Page 45 of 124 
y to be conducted in 
his trial distributed in 3 
2 to less than 18 years) 
o high risk of TLS, with 
hemotherapy regardless 
cation model issued by 
as reported in Appendix 
ssed for eligibility at the 
frame window) prior to 
y 1) will be scheduled 2 
nd Visit 1 (Day 1) may 
t, eligible patients will 
administered to cohort. 
first ≈24 adolescents the 
d: 60 mg once daily to 
lts treatments will start 
e comparison of PK/PD 
t might slightly deviate 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
from the planned number since p
treated. 
Treatment will start two days prio
9 consecutive days, on the basis o
Follow Up/End of Study Visit (V
(±2 days of accepted timeframe).
Overall, the study will include 10
treatment duration: 
Screening Visit (Day -9 to Day 1)
NOTE: re-screening will be allow
maximally re-screened once. 
Visit 1 (Day 1): Start of Treatmen
Visit 2 (Day 2) to Visit 7 (Day 7): 
Visit 8 (Day 8): Evaluation Visit 
Visit 9 (Day 9): Optional, in case o
Visit 10 (Day 14±2): Follow-Up/E
Regardless of the selected hypour
the primary endpoints will start a
terminate after seven days of hy
chemotherapy initiation. 
The average duration of each patie
8.2 DISCUSSION OF STUDY 
The present phase I/II trial has b
available scientific guidelines and
phase III FLORENCE study [30]
inappropriate exposure to non eff
guideline CHMP/EWP/147013/20
The study outline was part of th
Pediatric Committee of the Europe
The primary objective of this pha
Final Versi
Confidential 
Menarini Ricerche S.p.A
patients who satisfactory passed the screenin
r to the planned beginning of chemotherapy an
of chemotherapy duration that will be decided
Visit 10, Day 14±2 days) will be performed for
0 to 11 pre-planned visits, depending on the 
wed but requires sponsor/medical monitor’s ap
nt 
Treatment Period 
of prolonged treatment 
End of Study Visit 
ricemic treatment duration, the treatment perio
at Visit 1 (Day 1), corresponding to the patie
ypouricemic treatment, which is expected to b
ent participation in this trial will be of approxim
DESIGN, INCLUDING THE CHOICE OF C
been designed taking into account the releva
d recommendations, standard clinical practice
] in adults. The study has been designed in o
ficacious/non safe febuxostat doses in the pedi
004 [33].  
he febuxostat Pediatric Investigational Plan
ean Medicines Agency [32] and endorsed by th
ase I/II study is to assess the pharmacokinetic
Study Code FLO-02
ion 1.0, 12 April 2016
Page 46 of 124 
ng have the right to be 
nd will continue for 7 to 
d by the Investigator. A 
r each patient at Day 14 
selected hypouricemic 
pproval. A patient may 
od for the assessment of 
ent’s baseline, and will 
be five days following 
mately 3 weeks.  
CONTROL GROUP 
ant published literature, 
e and the results of the 
order to avoid/minimize 
iatric population, as per 
(PIP) agreed with the 
he EMA [17]. 
s (PK) of febuxostat in 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
pediatric patients (≥6<18 years of 
selected doses is comparable to th
secondary objectives are to comp
febuxostat between pediatric pa
encompasses approximately 24 pa
patients in the adults group. Th
resembles that already successfull
two different febuxostat dosages,
that seen with 240 mg once daily 
allow a PK study of febuxostat in 
The pharmacokinetic of febuxosta
in patients with hyperuricemia and
PK analyses in patients are consist
subjects are representative for PK
analyses in special populations d
mild or moderate renal impairmen
weight and gender on febuxosta
suggesting no need of dose adjus
were taken into account to op
CHMP/EWP/147013/2004 [33]. A
adolescent patients is expected t
pharmacokinetics of children aged
To resemble the FLORENCE s
hematological malignancies who 
of the line of treatment, and at inte
receive treatment for 7 to 9 consec
adolescents will be administered o
and 80 or 120 mg for adolescents.
and adolescents will be sequentia
3). The first ≈24 children will rece
the dose of 80 mg once daily. Aft
children and 120 mg once daily to
the treatment schedule previously 
to the enrolment of patients w
chemotherapy regimen with the ex
Final Versi
Confidential 
Menarini Ricerche S.p.A
f age) in order to ascertain that the systemic exp
hat achieved in adults administered with a do
pare the pharmacokinetic/pharmacodynamics 
atients (≥6 and <18 years) and adults. The
atients per treatment dose in children and adole
he choice of the 120 mg once daily febuxo
ly and safely used in the phase III FLORENC
 both expected to result in an exposure to feb
in adults, will be tested in each pediatric subse
the target population. 
at has been extensively investigated both in adu
d gout. In general, febuxostat PK parameters e
tent with those obtained from healthy subjects
K assessment in the patient population with 
demonstrated that dosage adjustment is not re
nt [29]. The investigation on the influence of 
at PK, PD and safety were considered not 
stment based on these parameters in adult pa
ptimize the sample size of the present stu
According to the PK profile of febuxostat, th
to be similar to the one in adults, whilst m
d 6 to 11 years are expected.  
study outline [30] and the future clinical p
are scheduled to be treated with cytotoxic ch
ermediate to high risk of TLS, will be screene
cutive days, starting from 2 days prior to chem
one out of the two dose levels of febuxostat, 40
. As for an extreme cautious approach, the two
ally administered (Cohort 2 after Cohort 1 and
eive the lower dose of 40 mg once daily, and th
fterwards, the higher doses will be administere
o adolescents. Adults will receive 120 mg once
adopted in the FLORENCE study [30]. No re
with different types of hematological mal
xception of those including investigational pro
Study Code FLO-02
ion 1.0, 12 April 2016
Page 47 of 124 
posure attained with the 
ose of 120 mg/QD. The 
(PK/PD) and safety of 
e required sample size 
escents groups, and ≈24 
ostat dosage for adults 
CE study [30], whereas 
buxostat not exceeding 
et of patients in order to 
ult healthy subjects and 
estimated by population 
, indicating that healthy 
gout. Pharmacokinetic 
equired in patients with 
covariates such as age, 
clinically meaningful, 
atients [22]. These data 
udy, as per guideline 
he pharmacokinetics in 
minor differences in the 
practice, patients with 
hemotherapy, regardless 
ed. Eligible patients will 
motherapy. Children and 
0 or 60 mg for children, 
o dose levels in children 
d Cohort 4 after Cohort 
he first ≈24 adolescents 
ed: 60 mg once daily to 
e daily in accordance to 
striction will be applied 
lignancies, nor to the 
oducts. The inclusion of 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
patients with hematological malig
appropriate considering the results
be included only providing that th
would be otherwise treated with al
8.3 SELECTION OF STUDY P
After providing informed consent,
inclusion and exclusion criteria th
them at Visit 1 (Day 1). Patients 
8.3.1) and any of the exclusion cri
8.3.1 Inclusion criteria 
male and female children
years of age and adults fro
a. scheduled for first
because of hemato
b. at intermediate or 
c. with serum uric ac
d. with no access to r
Final Versi
Confidential 
Menarini Ricerche S.p.A
gnancies at intermediate to high risk of deve
s of the FLORENCE study [30] and that patien
hey either have no access or have contraindicat
llopurinol. 
POPULATION 
, the eligibility of patients to enter this study w
hat will be checked at Screening Visit (Day -9 
will be included only if they meet all inclusi
iteria (see section 8.3.2). 
n of 6 to less than 12 years of age, adolescent
om 18 years: 
t cytotoxic chemotherapy cycle, regardless o
ologic malignancies, and  
high risk of TLS [4], and 
cid (sUA) levels < 10 mg/dL at Visit 1 (Day 1
rasburicase; 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 48 of 124 
eloping TLS is deemed 
nts at high TLS risk will 
tions to rasburicase, and 
ill be assessed based on 
to Day 1) and some of 
ion criteria (see section 
ts of 12 to less than 18 
f the line of treatment, 
1), and 
            


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.3.2 Exclusion criteria 
1. patients known to be hyp
formulation; 
6. patients with severe renal in
7. patients with severe hepatic 
8. patients with diagnosis of L
8.3.3 Withdrawal of patien
Participation in the study is strictl
any time for any reasons without 
care. Patients may also be withdra
any time.  
Patients should not receive furth
termination) in case of medical em
• adverse events with a possible
severity grade ≥3 CTCAE ver
• appearance of skin rash or o
(NOTE: in case of severe alle
patients at any time; for gu
Final Versi
Confidential 
Menarini Ricerche S.p.A
persensitive to febuxostat or to any of th
nsufficiency; 
insufficiency; 
Laboratory TLS (LTLS) or Clinical TLS (CTL
nts from therapy or assessment 
ly voluntary and patients have the right to with
giving explanation. This will not affect their ri
awn at the Investigator's discretion or at specif
her study medication and will be withdrawn 
mergency or necessity including but not limited
e, probable or certain drug-causality as per Inv
sion 4.03; 
of any signs which may indicate allergic/hyp
ergic/hypersensitivity reactions, febuxostat m
uidance please refer to the EU SmPC, Ap
Study Code FLO-02
ion 1.0, 12 April 2016
Page 49 of 124 
he components of the 
LS) at Visit 1 (Day 1). 
hdraw from the study at 
ights for future medical 
fic Sponsor’s request at 
from the study (study 
d to: 
vestigator's judgment of 
persensitivity reactions 
must not be re-started in 
ppendix III: TLS Risk 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Assessment); 
• severe hepatic insufficiency;
• severe renal insufficiency; 
• investigator’s judgment if tre
safety. 
• protocol violation (e.g. prohibi
• patient’s request. 
In the event that the patient is wit
informed immediately and the
discontinuation will be document
the eCRF. 
Any patient who is discontinued
undergo the procedures required
discontinuation. The safety Follow
well, according to protocol sched
AE or for any safety reasons, th
necessary) according to the med
resolved or the Investigator dee
indicated. 
If a patient prematurely terminate
purpose of the study. In regard t
samples already obtained but not y
 
8.4 IDENTITY OF THE INVE
8.4.1 Description of Invest
 
INN (if applicable) 
 
Chemical Name (if 
applicable) 
Doses: 
40 mg/da
Dosage form 
20 mg or
80 mg or
Final Versi
Confidential 
Menarini Ricerche S.p.A
eatment discontinuation is considered in the i
ited medication, poor compliance with study p
thdrawn from the study for whatever reason, th
e date, reasons (if known), and circums
ted in the source patient’s record and in the co
d from the treatment for one of the above re
d for Visit 8-Evaluation (see section 8.6.1.6)
w Up/End of Study (Visit 10, Day 14±2 days)
dule (see section 8.6.1). If study participation 
he patient has to be followed-up (with addi
dical judgment of the Investigator, until the 
ems further observations or examinations as
es the study, data already collected will be use
to biological samples already collected, the p
yet analysed shall be destroyed or analysed.  
ESTIGATIONAL PRODUCT  
tigational Medicinal Product 
ay, 60 mg/day, 80 mg/day, 120 mg/day. 
ral film coated tablet, 
ral film coated tablet, 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 50 of 124 
interest of the patient’s 
procedures/treatment); 
he Investigator must be 
stances for premature 
orresponding section of 
eported reasons should 
 immediately after the 
should be performed as 
is terminated due to an 
itional examinations, if 
abnormal condition is 
s no longer medically 
ed and analysed for the 
patient will be asked if 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
120 mg o
8.4.2 Packaging, labeling, 
The packaging and labeling of IM
Pharmaceutical Development, A. 
12489 Berlin, Germany. 
The febuxostat film coated tablets
foil (OPA 25 µm / Al 45 µm / PV
foil with heat seal lacquer), synony
The febuxostat film coated tablet
(polychlorotrifluoroethylene) / PV
sealed with a 20 µm lacquered pus
The IMP will be provided in treat
1). The blisters (primary packagin
For the 40 mg dose cohort, the bl
tablets of 20 mg daily intake, med
For the 60 mg dose cohort, the bl
tablets of 20 mg daily intake, med
For the 80 mg dose cohort, the bl
tablet of 80 mg daily intake, medic
For the 120 mg dose cohort and a
coated tablets (120 mg) (1 tablet o
Labeling: the IMP will be labeled
national requirements. The treatm
be attached to the corresponding s
peel-off part reports the treatment
fixed section of the label will re
administer and store the IMP. 
Storage: at the study site, the IM
storage recommendations are in p
original package”. The IMP must 
unauthorized individuals. 
Final Versi
Confidential 
Menarini Ricerche S.p.A
oral film coated tablet. 
and storage 
MP will be performed under the responsibility
Menarini Research & Business Service GmbH
s (20 mg) are packed in blisters consisting of 
VC 60 µm) sealed with rigid aluminium foil (
ym: Al-Al blisters. 
s (80 mg and 120 mg) are packed in blisters 
VC based film lamination (ACLAR RX-160 
sh through aluminium foil. 
tment boxes (blister cards) to be dispensed sta
ng) will be permanently fixed in blister cards (s
lister cards will contain 28 febuxostat film co
dication for 14 days incl. surplus). 
lister cards will contain 42 febuxostat film co
dication for 14 days incl. surplus). 
lister cards will contain 14 febuxostat film co
cation for 14 days incl. surplus). 
adult treatment group, the blister cards will con
of 120 mg daily intake, medication for 14 days 
d in compliance with the current valid internati
ment box (blister card) labels will have a peel-o
section in the drug accountability log upon disp
t box number to identify the treatment as assig
eport the contents of the treatment box and t
MP has to be stored at controlled room temp
place: “Do not store below 15°C and above 25
be kept in a secure area, out of reach of child
Study Code FLO-02
ion 1.0, 12 April 2016
Page 51 of 124 
y of the Department of 
H, Glienicker Weg 125, 
a laminated aluminium 
(20 µm hard aluminium 
consisting of a PCTFE 
15 µm / PVC 250 µm) 
arting from Visit 1 (Day 
econdary packaging).  
oated tablets (20 mg) (2 
oated tablets (20 mg) (3 
oated tablets (80 mg) (1 
ntain 14 febuxostat film 
incl. surplus). 
onal and corresponding 
off section which has to 
pensing of the IMP. The 
gned through IxRS. The 
the instructions how to 
perature. The following 
5 °C” and “Store in the 
dren and inaccessible to 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.4.3 Drug accountability 
Upon receipt of all IMP, study si
stated on the enclosed shipping for
The IxRS will be used to record th
each patient, including dates, qu
numbers assigned to the IMP (trea
The Investigator will be respons
entering the treatment box numb
administered to in- as well as out
any used/unused IMP will be rec
form.  
8.4.4 Destruction of surplu
At the end of the study, all re
Investigator at the site. The IMP 
Development, A. Menarini Resear
8.5 TREATMENTS  
8.5.1 Treatment Allocation
The study will be performed accor
Eligible patients will receive stud
drug administration” procedures a
The IMP box assignment will be 
any randomized allocation. The f
≈24 children to the 60 mg dose. 
following  ≈24 adolescents to the 
For children, the 20 mg febuxosta
product ADENURIC® 80 mg and 
Table 1
Patient Population
Children 
Adolescents 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
ite personnel will open the shipment package
rm, and confirm the receipt through IxRS. 
he IMP delivery to the study site, the inventor
uantities, batch/serial numbers, expiry dates,
atment box number) and patients (patient numb
sible for documenting the dispensing of the 
ber in the source document and in the eCRF 
t-patient regimen. Furthermore, the number o
corded by the Investigator in the study speci
us medication 
emaining IMP will be reconciled under the
will be subsequently returned to the Departm
rch & Business Service GmbH or appointed de
n 
rding to an open design; no blinding technique
dy treatment at Visit 1 (Day 1) after completin
and re-checking of the eligibility criteria.  
performed by means of the IxRS system (see 
first ≈24 children will be allocated to the 40 m
The first ≈24 adolescents will be allocated t
120 mg dose. The ≈24 adults will be allocated 
at tablets will be used, whereas for adolescent
120 mg will be employed as represented below
1. Febuxostat: Treatment dose and form 
n 
Treatment dose 
Treatment
febuxostat 40 mg 
2 tablets 2
febuxostat 60 mg 
3 tablets 2
ADENURIC® 80 mg 
1 tablet 8
Study Code FLO-02
ion 1.0, 12 April 2016
Page 52 of 124 
e, verify the contents as 
ry at the site, the use by 
, and the unique code 
ber). 
IMP to the patient by 
when the treatment is 
of tablets dispensed and 
ific drug accountability 
e responsibility of the 
ment of Pharmaceutical 
epots. 
e will be adopted.  
ng the relevant “prior to 
section 10.1.2) without 
mg dose, the following 
to the 80 mg dose, the 
to the 120 mg dose. 
ts and adults the market 
w: 
t form 
20 mg 
20 mg 
80 mg 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Adults 
 
8.5.2 Treatment administr
Eligible patients will receive oral
- 
Children  
Cohort 1: 40 mg once daily; 
Cohort 2: 60 mg once daily. 
- 
Adolescents  
Cohort 3: 80 mg once daily; 
Cohort 4: 120 mg once daily. 
- 
Adults  
120 mg once daily. 
Minimum treatment duration will 
prior to the planned start of first c
prolong the treatment duration up
the patient.  
8.5.3 Treatment complian
The study treatment will be dispe
7) at the site by the Investigator.
duration up to 9 days on the basis 
The Investigator will be responsi
entering the treatment box numb
administered to in- as well as o
used/unused IMP will be recorde
including dates, quantities, batch/
to the IMP (treatment number) and
8.5.4 Dosage modification 
No dose adjustment is allowed. 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
ADENURIC® 120 mg 
1 tablet 12
ADENURIC® 120 mg 
1 tablet 12
ration - frequency and duration of ap
l administration of the following dose of febu
be of 7 days starting from Visit 1 (Day 1), w
chemotherapy cycle. The Investigator will be 
p to 9 days on the basis of the chemotherapy re
ce 
ensed at each study visit starting from Visit 1 (
. The Investigator will be given the possibilit
of the chemotherapy regimen chosen. 
ible for documenting the dispensation of the 
ber in the source document and in the eCRF 
out-patients. Furthermore, the number of tabl
ed by the Investigator in the study specific dru
/serial numbers, expiry dates, and the unique 
d patients (patient number). 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 53 of 124 
20 mg 
20 mg 
pplication 
uxostat per age group: 
which shall occur 2 days 
given the possibility to 
egimen administered to 
(Day 1) to Visit 7 (Day 
ty to prolong treatment 
IMP to the patient by 
when the treatment is 
lets dispensed and any 
ug accountability form, 
code numbers assigned 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.5.5 Concomitant Medica
Patients are not allowed to receive
 
any other investigational a
 
any other hypouricemic ag
 
mercaptopurine/azathiopri
In case of concomitant use of the
monitoring is recommended durin
to be controlled. 
Concomitant and prior (i.e. within
because the use of the above rep
patient eligible to participate in th
and occasional use of any conco
until the final Follow Up/End of S
Patients have to receive adequate
recommended according to TLS m
Concomitant and prior (i.e. within
8.6 STUDY PROCEDURES A
8.6.1 Study Schedule 
A maximum of 11 study visits ar
(see section 2.1) and summarized
Starting from Start of Treatment 
must be performed daily; an additi
days of treatment, upon Investiga
in-hospital or as ambulatory visits
The Follow up/End of Study Visit
The treatment period can last fr
chemotherapy regimen administe
endpoints will be collected during
8, Day 8). Each patient will comp
10, Day 14 ± 2 days). 
A summary of the study assessme
Final Versi
Confidential 
Menarini Ricerche S.p.A
ation 
e: 
agent  
gent, such as allopurinol, rasburicase or proben
ine. 
eophylline in patients receiving febuxostat 120
ng the treatment period. In particular, theophy
n 30 day before Visit 1, Day 1) medications sha
ported medications may represent an exclusion
he study and to receive the study treatment. F
mitant medication has to be recorded starting
Study Visit (Visit 10, Day 14±2 days). 
e hydration: increased hydration ranging from 
management guidelines. 
n 30 day before Visit 1, Day 1) medications wil
AND ASSESSMENTS 
re scheduled including Screening, as depicted 
below. 
(Visit 1, Day 1) to the Evaluation Visit (Vis
ional visit can be scheduled on Day 9 (Visit 9)
ator’s decision to prolong the treatment duratio
, according to the local clinical practice. 
t is scheduled at Day 14 (± 2 days). 
rom 7 to 9 days, evaluated by the Investiga
ered to the patient. All assessments that are
g the treatment period (Day 1-Day 7) and at the
plete the study at the time of the Follow up/En
ents at each visit is specified below. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 54 of 124 
necid; 
0 mg strength, a careful 
ylline blood levels have 
all be carefully checked 
n criterion to make the 
Furthermore, the regular 
g from Screening Visit 
2 to 3 L/m2 per day is 
ll be recorded in eCRF. 
in the study flow chart 
sit 8, Day 8), site visits 
 for patients requiring 9 
on. Visits may occur as 
ator on the base of the 
e relevant to the study 
e Evaluation Visit (Visit 
nd of Study Visit (Visit 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Written informed consent shall be
local regulations) or by legal g
procedures. 
8.6.1.1 Screening Visit (Day -9
Potentially eligible patients w
chemotherapy cycle will undergo 
 assessment of inclusion/ex
 demographic data collectio
 medical history; 
 prior and concomitant med
 physical examination and
[BR], body temperature [T
 Karnofsky performance sta
 12 Lead ECG; 
 blood sampling and urine
applicable); 
 record of adverse events. 
NOTE-1: Study procedures under
NOTE-2: Results of safety labor
pregnancy test, when appropriate)
patient’s management can be reco
they have been done within 24 hou
NOTE-3: Re-screening is allowe
maximally be re-screened once. 
8.6.1.2 Visit 1, Start of Treatm
Start of Treatment Visit will be p
Start of Treatment Visit, the follow
Prior to the drug administration: 
Final Versi
Confidential 
Menarini Ricerche S.p.A
e provided by adult patients or by parents (on
guardian for children and adolescents, PRIO
9 to Day 1) 
with hematological malignancies scheduled
the following procedures: 
xclusion criteria; 
on; 
dication; 
vital signs (i.e. blood pressure [BP], heart ra
T]); 
atus (KPS) / Lansky Play performance status (
e collection for safety laboratory tests, includ
r Screening Visit may occur also on more than 
ratory tests (biochemistry, haematology, coag
) and ECG which have been performed in the 
orded in the e-CRF under Screening Visit pro
urs prior to the Screening Visit (Visit 1, Day 1)
ed but requires sponsor/medical monitor’s ap
ment (Day 1) 
performed 2 days prior to the scheduled che
wing procedures will be performed: 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 55 of 124 
ne or both, according to 
OR to start any study 
d for first cytotoxic 
ate [HR], breathing rate 
LPS) evaluation; 
ding pregnancy test (if 
one day. 
gulation, urinalysis and 
context of the standard 
ocedures, provided that 
). 
pproval. A patient may 
emotherapy. During the 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 record of adverse events an
 re-check of inclusion/exclu
 physical examination and v
 KPS/LPS evaluation; 
 blood sampling and urine 
performed within 24 hours
 blood sampling for centra
centralized laboratory test 
reduce the patient’s discom
 assessment of LTLS/CTLS
 
allocation of investigation
Study drug administration: 
 administration of febuxos
After study drug administration: 
 assessment of the age-app
NOTE: Screening Visit and Visit 
performed only once. 
8.6.1.3 Visit 2 (Day 2) 
 record of adverse events an
 vital signs; 
 KPS/LPS evaluation; 
 pre-dose PK blood samplin
 blood sampling for safety 
 study drug administration;
 assessment of the age-appr
Final Versi
Confidential 
Menarini Ricerche S.p.A
nd change in concomitant medication; 
usion criteria and patient’s eligibility confirmat
vital signs; 
collection for safety laboratory tests (NOTE:
s do not need to be repeated at Visit 1, Day 1);
alized laboratory test (sUA); whenever possib
(sUA) will be collected in conjunction with sa
mfort of additional venopunctures; 
S; 
nal medicinal product (IMP) treatment box as
stat as per age group. 
propriate formulation acceptability (only for c
1 (Day 1) may occur on the same day. Comm
nd change in concomitant medications; 
ng; 
laboratory test, including centralized laborator
; 
ropriate formulation acceptability (only for chi
Study Code FLO-02
ion 1.0, 12 April 2016
Page 56 of 124 
tion; 
: safety laboratory tests 
ble blood sampling for 
afety laboratory tests to 
s per IxRS assignment. 
children). 
mon assessments will be 
ry test (sUA); 
ildren). 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.6.1.4 Visit 3 (Day 3) 
 record of adverse events an
 vital signs; 
 KPS/LPS evaluation; 
 12 Lead ECG; 
 pre-dose PK blood samplin
 blood sampling for safety 
 study drug administration;
 assessment of the age-appr
 assessment of LTLS/CTLS
 starting of chemotherapy r
8.6.1.5 Visits 4-7 (Days 4-7) 
On each day from Day 4 to Day 7
 record of adverse events an
 vital signs; 
 KPS/LPS evaluation; 
 pre-dose PK blood samplin
 blood sampling for safety 
 study drug administration;
 assessment of the age-appr
 4 additional post-dose PK
time intervals: 0.5-2 hours
 urine collection for safety 
 assessment of LTLS/CTLS
8.6.1.6 Visit 8 (Day 8) 
On Day 8, an Evaluation Visit wi
Final Versi
Confidential 
Menarini Ricerche S.p.A
nd change in concomitant medications; 
ng; 
laboratory test, including centralized laborator
; 
ropriate formulation acceptability (only for chi
S; 
regimen. 
7, the following assessments will be performe
nd change in concomitant medications; 
ng; 
laboratory test, including centralized laborator
; 
ropriate formulation acceptability (only for chi
K blood sampling ONLY at Day 7 (Visit 7) at
s, 2-4 hours, 4-6 hours and 6-8 hours; 
laboratory tests ONLY at Day 4 (Visit 4); 
S. 
ill be performed, including the following asse
Study Code FLO-02
ion 1.0, 12 April 2016
Page 57 of 124 
ry test (sUA); 
ildren); 
ed: 
ry test (sUA); 
ildren); 
t the assigned sampling 
essments: 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 record of adverse events an
 physical evaluation and vit
 KPS/LPS evaluation; 
 12 Lead ECG; 
 PK blood sampling (it 
hypouricemic treatment);
 blood sampling for safety 
 urine collection for safety 
 assessment of LTLS/CTLS
ONLY for patients scheduled to p
 study drug administration;
 assessment of the age-appr
8.6.1.7 Visit 9 (Day 9) 
To be performed ONLY for patie
 record of adverse events an
 vital signs; 
 KPS/LPS evaluation; 
 study drug administration;
 assessment of the age-appr
 blood sampling for safety 
8.6.1.8 Visit 10, Follow-up/En
A final safety Follow-up/End of S
 record of adverse events an
 physical examination and v
 KPS/LPS evaluation; 
 12 Lead ECG; 
Final Versi
Confidential 
Menarini Ricerche S.p.A
nd change in concomitant medications; 
tal signs; 
is a pre-dose PK sampling for patients
laboratory test including centralized laboratory
laboratory tests; 
S. 
prolong hypouricemic treatment: 
; 
ropriate formulation acceptability (only for chi
ents scheduled to prolong hypouricemic trea
nd change in concomitant medications; 
; 
ropriate formulation acceptability (only for chi
laboratory tests. 
d of Study (Day 14 ± 2) 
Study Visit will be performed at Day 14 (± 2)
nd change in concomitant medications; 
vital signs; 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 58 of 124 
scheduled to prolong 
y test (sUA); 
ildren). 
atment: 
ildren); 
: 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 blood sampling and urine c
 
8.6.2 Assessment of Pharm
8.6.2.1 Pharmacokinetic param
Pharmacokinetic parameters will
sampling model with nonlinear m
A list of parameters that can be e
2 below. Additional PK paramet
Methods for PK parameters estim
Ta
Cmax  
Maximum plasma con
Tmax  
Time to Cmax 
Vd/F  
Apparent volume of d
CL/F  
Apparent clearance 
Ka  
Absorption rate const
AUC(0-t) 
 
The area under the pl
last quantifiable conce
AUC(0-τ) 
The area under the p
where tau is the length
AUC(0-∞) The area under the pla
 
8.6.2.2 Sampling and handling
8.6.2.2.1 Drug assay 
In order to assess febuxostat pha
adolescent and adult patients, blo
after the first treatment administr
blood samples will be drawn at
additional blood samples are req
intervals: 0.5-2 hours, 2-4 hours, 
Final Versi
Confidential 
Menarini Ricerche S.p.A
collection for safety laboratory tests. 
macokinetics/Pharmacodynamics 
meters 
l be calculated from the plasma concentratio
mixed-effects modeling methods. 
estimated according to the PK structural mod
ters may be estimated 
mation are described in section 9.3.2. 
able 2. Pharmacokinetic parameters 
ncentration 
distribution 
tant   
lasma concentration versus time curve from 
entration 
plasma concentration versus time curve ove
h the dosing interval (24 hours) 
asma concentration versus time curve from ti
g of blood samples for drug assays 
armacokinetics following repeated dose adm
ood samples will be collected on Visits 2, 3
ration and on each following visit until the Ev
t trough together with the safety laboratory
quired for each patient on Visit 7 (Day 7) at
4-6 hours and 6-8 hours post study drug intak
Study Code FLO-02
ion 1.0, 12 April 2016
Page 59 of 124 
on data using a limited 
del are defined in Table 
time 0 to time of the 
r the dosing interval, 
ime zero to infinity  
ministration in children, 
, 4, 5, 6, 7 and 8 (i.e., 
valuation Visit). These 
y blood samples. Four 
t the selected sampling 
ke. 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.6.2.2.2 Analytical method
The concentrations of febuxosta
The method will be fully valid
guidelines and international regul
8.6.2.3 Centralized Laborator
At each Visit starting from Visi
laboratory test (sUA) will be used
will be collected in conjunction 
additional venopunctures. All sam
the serum shipped to be centrally a
Final Versi
Confidential 
Menarini Ricerche S.p.A
s 
at in plasma will be quantified using a 
 bioanalytical method by Menarini R
dated according to established Good Labor
latory recommendations. 
ry Evaluation for Pharmacodynamic Param
it 1 (Day 1) until Evaluation Visit (Visit 8,
d for pharmacodynamic parameter sUA. When
with safety laboratory tests to reduce the p
mples for centralized laboratory test will be pr
analyzed at the Central Laboratory. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 60 of 124 
-
Ricerche S.p.A. (Italy). 
ratory Practice (GLP) 
meter 
 Day 8), a centralized 
ever possible, sampling 
patient’s discomfort of 
rocessed at the site and 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 
8.6.3 Assessment of Safety
8.6.3.1 Medical History 
General medical history and ongo
Screening Visit in order to obtain 
study. 
General medical history will 
malignancy) and conditions, eith
criteria and those which are releva
The ongoing hematological malig
leukemia), the date of diagnosis an
8.6.3.2 Physical Examinations
A complete physical examination
Follow up/End of Study Visits. It
the following body areas: HEEN
Respiratory, Gastrointestinal, Neu
Vital signs will be recorded thro
measured: 
 Heart rate (HR, beats/min)
 Blood pressure (BP, systol
 Breathing rate (BR, breath
 Body Temperature (T, °C)
Final Versi
Confidential 
Menarini Ricerche S.p.A
y  
ing hematological malignancy medical history
all information necessary to confirm the inclus
include all the diseases (excluding the o
her chronic or not, which are needed to ass
ant according to the Investigator. 
gnancy medical history will include the type of
nd the presence or absence of renal dysfunction
s and Vital signs  
n will be performed at Screening, Start of Tre
t includes a general appearance observation an
NT/Neck, Lymph Nodes, Thyroid, Abdomen,
urological, Musculoskeletal/Extremities. 
oughout the study at each visit. The followi
); 
lic and diastolic, mmHg);  
hs/min); 
). 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 61 of 124 
y will be collected at the 
sion of the patient in the 
ongoing hematological 
ess inclusion/exclusion 
f tumor (i.e. lymphoma, 
n and/or involvement.  
atment, Evaluation and 
nd a complete exam of 
, Skin, Cardiovascular, 
ing parameters will be 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.6.3.3 Safety Laboratory Eva
Patient’s safety will be monitor
assessments shall include all par
Bishop Criteria (see Appendix I: D
Safety tests will be locally perform
The laboratory print-outs should b
and signed by the Investigator a
respective normal ranges as well 
value shall be clinically assessed
assessments for out of range value
The volume of blood to be drawn 
Urinalysis will be performed at S
test results shall be clinically asses
in eCRF. 
Tests are shown in Table 3. 
Table 3: Seru
SERUM CHE
Creatinine 
sUA 
Potassium 
Phosphorus 
Calcium 
BUN / Urea 
Albumin 
Alkaline phosphatase 
Amylase 
Glucose 
Total protein 
Total bilirubin and Dire
ALT and AST 
LDH 
GGT 
INR 
prothrombin time/proth
Sodium 
Chloride 
Beta-HCG (ONLY at S
applicable) 
CLcr calculation accord
Final Versi
Confidential 
Menarini Ricerche S.p.A
aluation 
red daily at each Visit through laboratory t
ameters for the evaluation of LTLS/CTLS, a
Definition of LTLS and CTLS). 
med in order to ensure prompt patient’s manage
be identified with the patient number. All prin
and filed in the patient’s record. The curren
as any update needs to be notified to the Spo
d by the Investigator. Safety laboratory resu
es will be recorded in eCRF. 
for each assay will amount to a maximum of 4
creening, Visit 1, Visit 4, Visit 8 and repeated
ssed by the Investigator and the only assessme
um, Blood and Urine Sample Analyte Listin
EMISTRY 
HEMATOLOGY 
UR
Haemoglobin 
pH 
Haematocrit 
Dens
RBC count 
 
Platelet count 
 
WBC count and  
(absolute and %): 
Nitri
neutrophil 
Prote
lymphocyte 
Gluc
eosinophil 
Keto
basophil 
RBC
monocytes 
WBC
ect bilirubin 
 
Epith
 
Casts
 
Bact
 
Yeas
 
Crys
hrombin activity 
 
 
 
 
 
 
creening if 
 
 
ESTIMATED PARAMETERS
ding to Cockcroft and Gault formula 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 62 of 124 
tests. Safety laboratory 
according to Cairo and 
ement. 
nt-outs should be dated 
nt valid version of the 
onsor. Any out of range 
ults as well as clinical 
4 ml. 
d at Visit 10. Urinalysis 
ents have to be recorded 
ng 
RINALYSIS 
sity 
ite 
ein 
cose 
ones 
C 
C 
helial cells 
s 
teria 
st 
stals 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
In order to guarantee the proper m
allowed anytime, upon Investigato
8.6.3.4 12 Lead ECG  
12 Lead ECG will be performed 
Visits: Screening Visit, Visit 3, Vi
Standard 12 Lead ECG will be p
identified with patient number, ye
All print-outs should be assessed
record. 
8.6.3.5 Performance Status ev
Performance Status (PS) evalua
Karnofsky PS scale will be used f
used for patients aged less than 
performance status scales). 
8.6.4 LTLS and CTLS Ass
Investigators will assess the occur
(Day 1) and then on each study v
8). The baseline assessment (Visit
to confirm the patient’s eligibility.
Investigators will follow the Cairo
CTLS for their evaluation; they w
record and report it in the relevant
8.6.5 Assessment of the ag
As per EMA guideline of August 
assessed through a 5-point hedon
immediately after drug intake as re
Final Versi
Confidential 
Menarini Ricerche S.p.A
management of the patient, any additional sam
or judgment.  
locally, using standard equipment available a
isit 8 and Visit 10. 
performed at rest in supine position. All EC
ar of birth, and gender, as well as with the date
d, dated and signed by the Investigator and 
valuation 
ation will be carried out throughout the stu
for patients aged 16 years and older; the Lansk
16 years [34-38]. (see Appendix IV: Karno
sessment 
rrence of LTLS and CTLS based on local lab
visit starting from Visit 3 (Day 3) until Evalua
t 1, Day 1) will be performed prior to the Star
. 
o and Bishop criteria reported in Appendix I: D
will document the occurrence of  LTLS and CL
t section of the eCRF. 
ge-appropriate formulation acceptabi
1st 2013[39], the acceptability of febuxostat tab
nic scale anchored with the word super bad 
eported below: 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 63 of 124 
mpling or examination is 
at site, at the following 
G print-outs should be 
e and time of recording. 
stored in the patient’s 
udy at each visit. The 
ky Play PS scale will be 
ofsky and Lansky Play 
boratory tests, at Visit 1 
ation Visit (Visit 8, Day 
rt of Treatment in order 
Definition of LTLS and 
LTS in patient’s medical 
ility 
blets in children will be 
d  and super good [40] 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.7 ADVERSE EVENT DEFIN
8.7.1 Definitions 
8.7.1.1 Adverse Event (AE) 
Any untoward medical occurrence
and which does not necessarily ha
An AE can therefore be any un
finding), symptom, or disease tem
not considered related to the medi
8.7.1.2 Drug Relationship 
The relationship between an AE a
1. Certain: The AE occurs 
cannot be explained by a
withdrawal of the drug 
definitive pharmacological
if necessary. 
2. Probable: The AE occurs
unlikely to be attributed t
clinically reasonable resp
reappearance after drug rei
3. Possible: The AE occurs w
could also be explained b
drug withdrawal (dechallen
4. Unassessable: The relatio
contradictory and cannot b
5. Unlikely: A causal relation
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
NITIONS, MONITORING/ RECORDING A
e in a patient or clinical trial subject administer
ave a causal relationship with this treatment. 
nfavorable and unintended sign (including a
mporally associated with the use of a medicin
cinal product. 
and study drugs will be judged according to the
in a plausible time relation to the administ
a concurrent disease or other drugs or chem
(dechallenge) should be clinically plausible
lly or phenomenologically, using a satisfactory
s in a reasonable time relation to the administ
to a concurrent disease or other drugs or chem
ponse on withdrawal (dechallenge). Rechall
introduction) is not required to fulfil this defini
with a reasonable time relation to the administr
by a concurrent disease or other drugs or che
nge) may be lacking or unclear. 
onship cannot be judged, because of the inform
be supplemented or verified. 
nship cannot be definitively ruled out, but 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 64 of 124 
AND MANAGEMENT  
red a medicinal product 
an abnormal laboratory 
nal product, whether or 
e following categories: 
tration of the drug and 
micals. The response to 
e. The event must be 
y rechallenge procedure 
tration of the drug, it is 
micals and it follows a 
lenge information (AE 
ition. 
ration of the drug, but it 
emicals. Information on 
mation is insufficient or 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
– other drugs, chemi
– the temporal rela
improbable. 
6. Not Related: Any of the f
– existence of a clear
– unreasonable temp
– non-plausibility. 
8.7.1.3 Adverse Drug Reaction
ADRs are all untoward and uninte
dose administered. 
The definition implies a reasona
Investigational Medicinal Product
suggest a causal relationship. 
ADRs are considered all AEs for w
1. Certain 
2. Probable 
3. Possible 
4. Unassessable 
AEs are not considered as ADRs w
5. Unlikely 
6. Not related 
8.7.1.4 Seriousness 
An AE/ADR is considered Seriou
• results in death; 
• is life-threatening; 
Final Versi
Confidential 
Menarini Ricerche S.p.A
icals, or underlying disease provide plausible e
ation to the administration of the drug ma
following are present: 
r alternative explanation, and/or 
poral relationship between Drug and Event, and
ns (ADRs) 
ended responses to an investigational medicina
able possibility of a causal relationship betw
t (IMP). This means that there are facts (evid
which the relationship is considered as: 
when the relationship is judged as: 
us when: 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 65 of 124 
explanations and/or 
akes a causal relation 
d/or 
al product related to any 
ween the event and the 
dence) or arguments to 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
NOTE: Life-threatening is
time of the event; it does n
if it were more severe. 
• requires inpatient hosp
• results in persistent or 
• is a congenital anomaly
• is another medically im
intervention to prevent
an infectious agent via
under the category of
criteria. 
An AE/ADR is considered Non-
Serious AE/ADR. 
 
NOTE: Hospitalization for chem
 
8.7.1.5 Adverse Event (AE)/Ad
The intensity level of a Serious o
definitions: 
• Mild: does not interfere w
mild abnormality. 
• Moderate: interferes with
moderate abnormality. 
• 
Severe: makes it impossib
there is a significant abnor
In addition, the Investigator wil
Adverse Event) for grading each 
Adverse Events (CTCAE) Ver
U.S.Department of Health and H
Institute for details). 
Final Versi
Confidential 
Menarini Ricerche S.p.A
s considered any AE in which the patient was
not refer to an event which hypothetically mi
pitalisation or prolongation of existing hospita
significant disability/incapacity; 
y/birth defect; 
mportant condition that may jeopardise the p
t one of the outcomes listed above. Any sus
a a medicinal product is considered serious a
f medically important events in the absence
-serious when it does not fulfill the condition
otherapy administration shall not qualify as a
dverse Drug Reaction (ADR) Intensity   
or a Non-serious AE or ADR is attributed acco
with routine activities; in case of laboratory
h the routine activities; in case of laboratory
ble to perform routine activities; in case of 
rmality. 
ll adopt the NCI-CTCAE v 4.03 (Common
AE (please refer to Appendix V: Common T
rsion 4.0. Published: May 28, 2009 (v 4
Human Services – National Institute of Hea
Study Code FLO-02
ion 1.0, 12 April 2016
Page 66 of 124 
s at risk of death at the 
ight have caused death 
alisation; 
patient or may require 
pected transmission of 
and should be assessed 
e of other seriousness 
ns for the definition of 
adverse event.  
ording to the following 
y tests, when there is a 
y tests, when there is a 
laboratory tests, when 
n Terminology Criteria 
erminology Criteria for 
4.03: June 14, 2010). 
alth – National Cancer 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
8.7.1.6 Adverse Event (AE)/Ad
An AE/ADR is considered Unex
not consistent with the informa
ADENURIC® 120 mg and the saf
8.7.1.7 Serious Unexpected Ad
Any serious adverse event judge
8.7.1.3), and considered as unexp
SUSARs are subject to expedited
Possibility” of relationship with t
 
8.7.2 Monitoring and Reco
At each visit the Investigator wil
informed consent signature to the 
AEs communicated by the patie
letters or emails will also be re
confirmation and assessment of th
When an AE has occurred, the I
pages any case, both serious 
observed in or reported by the 
causal relationship with the study
Any available information and d
etc.) shall be recorded in  the eCR
In addition, if after the end of the
AEs already recorded, this inform
 
8.7.3 Management of Serio
8.7.3.1 Reporting Duties of the
The Investigator must record all th
related to the investigational drug
later than 24 hours after the first 
Final Versi
Confidential 
Menarini Ricerche S.p.A
dverse Drug Reaction (ADR) Expectednes
xpected when the nature, severity, or outco
ation provided in the Reference Safety Doc
fety section from the Febuxostat IB, last vers
dverse Drug Reaction (SUSAR) 
ed by the Investigator or the Sponsor as dru
pected qualifies as a serious unexpected ADR
d reporting, as specified in section 8.7.3.2, as
the IMP. 
ording of Adverse Events 
ll assess any occurred subjective or objective
End of Study Visit (Visit 10, Day 14, ±2days)
ent or by the patient’s relatives or delegates
corded. In these cases the Investigator will 
he occurred AE. 
Investigator shall record on the respective
and non-serious, whether or not though
patient (or relatives/delegates), specifying 
y treatment. 
diagnostic measure (laboratory and instrume
RF. 
e study the Investigator becomes aware of an
mation can be recorded in the eCRF until it is av
ous Adverse Events (SAEs) 
e Investigator 
he available information concerning any SAE (
g) in the corresponding section of the e-CRF
knowledge of the occurrence of the event. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 67 of 124 
s 
ome of the AE/ADR is 
cument (the SmPC of 
ion available). 
ug-related (see section 
R (SUSAR). 
s having a “Reasonable 
e AE, starting from the 
. 
s through phone calls, 
try to obtain medical 
e eCRF-AE recording 
t to be drug-related, 
the judgement on the 
ental tests, procedures, 
ny AEs or follow-up in 
vailable.  
(whether or not deemed 
F, eCRF-AE pages, no 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Once the information is saved, a
Sponsor’s DSM, so that the SAE c
The Investigator will be provided 
of the e-CRF System. In such cas
pages form no later than 24 hour
the system works again.   
Whenever the paper CRF-AE pag
DSM:  
 
 
For the initial SAE the Investigat
 AE medical term. 
 Seriousness criteria. 
 Causality assessment.  
 Study Code and Patient Ide
used]. 
 Reporter’s name and telepho
used]. 
If not already reported, the full des
In case of serious cutaneous/hy
required to perform any attempt fo
in the specific FU forms that will b
The mentioned FU forms duly fil
e-mail, while for the possible pho
DSM for receiving adequate instru
Final Versi
Confidential 
Menarini Ricerche S.p.A
a notification e-mail will be automatically gen
can be retrieved. 
with the paper CRF-AE pages to be used onl
e, the Investigator will be responsible for send
rs after the first knowledge and inserting the d
ges are used, they must be submitted by fax or 
tor should enter at least the following data:
ntification (patient number) [when the pap
one number for clarification [when the pap
scription of the event and outcome must follow
ypersensitivity reactions and/or hepatic eve
or collecting all the available additional clinica
be provided to the Investigator.  
led will be sent by the Investigators to the Sp
otographic documentation the Investigator wil
uction for sending.  
Study Code FLO-02
ion 1.0, 12 April 2016
Page 68 of 124 
nerated and sent to the 
y in case of breakdown 
ding the paper CRF-AE 
data in eCRF as soon as 
e-mail to the Sponsor’s 
 
er CRF-AE pages are 
per CRF-AE pages are 
w within 1 working day. 
ents, the Investigator is 
al information, by filling 
onsor’s DSM by fax or 
ll contact the Sponsor’s 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
The Sponsor’s confirmation of rec
Any questions arise during the pr
of electronic queries (i.e. queries 
will be sent by fax or e-mail.  
Any information provided by the
processed in the same way as the i
When relevant, also the eCRF 
laboratory tests will be retrieved b
Any further significant informati
laboratory reports, tests, procedur
later than 24 hours after the knowl
The Investigator must also comp
to the local concerned Regulatory
8.7.3.2 Reporting Duties of the
The Sponsor shall ensure that all
adverse drug reaction (SUSAR
(including EudraVigilance Clinic
been assigned) and Ethics Com
these deadlines after the first kn
receives the notification of the SU
• Fatal and life threatening 
• Other unexpected serious 
The Sponsor shall ensure that a
follow-up information according 
The following safety issues wil
possible necessary actions: 
• SAEs associated with the 
• Potential clinically signifi
• An anticipated end or su
drug. 
Final Versi
Confidential 
Menarini Ricerche S.p.A
ception of the AE report must be kept in the pa
rocessing and medical review of the SAE will
in the e-CRF).  In case of breakdown of the 
e Investigator as a query reply or as a follow
initial AE report within the required timeframe
pages concerning medical history, concom
by the Sponsor’s DSM. 
ion and supporting documentation that becom
res, autopsy evidence of the cause of death, etc
ledge, by the Investigator to the Sponsor’s DSM
ply with the local applicable obligation(s) on 
y Authority/Ethics Committee. 
e Sponsor 
l relevant information about any suspected s
R), will be expeditiously reported to the c
cal Trial Module for clinical trials for which a
mmittees (following general and local rules 
nowledge, intended as the day when the Sp
USAR: 
unexpected cases, no later than 7 days; 
cases, no later than 15 days. 
all relevant new information will be also ex
to the above mentioned deadlines. 
l be subjected to expedited management fo
trial procedures; 
icant findings emerging from non-clinical stu
uspension for safety reasons of another tria
Study Code FLO-02
ion 1.0, 12 April 2016
Page 69 of 124 
atient’s records.  
l be managed by means 
e-CRF System, queries 
w-up AE report will be 
e.  
mitant medication, and 
me available (copies of 
c.) shall be provided no 
M by fax or email. 
the reporting of ADRs 
serious and unexpected 
competent Authorities 
a EudraCT number has 
and procedures), with 
onsor’s DSM or CRO 
xpeditedly reported as 
or the identification of 
udies; 
l with the same study 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
When appropriate and applicabl
Investigators. 
 
8.7.4 Management of Non
abnormalities  
The Investigator must record all
deemed related to the investigation
within 5 calendar days after the f
Once the information is saved, a
Sponsor’s DSM, so the NSAE can
When relevant, also the CRF p
laboratory test will be retrieved b
Any further significant informati
laboratory, tests, procedures etc.
reports to the Sponsor’s DSM.  
In addition, during the clinical tri
signature or worsening of previou
by the Principal Investigator (val
intervention or diagnostic tests, 
AEs. However, all abnormalities
on a bi-monthly basis. 
 
8.7.5 Management of Preg
The Investigator is expected to r
of pregnancy exposure occurring
while participating in the stud
mentioned form will be sent by 
made aware of the pregnancy. 
The “Pregnancy Exposure Repor
The Investigator is requested to f
If the pregnancy results in an ab
managed as above described. 
Final Versi
Confidential 
Menarini Ricerche S.p.A
le the Sponsor will arrange the adequate in
n-Serious Adverse Events (NSAEs) 
l the available information concerning any N
nal drug) in the corresponding section of the e-
first knowledge of the occurrence of the event.
a notification e-mail will be automatically gen
n be retrieved 
pages concerning medical history, concom
by the Sponsor’s DSM. 
ion and supporting documentation that becom
...) shall be provided by the Investigator tro
ial, abnormalities in laboratory analyses (new
usly known abnormalities), which are consid
lues significantly above or under normal rang
or may result in the IMP discontinuation), 
s in laboratory values should be collected and
gnancy Exposure Cases 
record in the provided “Pregnancy Exposure R
g in a female patient or in a patient’s partner
dy, occurring during the treatment and fo
fax or email to the Sponsor’s DSM within 
rt Form” are distributed to the sites to be used
follow each case of pregnancy exposure until 
bnormal outcome, this will be recorded in th
Study Code FLO-02
ion 1.0, 12 April 2016
Page 70 of 124 
nformation also to the 
and/or laboratory 
NSAE (whether or not 
-CRF, eCRF-AE pages, 
nerated and sent to the 
mitant medication, and 
me available (copies of 
ough additional written 
wly occurring after ICF 
ered clinically relevant 
ge or which require an 
should be reported as 
d reviewed by Sponsor 
Report Form” any case 
r enrolled on the study 
ollow-up periods. The  
5 days after the being 
d for this purpose. 
the outcome. 
he eCRF as a SAE and 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 
8.7.6 Annual Safety Repor
Once a year throughout the clini
national CAs and IRB/IECs of a 
into account all new safety inform
 
8.7.7 Breaking of the Rand
The study will be performed a
Randomization Code procedure i
 
8.7.8 Serious and Non-seri
After the End of Study Visit, the 
ongoing SAEs or non-serious AE
the Investigator becomes aware o
These SAEs should be recorded in
SAE report form will be used as a 
Patients who discontinued the tre
the patient’s condition stabilizes,, 
delayed toxicity. 
8.8 PHARMACOKINETIC/PH
8.8.1 Primary Endpoints
Pharmacokinetic endpoints will i
 
Primary PK parameters: CL
 
Derived PK parameters: AU
8.8.2 Secondary Endpoint
 
Pharmacodynamic:  
− Area under the curve of sU
Day 8) (AUC sUA 1-8) base
 
PK/PD: 
− The PK/PD relationship wil
 
Clinical:  
Final Versi
Confidential 
Menarini Ricerche S.p.A
rting 
ical trial, the Sponsor will assure the submis
safety report (Development Safety Update R
mation received during the reporting period. 
domization Code 
according to an open, non-randomized des
is not applicable to this trial. 
ious Adverse Events Follow-up 
Investigator is not requested to actively follow
s of special interest are present. However, if a
of any reportable SAEs, they should be duly re
n the eCRF until it is available. If the eCRF is 
a backup.  
atment for safety reason will be followed unt
or until recovery from all toxic effects and lon
HARMACODYNAMIC AND SAFETY ENDP
nclude: 
L/F, Vd/F and Ka. 
UC, Tmax and Cmax. 
s  
UA from baseline (Visit 1, Day 1) to the Eva
ed on central laboratory results. 
ll be evaluated based on sUA levels and febu
Study Code FLO-02
ion 1.0, 12 April 2016
Page 71 of 124 
ssion to the concerned 
Report, DSUR), taking 
sign. Breaking of the 
w-up the patient unless 
after the end of the trial, 
eported to the Sponsor. 
not available, the paper 
til the event disappears, 
nger in case of expected 
POINTS 
aluation Visit (Visit 8, 
xostat exposure. 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
− Incidence of Laboratory T
Evaluation Visit (Visit 8, D
− Incidence and grading of C
to the Evaluation Visit (Vis
 
Safety:  
− Incidence, severity (both 
seriousness and treatment c
NOTE: An AE is considered as ‘T
first time or if it worsens in terms
Day 1).  
− Frequency of clinically sig
tests, vital signs and 12-Lea
− Change in PS according to 
 
Assessment of the age-appro
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
TLS (LTLS), from Start of Chemotherapy (V
Day 8), based on local laboratory results; 
Clinical TLS (CTLS), from Start of Chemoth
sit 8, Day 8), based on local laboratory results
through Mild/Moderate/Severe scale and 
causality of Treatment Emergent Signs and Sy
Treatment-Emergent Signs and Symptoms (TE
s of seriousness or severity after the first stud
gnificant abnormalities in physical examina
ad-ECG; 
Karnofsky/Lansky scale. 
opriate formulation acceptability in children.
Study Code FLO-02
ion 1.0, 12 April 2016
Page 72 of 124 
Visit 3, Day 3) to the 
herapy (Visit 3, Day 3) 
s; 
NCI-CTCAE grade), 
ymptoms (TESS); 
ESS)’ if it occurs for the 
dy drug intake  (Visit 1, 
tion, safety laboratory 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
9. STATISTICAL ME
SIZE 
9.1 DETERMINATION OF SA
A sample size of approximately 2
each age and dose group (cohort 
Assumin
screened in order to obtain the pla
9.2  ANALYSIS POPULATIO
 Safety population: all patie
 Pharmacokinetic (PK) pop
and have a reliable drug pl
parameter of interest. 
 Intention to Treat (ITT) p
 Per Protocol (PP) popula
experienced major protocol 
 Per Protocol PK (PP-PK) 
major protocol violation(s) r
9.3 STATISTICAL ANALYSI
9.3.1 Descriptive statistics
All study variables will be prese
statistics according to the variabl
• Continuous variables: numbe
error of the mean, minimum, 
• Categorical variables: numbe
Final Versi
Confidential 
Menarini Ricerche S.p.A
ETHODS AND DETERMINATION
AMPLE SIZE 
24 patients should be included in the Pharmac
1-4, adults). A total of 120 patients was estim
ng a 10% screening failure rate, approximately
anned total number of 120 patients exposed to t
ONS 
ents who received at least one dose of study d
pulation: all patients who received at least o
asma concentration measurement relevant fo
opulation: all patients allocated to a treatmen
ation: all patients of the ITT population 
violation(s). 
population: all patients from PK population
relevant for PK analyses. 
S 
ented by dose and age group, by using the a
e nature, unless otherwise specified: 
er of non-missing observations, mean, standa
median, maximum. 
er of non-missing observations and column pe
Study Code FLO-02
ion 1.0, 12 April 2016
Page 73 of 124 
N OF SAMPLE 
cokinetic population for 
mated to be sufficient to 
y 135 patients should be 
treatment. 
drug. 
one dose of study drug 
or the pharmacokinetic 
nt box. 
excluding those who 
n who do not have any 
appropriate descriptive 
ard deviation, standard 
ercentages (N, %). 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
9.3.2 Population Pharmac
The plasma concentration data 
mixed-effects modeling metho
pharmacokinetic parameters and 
parameters.  
Final Versi
Confidential 
Menarini Ricerche S.p.A
cokinetic (Pop-PK) analysis 
will be analyzed in children, adolescent an
ods. These methods give both estimate
their measures of variability, along with estim
Study Code FLO-02
ion 1.0, 12 April 2016
Page 74 of 124 
nd adults by nonlinear 
s of the population 
mates of each patient’s 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
9.3.3 Primary analysis 
All pharmacokinetic results (e.g.,
dose and age group using approp
mean, standard deviation (SD), g
(CV%), median, minimum, and m
Relevant PK parameters (e.g., 
compared to those in adults to de
The primary analyses will be co
PP-PK population. 
9.3.4 Secondary analysis 
• 
Pharmacodynamic endpo
Area under plasma uric acid con
the Evaluation Visit (Visit 8, Da
rule which approximates the integ
A graphic example is provided in
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
, PK parameters and plasma concentrations) w
priate graphs and descriptive statistics (i.e., n
geometric mean, 95% confidence intervals, c
maximum).  
AUC, Cmax) in children and adolescents 
emonstrate sufficient similarity of febuxostat p
onducted on the PK population and for explo
oint:  
ncentration curves (AUC sUA1-8) from baseli
ay 8) will be computed for dose and age gro
gral or the area under a curve.  
n order to show which is the area considered t
Study Code FLO-02
ion 1.0, 12 April 2016
Page 75 of 124 
will be summarized by 
number of patients (n), 
coefficient of variation 
will be descriptively 
pharmacokinetics. 
oratory reasons on the 
ine (Visit 1, Day 1) to 
oup using a trapezoidal 
to calculate AUC. 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Figure 1 
The trapezoidal rule is a numeric
curve. Trapezoidal rule first invo
low limit identified with a and up
area of the trapezium formed and
the area under the curve.  
The trapezoidal rule will be prese
Last observation carried forward
study prematurely and a linear in
visits. 
The pharmacodinamic analysis w
population. 
• 
PK/PD endpoint: 
Observed exposure-response data
group.
Plasma uric acid mgxh/dL
       0
       1
       2
       3
       4
       5
       6
       7
       8
       9
      10
      11
0
Final Versi
Confidential 
Menarini Ricerche S.p.A
al method to be used to approximate the integ
olves dividing the area into a number of strip
pper limit with b. Then, approximating the ar
d summing these approximations, the final n
ented by mean of a definite integral:  
∫
b
a
dx
x
f
)
(
 
d method (LOCF) will be applied for patients
nterpolation method will be used to impute the
will be run on PK population and for explorato
a will be descriptively and graphically summ
Days
1
2
3
4
5
6
7
8
Study Code FLO-02
ion 1.0, 12 April 2016
Page 76 of 124 
 
gral or the area under a 
ps of equal width, with 
rea of each strip by the 
numerical result will be 
s who discontinued the 
e missing data between 
ory reasons on ITT 
arized by age and dose 
9


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
The aim of this analysis is to sup
pediatric patients (≥6<18 years o
clinically relevant. 
This analysis will be conducted o
• 
Clinical endpoints: Incid
- The assessment for LTL
Visit (Visit 8, Day 8)  wil
1: PRESENCE  
2
l
o
0: ABSENCE 
l
l
o
- The assessment for CTL
Visit (Visit 8, Day 8) is de
1: PRESENCE  
p
s
a
0:  ABSENCE 
a
c
d
Chi Square test will be us
by dose and age group. 
The efficacy analyses will be run
population.  
• 
Assessment of the age-ap
Assessment of the age-appropriat
Final Versi
Confidential 
Menarini Ricerche S.p.A
pport the assumption of a comparable PK/PD
of age) and adults and to evaluate if potentia
on the PK population. 
dence of LTLS and CTLS 
S from Start of Chemotherapy (Visit 3, Day
ll be defined as: 
2 or more laboratory abnormalities includin
levels above normal for serum uric acid, pot
or a 25% decrease or levels below normal for
less than 2 laboratory abnormalities includin
levels above normal for serum uric acid, pot
or a 25% decrease or levels below normal for
S from Start of Chemotherapy (Visit 3, Day
efined as: 
presence of LTLS in addition to 1 or m
significant clinical complications: renal 
arrhythmias, sudden death and seizures. 
absence of LTLS or absence of any
complications: renal insufficiency, cardiac
death and seizures. 
ed to compare statistically the rate incidence 
n on the ITT population and for exploratory re
ppropriate formulation acceptability 
te formulation acceptability will be evaluated
Study Code FLO-02
ion 1.0, 12 April 2016
Page 77 of 124 
D relationship between 
al deviations in PK are 
y 3) to the Evaluation 
ng: a 25% increase or 
assium, and phosphate 
r calcium. 
ng: a 25% increase or 
assium, and phosphate 
r calcium. 
y 3) to the Evaluation 
more of the following 
insufficiency, cardiac 
y significant clinical 
 arrhythmias, sudden 
of LTLS and CTLS 
easons on PP-
d through a 5-point 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
hedonic scale anchored with the w
descriptive statistics by febuxosta
population. 
9.3.5 Subgroup analysis 
Subgroup analysis will be defined
9.3.6 Safety analysis  
The safety analysis will be run on
Safety analysis will consider AE
PS and 12-Lead ECG data. 
Safety variables will include tr
occurred or worsened after first 
parameters, physical examination
TESS will be summarized by prim
PT/SOC, the number of TESS, t
with TESS will be given. TESS w
through mild, moderate, and seve
not related), and for those leading
Serious TESSs will be analyzed a
AEs/SAEs which are not conside
Any AE/SAE with a relationship
considered as treatment-related A
Laboratory parameters, vital sign
throughout appropriate descriptiv
9.3.7 Data imputations 
Overall, the missing value will no
For AUC sUA calculation the la
patients who discontinued the st
impute the missing data between 
9.4 PROTOCOL VIOLATION
Final Versi
Confidential 
Menarini Ricerche S.p.A
word super bad  and super good and summari
at dose in children. The analysis will be condu
d according to the nature of data.  
n the safety population.  
Es, laboratory parameter values, vital signs, 
reatment emergent AEs/SAEs (TESS), nam
study drug intake or clinically relevant chan
n, PS, 12-Lead ECG and vital signs. 
mary System Organ Class (SOC) and preferr
the number of patients with TESS, and the 
will be listed by dose and age group and strat
ere scale and NCI-CTCAE grade), relationsh
g to study discontinuation.  
analogously as TESSs.  
ered TESS will be included in a separate listin
p to the IMP other than “not related”, or “un
AEs/SAEs (i.e. ADRs/SADRs).  
ns, physical examination, PS and 12-Lead EC
ve statistics by dose and age group. 
ot be imputed because an observed cases appr
ast observation carried forward method (LOC
tudy prematurely and a linear interpolation m
visits. 
NS AND DATA REVIEW MEETING 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 78 of 124 
ized by means of 
ucted on the safety 
physical examination, 
mely any reported AE 
ge in safety laboratory 
red term (PT). For each 
percentage of patients 
tified by severity (both 
hip to the IMP (related/ 
ng. 
nlikely related” will be 
CG will be summarized 
roach will be used. 
CF) will be applied for 
method will be used to 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Categories of protocol violations
integrated in the Statistical Analy
9.5 STATISTICAL ANALYSI
The statistical analysis plan (SAP)
describe in detail study endpoint
analyses not planned in the proto
original primary analyses will o
generated.  
Minor deviations (e.g. not involvi
during the study will be detailed o
database lock will be considered a
Final Versi
Confidential 
Menarini Ricerche S.p.A
s will be defined before the lock of the study
ysis Plan (SAP).  
S PLAN 
) will be finalized before the database lock of t
ts and the statistical analyses performed, inc
ocol. In case of changes of the original prim
occur during the study, a substantial protoco
ing changes in the primary endpoint and analy
only in the SAP. All statistical analyses not pre
additional/exploratory analyses.  
Study Code FLO-02
ion 1.0, 12 April 2016
Page 79 of 124 
y database and will be 
the study. The SAP will 
cluding also additional 
mary endpoint or of the 
ol amendment will be 
ysis) which might occur 
e-specified and run after 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
10. DATA QUALITY MAN
10.1 DATA COLLECTION 
Data collection activities will be c
collected using the data capture sy
by the patient study identification 
The patient ID will be a number co
- CCC is the international 
have a 1 or 2-digits phone
- SS is the site number in
ascending; 
- PPP is the patient numb
ascending. 
Data will be collected, processed
with applicable data protection re
10.1.1 Case Report Forms
Clinical data collected during the 
which is a validated system. The 
protocol and to review and perfor
adherence.  
The eCRF will be made available 
a validated system. The accounts w
The Investigator or designee will b
the eCRF Completion Guidelines
collection and cleaning, data shall 
become available and not later th
source data (the definition of the s
Investigators will ensure the a
electronically the eCRF using the 
An audit trail within the system w
10.1.2  IxRS 
The IxRS system 
site personnel for the patient scre
Final Versi
Confidential 
Menarini Ricerche S.p.A
NAGEMENT 
carried out under the responsibility of the Spon
ystems described in the following sections. Pa
number (patient ID), assigned at the Screening
omposed of eight-digits CCCSSPPP:  
phone code of the country (with a leading z
e code); 
n the country: it will start from 01 for each
ber in the site; it will start from 001 for 
d, evaluated, reviewed and stored in anonymo
egulations. 
study at sites will be recorded in an (e)CRF 
Sponsor will be responsible to develop the eC
rm the user acceptance test of the eCRF in o
to the study personnel by means of the i-Med
will be individual and password-protected.  
be responsible for entering study data into the 
s provided by the Sponsor. In order to impro
be entered into the eCRF as closely as possibl
han within 5 working days. The eCRF data wi
source data can be found in section 10.3). 
accuracy, completeness and consistency of 
personal password.  
will track all changes made to the data.  
, provided by 
 is a valida
eening (including assignment of the patient ID
Study Code FLO-02
ion 1.0, 12 April 2016
Page 80 of 124 
nsor. Patient data will be 
atients will be identified 
g Visit.  
zeros for countries that 
h country and will be 
each site and will be 
ous form in accordance 
using Medidata RAVE 
CRF based on this study 
order to ensure protocol 
didata interface which is 
eCRF in accordance to 
ove the quality of data 
le to the time when they 
ill not be considered as 
f data entered signing 
ated system used by the 
D), box assignment and 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
patient status change. Site staff w
IxRS. 
An IxRS user manual will be prep
Some data such as patient ID an
integrated in eCRF. The integratio
10.1.3  Patient diary  
As per EMA Guideline of August
in children through a 5-point hed
Patients will complete a daily d
representing their experience of th
The assessment results will be ent
 
10.1.4  Central Laboratory/
The following Central Laboratori
• 
Research Toxicolog
samples logistic  ma
• 
Menarini Ricerche S
for Pharmacokinetic
 
Central laboratories data will b
transferred to Menarini Clinical R
10.1.5  Data capture system
Versions of the data capture syste
the data capture system versions 
the validation documentation will
updated at any data capture system
10.2 CLINICAL DATA MANA
Final Versi
Confidential 
Menarini Ricerche S.p.A
will be provided with a personal user name and
pared by 
 and provided to si
nd visit dates collected through IxRS system 
on process will be detailed in a specific integrat
t 1st 2013 [39], the acceptability of febuxostat
donic scale anchored with the word super bad
diary, they will mark, immediately after drug
he drug intake. Five levels of acceptability will 
ered in eCRF by the site personnel. 
/Examination data 
ies will be used during the study: 
gy Center (RTC) - Pomezia, Rome (Italy) 
anagement and centralized laboratory test: sU
S.p.A. - Pre-Clinical Research Department -
cs analysis: febuxostat plasma concentrations
be managed according to internal laborato
Research department for statistics and pharma
ms versions and validation documenta
ems can change during the study. The Sponso
used and the validation documentation of eac
l be provided to the site at the site initiation 
m version change. 
AGEMENT 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 81 of 124 
d password to access to 
ite personnel by CRO.  
could be automatically 
tion document. 
tablets will be assessed 
d and super good [40]. 
g intake, the icon best 
be provided: 
for plasma and serum 
UA 
Pomezia, Rome (Italy) 
s 
ory SOPs and will be 
acokinetics analyses.  
ation 
r will maintain a list of 
ch version. The list and 
visit (SIV) and will be 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Data Management will be carrie
electronically verified through the
resolved by means of electronic qu
the trial, including medical revisio
Data from sources other than eCR
The data manager has the respon
sources. Discrepancies found in th
A clear overview of all clinical dat
10.3 SOURCE DATA 
Source data are defined as all data
findings, observations or other act
evaluation of the trial. 
Original documents and data reco
laboratory notes, ECG records, pa
sites will also maintain a paper 
returned IMP per patient. 
Source data should be held availab
authorized persons such as auditor
Direct access to source data is def
records and reports that are impo
allowed to direct access to study
within the constraints of the app
patient identities and sponsor prop
Data should be consistent with the
writing. All the original documen
in each patient’s record. 
10.4 QUALITY CONTROL/QU
10.4.1 Study Monitoring 
This trial will be monitored in acc
Monitoring will be carried out und
to the trial sites along the study c
data, and all other study documen
Final Versi
Confidential 
Menarini Ricerche S.p.A
ed out under the responsibility of the Spons
e use of on-line and off-line checks. Discrepan
ueries. Data will be locked by the data manage
on of the data, are complete and no more entrie
RF will be provided to the data manager on an 
nsibility to reconcile data captured in the eC
he reconciliation of the data, will be addressed b
ata management activities will be given in the d
a in original records and certified copies of orig
tivities in a clinical trial that are necessary for
ords include, but are not limited to hospital/pat
atients’ identification forms, and pharmacy dis
drug accountability forms for the IMP to do
ble for perusal by the Sponsor representatives f
rs and inspectors of Regulatory Authorities.  
fined as the permission to examine, analyze, ve
ortant for evaluation of a clinical trial (see a
y source data and documents should take all 
plicable regulatory requirements to maintain
prietary information.  
e source documents and discrepancies, if any, 
ntation pertinent to the study procedures must 
UALITY ASSURANCE 
cordance with the ICH Note for Guidance on 
der the responsibility of the CRO. The site mon
conduct. Facilities, study drug, storage area, 
ntation will be inspected/reviewed by the site m
Study Code FLO-02
ion 1.0, 12 April 2016
Page 82 of 124 
sor. eCRF data will be 
ncies in the data will be 
er when all activities for 
s are expected.  
agreed scheduled basis. 
CRF, with external data 
by means of queries. 
data management plan. 
ginal records of clinical 
r the reconstruction and 
tients’ medical records, 
spensing records. Study 
ocument dispensed and 
for the study or to other 
erify and reproduce any 
also 10.4.1). Any party 
reasonable precautions 
n the confidentiality of 
should be explained in 
be available for review 
Good Clinical Practice. 
nitor will perform visits 
eCRF, patient’s source 
monitor for adherence to 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
the protocol and Good Clinical P
completion and accuracy. Accura
direct comparison of the entries m
Any resulting discrepancies will b
agrees to allow access to all study
to assist the monitor during the m
procedures require that 100% of
consents, adherence to inclusion/
the proper recording of efficacy an
detail in the study-specific monito
10.4.2 Quality Assurance 
Independent study audit(s) and/or 
independent audit/inspection can 
the independent QA Departmen
Authority. At all times, the confid
Final Versi
Confidential 
Menarini Ricerche S.p.A
Practice. At each site visit, the monitor will 
acy will be checked by performing source da
made onto the eCRFs against the appropriate 
be reviewed with the Investigator and his/her
y related materials needed for the proper review
monitoring visits and during the data cleanin
f data are source data verified, particularly 
/exclusion criteria, drug accountability, docum
nd safety measurements. All monitoring activit
oring plan. 
inspection(s) may take place at any time durin
be carried by the Quality Assurance (QA) D
nt of Research Toxicology Centre (RTC) S
entiality of subject related documents will be m
Study Code FLO-02
ion 1.0, 12 April 2016
Page 83 of 124 
review the eCRFs for 
ata verification that is a 
source documentation. 
r staff. The Investigator 
w of study conduct and 
ng process. Monitoring 
focusing on informed 
mentation of SAEs and 
ties will be described in 
ng or after the trial. The 
epartment of the CRO, 
.p.A., or a Competent 
maintained. 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
11. PREMATURE TERMI
The whole trial may be disconti
following: 
• New information leading to u
to: 
- 
Occurrence of signifi
incidence of known A
- 
New evidence of unf
examinations, e.g. tox
• The Sponsors decision that con
• Discontinuation of developme
Competent Authorities and IRB
accordance with applicable regul
Final Versi
Confidential 
Menarini Ricerche S.p.A
INATION OF THE WHOLE STUD
inued at the discretion of the Sponsor in th
unfavorable risk-benefit judgment of the inves
icantly previously unknown AEs or unexpec
AEs. 
favorable safety or efficacy findings (from c
xicology). 
ntinuation of the trial is unjustifiable for medic
ent of the IMP. 
B/IECs will be informed about the discontin
ations. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 84 of 124 
DY 
he event of any of the 
stigational products due 
ctedly high intensity or 
clinical or non-clinical 
cal or ethical reasons. 
nuation of the trial in 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
12. END OF CLINICAL T
The clinical trial will end with th
study report. All essential docume
12.1 ARCHIVING OF ELECTR
Duplicate electronic media such a
the patient data in PDF format (e.
for archiving purposes. The electr
recording the files/data included. 
system name, study code and the
audit trails have to be included.  
Patient data relevant for each site 
of the material, verify whether the
the study and sign a dedicate form
archived at the Sponsor.  
Two copies of the same electronic
same content will be archived b
electronic media (one for routine 
with all study data (e.g. eCRF
procedures. 
Investigators and Sponsor will b
every 7 years to ensure long term 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
TRIAL AND ARCHIVING 
he collection and analysis of study data and t
ents will be archived by the Sponsor according 
RONIC DOCUMENTATION/DATA  
as CDs/DVDs (one for routine access and one f
g. eCRFs) for each site will be prepared by th
ronic media, of a not re-printable type, will b
The files should contain at least the edata cop
e eCRF version used; also the electronic signa
will be distributed to the Investigator, who ha
e provided electronic media represent a copy o
m provided by the Sponsor, the signed form h
c media prepared for the sites or cumulative ele
by the Sponsor. In addition the Sponsor is r
access and one for back-up) containing an in
F, IxRS, Central Laboratory), following ap
be also responsible to refresh their electronic
archiving of files/data. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 85 of 124 
the issue of the clinical 
to the relevant SOP. 
for back-up) containing 
e Sponsor or a delegate 
be appropriately labeled 
py clearly reporting the 
ature and the associated 
as to confirm the receipt 
of data generated during 
has to be collected and 
ectronic media with the 
responsible to create 2 
ntegrated SAS database 
ppropriate refreshment 
c media approximately 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
13. APPENDIX  
13.1  APPENDIX I: DEFINITIO
Diagnosis of LTLS: LTLS is
potassium, phosphate or calciu
change by at least 25% from ba
ELEMENT 
Uric Acid 
Potassium 
Phosphorus 
Calcium 
For adolescents and adults, the values o
 
Diagnosis of CTLS: CTLS is pr
significant clinical complication
death or seizure. Diagnostic pa
clarification about the creatinine 
age/gender adjusted according to
≥ 12 < 16 years, both male and 
male, 114.4 µmol/L).  
The CTLS grading classification (Cairo
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
ON OF LTLS AND CTLS 
s diagnosed if levels of 2 or more serum 
um are more than or less than normal at pr
aseline.  
VALUE 
CHANGE
≥ 476 µmol/L (or 8 mg/dL) 
≥ 6.0 mmol/L 
≥ 1.45 mmol/L (adults) or ≥ 
2.1mmol/L (children) 
≤ 1.75 mmol/L 
2
f phosphorus will be considered the same for the diagn
resent when LTLS is accompanied by at leas
: increased creatinine level ≥ 1.5 ULN, card
athway is quite the same between adults 
ULN (if not specified by the Local Laborato
o the following: > 1 <12 years, both male and
female, 88 µmol/L; ≥ 16 years, female, 105.
o and Bishop, 2004) 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 86 of 124 
values of uric acid, 
resentation or if they 
E FROM BASELINE 
25% increase 
25% increase 
25% increase 
25% decrease 
nosis of LTLS. 
st one of the following 
diac arrhythmia/sudden 
and children, with a 
ory, the value has to be 
d female, 61.6 µmol/L; 
.6 µmol/L; ≥ 16 years, 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
13.2 APPENDIX II: EU SMPC
EU SMPCS FOR
Final Versi
Confidential 
Menarini Ricerche S.p.A
CS FOR ADENURIC®  
R ADENURIC® 80 MG FILM-COATED TABLETS
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 87 of 124 
S 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 
 
 
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 88 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 
 
 
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
Study Code FLO-02
ion 1.0, 12 April 2016
Page 89 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 90 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 91 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 92 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 93 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 94 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 95 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 96 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 97 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 98 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 99 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 100 of 124 
 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
EU SMPCS FOR
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
R ADENURIC® 120 MG FILM-COATED TABLET
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 101 of 124 
TS 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 102 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 103 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 104 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 105 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 106 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 107 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 108 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 109 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 110 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 111 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 112 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 113 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 114 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 115 of 124 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
13.3 APPENDIX III: TLS RIS
PANEL A. M
Final Versi
Confidential 
Menarini Ricerche S.p.A
SK ASSESSMENT  
MEDICAL DECISION TREE FOR LYMPHOMA
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 116 of 124 
A
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
 
Aggressive lymphoma according to
> 10 cm in diameter) have to be con
 
Follicular large cell lymphoma (gr
classification; 
 
Patients with LRD are intermediate
 
Patients with IRD are high-risk for
acid, phosphate and/or potassium le
 
Legend. HL= Hodgkin lymphoma, FL= Fol
Lymphoma, BL= Burkitt Lymphoma/Leukae
Adult T-cell Lymphoma, DLBCL= Diffuse L
dehydrogenase, ULN= Upper Limit of Norm
Disease, HRD= High Risk Disease.
Final Versi
Confidential 
Menarini Ricerche S.p.A
 
 
 
 
Important Note 
o 2008 WHO classification with Bulky disease (define
nsidered IRD regardless of the LDH levels; 
rade 3b) has to be considered as aggressive lymphom
e-risk for TLS when renal dysfunction and/or renal inv
r TLS when renal dysfunction and/or renal involveme
evels are > ULN. 
llicular Lymphoma, MALT= Mucosa-Associated Lymphoid T
emia, LL= Lymphoblastic Lymphoma, ALCL= Anaplastic La
Large B-Cell Lymphoma, PTCL= Peripheral T-cell Lymphom
mal, WNL= Within Normal Limit, LRD= Low Risk Disease, I
 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 117 of 124 
 
ed as one lymphnode/tumor 
ma according to 2008 WHO 
volvement is present; 
ent is present OR when uric 
Tissue, MCL= Mantel Cell 
arge Cell Lymphoma, ATL= 
ma, LDH= lactate 
IRD= Intermediate Risk 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
PANEL B. 
Figure adapted from Cairo M, Coiffier B, R
Haematology 2010 [4]. 
Important Note 
 
Patients with LRD are intermediate
 
Patients with IRD are high-risk for
acid, phosphate and/or potassium le
 
Legend. CLL= Chronic Lymphoid Leukaem
Lymphoblastic Leukaemia, WBC= White Blo
Risk Disease, IRD= Intermediate Risk Disea
Final Versi
Confidential 
Menarini Ricerche S.p.A
MEDICAL DECISION TREE FOR LEUKEMIA
Reiter A and Younes A on behalf of the TLS Expert Panel.
e-risk for TLS when renal dysfunction and/or renal inv
r TLS when renal dysfunction and/or renal involveme
evels are > ULN. 
mia, CML= Chronic Myeloid Leukaemia, AML= Acute Myelo
ood Count, LDH=Lactate Dehydrogenase, ULN= Upper Lim
ase, HRD= High Risk Disease. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 118 of 124 
 
. British Journal of 
volvement is present; 
ent is present OR when uric 
oid Leukaemia, ALL= Acute 
mit of Normal, LRD= Low 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
13.4 APPENDIX IV: KARNOF
The Karnofsky score runs from 100
10 is “moribund, fatal process progr
of the Lansky Play performance sc
“fully active” and 10 is “completed 
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
FSKY AND LANSKY PLAY PERFORMANC
 to 10, where 100 is ”normal, no complaints, no 
ressing rapidly”. For children aged from 6 to less 
ale is recommended as per guideline CIBMTR 
disabled, not even passive play”. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 119 of 124 
CE STATUS SCALES 
evidence of disease” and 
than 16 years old the use 
2009 [34], where 100 is 
 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
13.5 APPENDIX V: COMMO
(CTCAE) VERSION 4.
U.S.DEPARTMENT OF H
OF HEALTH – NATIONA
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
ON TERMINOLOGY CRITERIA FOR 
.0. PUBLISHED: MAY 28, 2009 (V 4.03
HEALTH AND HUMAN SERVICES – NA
AL CANCER INSTITUTE 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 120 of 124 
ADVERSE EVENTS 
3: JUNE 14, 2010). 
ATIONAL INSTITUTE 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
14. REFERENCES 
1. 
U.S. Department of H
Evaluation and Resear
Research (CBER), Gu
Medicinal Products in
http://www.fda.gov/do
tion/Guidances/UCM0
2. 
Brown P, H.S., “Acute
Therapy 2009: p. 450-
3. 
Coiffier, B., et al., Gu
lysis syndrome: an evi
78. 
4. 
Cairo, M.S., et al., Rec
of tumour lysis syndro
an expert TLS panel c
5. 
Cairo, M.S. and M. Bi
and classification. Br 
6. 
Cheng, M.H., et al., M
healthy children. Clin
7. 
Gomez, P., et al., Norm
healthy infants, childr
8. 
EMA, Commission Im
marketing authorisatio
febuxostat”, a medicin
http://ec.europa.eu/hea
9. 
Truong, T.H., et al., F
lymphoblastic leukemi
110(8): p. 1832-9. 
10. 
Howard, S.C., D.P. Jo
Med, 2011. 364(19): p
11. 
Wossmann, W., et al.,
advanced stage Burkit
prophylactic use of ur
12. 
Annemans, L., et al., I
hyperuricemia and tum
non-Hodgkin's lympho
44(1): p. 77-83. 
13. 
Montesinos, P., et al., 
leukemia: identificatio
Haematologica, 2008.
Final Versi
Confidential 
Menarini Ricerche S.p.A
Health and Human Services, F.a.D.A., C
rch (CDER), Center for Biologics Eval
uidance for Industry, E11 Clinical Inve
n the Pediatric Population. 
ownloads/Drugs/GuidanceCompliance
073143.pdf, December 2000. 
e Leukemia in children”, excerpt from 
-456. 
uidelines for the management of pediatr
idence-based review. J Clin Oncol, 200
commendations for the evaluation of ri
ome (TLS) in adults and children with m
consensus. Br J Haematol, 2010. 149(4)
ishop, Tumour lysis syndrome: new the
J Haematol, 2004. 127(1): p. 3-11. 
Microchemical analysis for 13 constitue
n Chem, 1979. 25(5): p. 692-8. 
mal reference-intervals for 20 biochem
ren, and adolescents. Clin Chem, 1984
mplementing Decision of 8.4.2015 amen
on granted by Decision C(2008)1648 f
nal product for human use. 
alth/documents/community-register/htm
Features at presentation predict childre
ia at low risk for tumor lysis syndrome
ones, and C.H. Pui, The tumor lysis syn
p. 1844-54. 
, Incidence of tumor lysis syndrome in 
tt's lymphoma/leukemia before and afte
rate oxidase. Ann Hematol, 2003. 82(3
Incidence, medical resource utilisation
mour lysis syndrome in patients with ac
oma in four European countries. Leuk 
Tumor lysis syndrome in patients with
on of risk factors and development of a
. 93(1): p. 67-74. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 121 of 124 
Center for Drug 
luation and 
estigation of 
RegulatoryInforma
Conn’s Current 
ric and adult tumor 
08. 26(16): p. 2767-
isk and prophylaxis 
malignant diseases: 
): p. 578-86. 
erapeutic strategies 
ents of plasma from 
mical variables in 
. 30(3): p. 407-12. 
nding the 
for “Adenuric - 
ml/h447.htm, 2015. 
en with acute 
e. Cancer, 2007. 
drome. N Engl J 
children with 
er introduction of 
): p. 160-5. 
n and costs of 
cute leukaemia and 
Lymphoma, 2003. 
h acute myeloid 
a predictive model. 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
14. 
Mayer, M.D., et al., P
new non-purine select
impairment. Am J The
15. 
Osada, Y., et al., Hypo
TEI-6720, in rodents.
16. 
Komoriya, K., et al., H
oxidase inhibitor TEI-
455-60. 
17. 
EMA, European Medi
http://www.ema.europ
0167974.pdf, 2014. 
18. 
Horiuchi, H., et al., A 
potency in renal xanth
dehydrogenase inhibit
Pathol Pharmacol, 199
19. 
Hitchings, G.H., Effec
Rheum Dis, 1966. 25(
20. 
Becker, M.A., et al., F
inhibitor of xanthine o
volunteers. Nucleosid
21. 
Khosravan, R., et al., E
pharmacodynamics of
2008. 65(3): p. 355-63
22. 
Khosravan, R., et al., 
pharmacodynamics, a
inhibitor of xanthine o
23. 
Becker, M.A., et al., F
xanthine oxidase: a tw
double-blind, placebo
and efficacy in patient
24. 
Becker, M.A., et al., F
hyperuricemia and go
25. 
Schumacher, H.R., Jr.
placebo in reducing se
28-week, phase III, ra
Rheum, 2008. 59(11):
26. 
Becker, M.A., et al., C
lowering with febuxos
2009. 36(6): p. 1273-8
Final Versi
Confidential 
Menarini Ricerche S.p.A
Pharmacokinetics and pharmacodynam
tive inhibitor of xanthine oxidase in sub
er, 2005. 12(1): p. 22-34. 
ouricemic effect of the novel xanthine o
Eur J Pharmacol, 1993. 241(2-3): p. 18
Hypouricemic effect of allopurinol and 
-6720 in chimpanzees. Eur J Pharmaco
dicines Agency decision, P/0117/2014. 
pa.eu/docs/en_GB/document_library/P
comparative study on the hypouricemi
hine calculus formation of two xanthine
tors: TEI-6720 and allopurinol in rats.
99. 104(3): p. 307-19. 
cts of allopurinol in relation to purine b
(6 Suppl): p. 601-7. 
Febuxostat (TMX-67), a novel, non-pur
oxidase, is safe and decreases serum ur
des Nucleotides Nucleic Acids, 2004. 23
Effect of food or antacid on pharmacok
f febuxostat in healthy subjects. Br J Cl
3. 
The effect of age and gender on pharm
and safety of febuxostat, a novel nonpur
oxidase. J Clin Pharmacol, 2008. 48(9)
Febuxostat, a novel nonpurine selective
wenty-eight-day, multicenter, phase II, 
o-controlled, dose-response clinical tria
ts with gout. Arthritis Rheum, 2005. 52
Febuxostat compared with allopurinol i
out. N Engl J Med, 2005. 353(23): p. 24
., et al., Effects of febuxostat versus allo
erum urate in subjects with hyperurice
andomized, double-blind, parallel-group
: p. 1540-8. 
Clinical efficacy and safety of successfu
stat or allopurinol in subjects with gout
82. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 122 of 124 
ics of febuxostat, a 
bjects with renal 
oxidase inhibitor, 
83-8. 
d the novel xanthine 
l, 1993. 250(3): p. 
IP_decision/WC50
ic activity and 
e oxidase/xanthine 
 Res Commun Mol 
biosynthesis. Ann 
rine, selective 
rate in healthy 
3(8-9): p. 1111-6. 
kinetics and 
lin Pharmacol, 
macokinetics, 
rine selective 
: p. 1014-24. 
e inhibitor of 
randomized, 
al examining safety 
2(3): p. 916-23. 
in patients with 
450-61. 
opurinol and 
emia and gout: a 
up trial. Arthritis 
ul longterm urate 
t. J Rheumatol, 


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
27. 
Becker, M.A., et al., T
treatment of the hyper
Ther, 2010. 12(2): p. R
28. 
Schumacher, H.R., Jr.
of the FOCUS efficacy
p. 188-94. 
29. 
Hair, P.I., P.L. McCor
68(13): p. 1865-74. 
31. 
PERIODIC SAFETY U
febuxostat. 2015. 13.
32. 
S.A., M.I.O.L., Febux
PIP01-12. 2013. 
33. 
(CHMP), C.f.M.P.f.H
PHARMACOKINETIC
PRODUCTS IN THE 
http://www.ema.europ
2009/09/WC50000306
34. 
CIBMTR, Appendix L
Marrow Donor Progra
revision 1. 
35. 
Lansky, S.B., et al., Th
patients. Cancer, 1987
36. 
Schag, C.C., R.L. Hei
revisited: reliability, v
93. 
37. 
JH., K.D.B., The Clin
1949. MacLeod CM 
Agents(Columbia Uni
38. 
EMA, CPMP, Note fo
products in man. 
http://www.ema.europ
2009/10/WC50000396
Final Versi
Confidential 
Menarini Ricerche S.p.A
The urate-lowering efficacy and safety 
ruricemia of gout: the CONFIRMS tria
R63. 
., et al., Febuxostat in the treatment of g
y and safety study. Rheumatology (Oxf
rmack, and G.M. Keating, Febuxostat.
UPDATE REPORT for ACTIVE SUBST
xostat Pediatric Investigation Plan no: 
H.u., GUIDELINE ON THE ROLE OF 
CS IN THE DEVELOPMENT OF MED
PEDIATRIC POPULATION. 
pa.eu/docs/en_GB/document_library/S
66.pdf, 2006. 
L_Karnofsky/Lansky Play Performance
am and The medical College of Wiscon
The measurement of performance in chi
7. 60(7): p. 1651-6. 
nrich, and P.A. Ganz, Karnofsky perfo
validity, and guidelines. J Clin Oncol, 1
ical Evaluation of Chemotherapeutic A
(Ed), Evaluation of Chemotherapeut
iv Press): p. 196. 
or guidance on evaluation of anticancer
pa.eu/docs/en_GB/document_library/S
69.pdf, 2003. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 123 of 124 
of febuxostat in the 
al. Arthritis Res 
gout: 5-yr findings 
ford), 2009. 48(2): 
Drugs, 2008. 
TANCE: 
EMEA-001417-
DICINAL 
cientific_guideline/
e Status. National 
nsin, 2009. A00428 
ildhood cancer 
rmance status 
1984. 2(3): p. 187-
Agents in Cancer. 
tic 
r medicinal 
cientific_guideline/


Clinical Trial Protocol  
EudraCT No.: 2016-001445-61         
 
 
 
39. 
EMA, Guideline on ph
use. 
http://www.ema.europ
2013/07/WC50014700
40. 
Guinard, J.-X., Sensor
Science & Technology
 
Final Versi
Confidential 
Menarini Ricerche S.p.A
harmaceutical development of medicin
pa.eu/docs/en_GB/document_library/S
02.pdf, 2013. 
ry and consumer testing with children.
y, 2001. 11: p. 273–283. 
Study Code FLO-02
ion 1.0, 12 April 2016
Page 124 of 124 
nes for pediatric 
cientific_guideline/
Trends in Food 


Clinical Trial Protocol Amendment No. I
EudraCT No.: 2016-001445-61
FL©RET
Study Code FLO-02
Amendment Date 02 Feb 2017
MENARINI
RICERCHE
OPEN LABELÿ MULTI-CENTREÿ PARALLEL GROUP STUDY TO COMPARE THE
PHARMA«OKINETICS (PI(), PHARMACODYNAMICS (PD)
AND SAFETY OF FEBUXOSTAT BETWEEN
PEDIATRIC PATtENTS (>6<18 YEARS OF AGE) AND ADULTS
Protocol Version(s)
Previous Amendment(s)
Study code
Study Nick Name
EudraCT-Number
Invesfigafional Medicinal
Product
Final Version 1.0 dated 12 Apr 2016
Not applicable
FLO-02
FLORET
2016-001445-61
FEBUXOSTAT
The contents oflhis Nmÿ-Substantial Amendmcnt No. 1 dated 02 Feb 2017 refers to changes made
to the Clinical Trial Protocol Final Version 1.0 dated 12 Apr 2016.
Notification of this Non-Substantial Amendment No. 1 will be done tlu'ough the Colnpetent
Authorities, Ethical Committees, and Investigators involved in the study as appropriate.
Page 1 of 9


Clinical Trial Protocol Amendment No. 1
EudraCT No.: 2016-001445-61
Study Code FLO-02
Amendment Date 02 Feb 2017
1. Reasons for the Amendment
The content of this Non-Substantial amendment refers to the modification oh which blood specilnen
safety tests could be done (i.e. plasma or serum).
As the safety tests will be performed by each local laboratory to ensure prompt patient's
management, blood analysis will be done according to each local standard practice based on each
available validated analytical methods.
Such changes do not have any impact on the patient's safety evaluation as well as also in the
evaluation of patient's protocol eligibility (i.e. inclusion criterion lc: u6c acid level <10 mg/dL at
Visir 1). In particular, the ufic acid analysis can be done in both spechnen (plaslna or serum) and the
referente nonnal ranges are the same (Clinical Chemistry, Lawrence A. Laplan, Amadeo J.
Pesce, Mosby, 1996 : p 501-502; Miles RR., et al. Comparison ofserttm and heparinized plasma
samplesfor measm'ement ofchemistry analytes., Clin Cheto. 2004 Sep;50(9):1704-6.)
Moreover, Menarini Ricerche S.p.A. Clinical Research Organization and study team name/title
have been updated as well as typos corrected.
2. Protocol changes in detail
Report speci[ìc cha»ges for relevant protocol section (including paragraph number and pages),
additions shotdd be highlighted as tmderlined, whereas deletions as sí:'i!«e o::t, reporting whenever
possible the fidl qffected changes. Alternatively, the tracked changes can be strictly limited to the
affected lines.
• Amendment to Protocol Cover:
CmTent version (page 1):
oeo
SPONSOR                                        CO-ORDINATING                                          CRO
INVESTIGATOR
Menarini Ricerche S.p.A.
Clinical Research Sciences
Via Sette Santi, 1
50131 Florence- Italy
Phone: +39 05556809990
• Amendment to Protocol Section 2:
Current version (page 4/18):
Page 2 of 9


Clhlical Trial Protocol Amendment.No. 1
EudraCT No.: 2016-001445-61
FLORET
Study Code FLO-02
Amendment Date 02 Feb 2017
Section 2 Protocol Synopsis Inclusion Criteria (page 5-6), is amended as described below:
Patients meeting ALL the following criteria will be eligible to enter the Stlldy.
1. male and female children of 6 to less than 12 years of age, adolescents of 12 to less than 18
years of age, and adults:
a. scheduled for first cytotoxic chemotherapy cycle, regardless of the line of treatment,
because ofhematologic malignancies, and
b. at intennediate or high risk for TLS, and
c. with zeru:ìì uric acid (sUA) levels < 10 mg/dL at Visit 1 (Day 1), and
d.  with no access to rasburicase;
NOTE:
Evaluation of uric acid could be done both in serum or plasma specimen based Oh local laboratory
standard practices.
Section 2 Protocol Synopsis Study procedures and PIÿ2PD, Clinicai and Safeÿ, assessments,
(page 11-12), is amended as described below:
NOTE:
Blood safely laboratory tests will be performed at the Local Laboratory and will include:
albumin,  alkaline  phosphatase,  amylase,  alanine  aminotransferase  (ALT),  aspartate
aminotransferase (AST), blood urea nitrogen (BUN)/urea, seì'um creatinine, setìtam uric acid (sUA),
sodium, chloride, potassium, phosphorus, calcium, total bilirubin, direct bilirubin, ganuna-glutamyl
transpeptidase (GGT), ghtcose, lactate dehydrogenase (LDH), total proteins, protlu'ombin
time/protlu'ombin activity, international normalized ratio (INR), platelets, red blood cells (RBC),
helnoglobin, hematocrit and white blood cells (WBC) with differential count (absolute and %), and
beta human chorionic gonadotropin (13-HCG) if applicable.
• Amendment to Protocol Section 3:
Current version (pages ! 9/21);
Section 3 INVESTIGATOR(S) AND STUDY ADMINISTRATIVE STRUCTURE (page 19-
21), is amended as described below:
Sponsor
Corporate Director of Clinical Reseaÿ-h
Sciences/Sponsor's Representative
blead of Co:ìÿerate Therape-:tic A.ì"eaÿ
Oacology, !mmu::alogy & Anti::fecti':e
Menarini Ricerche S.p.A.
Clinical.......,..°  ....... ....s" Sciences
Via Sette Santi, 1
50131 Fiorence, ltaly
Page 3 of 9


Clini¢al Trial Protocol Amendment No. I
EudraCT No.: 2016-001445-61
FLORET
1 ,gÿÿ ÿí.ÿ,ÿÿ r r«J,--ÿ ÿx, ÿ. « ÿ-ÿ-
Study Code FLO-02
Amendment Date 02 Feb 2017
Oncology & Imnmnology Corporate Dhector
Clinical Research Physician
Study Manager
Head of Corporate Biostatistic and Data
Management
Data Manager
Head of Corporate Clinical Pharmacology and
Pharlnacometrics
Biostatistician
    
[] Amendment to Protocol Section 4:
Current version (pages 22/27):
Section 4.1 GLOSSARY (page 25-27), is amended as described below:
CL                      Clearance
C-ger                     Creatiìfine Clearanc-e
CL/F                    Apparent clearance
i « i,t,t
                      
oÿ1 t41|l ÿ,ÿ...PlÿÿtlIJLJLJLIÿ
SD                       Standard Deviation
• Amendment to Protocol Section 6:
Current version (page 36/43):
Section 6.1 Disease and Study Rationale, (pages 36-38), is amended as described below:
Page 4 of 9


Clinical Trial Protocoi Amendment No. 1
EudraCT No.: 2016-001445-61
FL©RET
Study Code FLO-02
Amendment Date 02 Feb 2017
According to Coiffier et al. [3], the fisk of developing TLS, or more simply the risk of developing
acute renal impairment, is significantly increased in patients with higher levels of uric acid velwus
those with lower levels. For every mg/dL increase in sUA, the risk of TLS raises by a factor 1.75
(p<0.0001), while the risk of renal events by a factor 2.21 (p=0.0012). This observation underlines
the impolÿance of preventing/containing the uric acid increase during chemotherapy.
2) Diagnosis: Laboratory TLS (LTLS) is diagnosed if levels of 2 or more serata values of uric acid,
potassium, phosphate or calcium are more or less than normal at presentation, or if they change by
at least 25% from baseline (see Errore. L'origìne riferimento non è stata trovata.). The only significant
differente between adults and children is the tlu'eshold of phosphate, which is higher in children in
an age-dependent way [5-7].
= Amendment to Protocol Section 8:
Cun'ent version (page 45/72):
Section 8.3.1 Inclnsion Criteria (page 48-49), is amended as described below:
male and female ctUldren of 6 to less than 12 years of age, adolescents of 12 to less than 18
years of age and adults fi'oro 18 years:
b,
C.
d.
NOTE:
scheduled for first cytotoxic chemotherapy cycle, regardless of the line of treatlnent,
because of hematologic malignancies, and
at intermediate or high risk of TLS [4], and
with .ÿerum uric acid (sUA) levels < 10 mg/dL at Visit 1 (Day 1), and
with no access to rasburicase;
Evaluation of uric acid could be done both in serum o1" plasma specimen based on local laboratory
standard practices.
Section 8.6.3.3 Safety LaboratolT Evaluation (page 62-63), is amended as described below:
Table 3: Seramÿ, Blood and Urine Sample Analyte Listing
ìÿl'7_ ni li I     i           ",   t
• .,ÿ  .......  BIOCHEMISI Rÿ       [    HEMATOLOGY   ]  URINAI,YSIS
Creatinine                             Haemogiobin          pri
sUA                                  Haematocrit           Density
Potassium                             RBC count
Page 5 of 9


Clinical Trial Protocol Amendment No. 1
EudraCT No.: 2016-001445-61
FLORET
Study Code FLO-02
Amendment Date 02 Feb 2017
Table 3: Sevuÿ, Blood and Urine Sample Analyte Listing
4ÿI-M-BIOCHEMISTRY                                                                                 URINAI,YSIS
Phosphorus
Calcium
BUN / Urea
Albulnin
Alkaline phosphatase
Amylase
Glucose
Total protehÿ
HEMATOLOGY
Platelet count
WBC count and
(absolute and %):
neutrophil
lymphocyte
Nitrite
eosnmphil
basophil
monocytes
Protein
Glucose
Ketones
Total bilirubin and Dh'ect bilirubin
ALT and AST
LDH
GGT
1NR
prothrombin tilne/prothrombin activity
Sodium
Chloride
Beta-HCG (ONLY at Screening if
applicable)
RBC
WBC
Epitheliai cells
Casts
Bacteria
Yeast
Cl3,stals
ESTI?,LUI'ED PAP, AMETEII-S
• Amendment to Protocol Section 9:
Current version (page 73/79):
Section 9.3.4 Clinical endpoints, hlcidence of LTLS and CTLS (page 77), is amended as
described below:
Cliuical en@oiuts: lucidence of LTLS attd CTLS
The assessment for LTLS from Start of Chemotherapy (Visit 3, Day 3) to the Evaluation
Visit (Visit 8, Day 8) will be defined as:
1" PRESENCE        2 or more laboratory abnormalities including: a 25% increase or
levels above normal for serum uric acid, potassium, and phosphate
or a 25% decrease or levels below normal for calcium.
0: ABSENCE         less than 2 laboratory abnormalities including: a 25% increase or
levels above normal for ,scruto uric acid, potassium, and phosphate
or a 25% decrease or levels below normal for calcium.
Page 6 of 9


Clinical Trial Protocol Amendment No. 1
EudraCT No.: 2016-001445-61
FLORET
• ,t. a.,.,ÿ ,,.ÿ, ,,,,v. ÿ ÿ «..zl.: «. ,oÿ
Study Code FLO-02
Amendment Date 02 Feb 2017
• Amendment to Protocol Section 13:
Current version (page 86/120):
Section 13.1 Appendix h Definition of LTLS and CTLS (page 86), is amended as described
below:
Diagnosis of LTLS: LTLS is diagnosed if levels of 2 or more .ÿerum values of uric acid,
potassiurn, plaosphate or calcium are more than or less than normal at presentation or if they
change by at least 25% from baseline.
ELEMENT                        VALUE
CHANGE FROM BASELINE
Uric Acid                 >_ 476 l.tmol/L (or 8 mg/dL)               25% hlcrease
Potassium                      > 6.0 mmol/L                     25% increase
Phosphorus                > 1.45 nunol/L (adults) or>
2. lÿmnol/L (children)                 25% increase
Calcium                      < 1.75 mmol/L                    25% decrease
For adolescents and adults, the values ofphosphorus will be considered the same for the diagnosis of LTLS.
Page 7 of 9




Clinical Trial Protocol Amendment No. 1
EudraCT No.: 2016-001445-61
FL©RET
Study Code FLO-02
Amendment Date 02 Feb 2017
PRINCIPAL INVESTIGATOR'S STATEMENT
a) Clinical Statemem
My signature below documents my agreement with the contents of this clinical triai protocol
amendment No. 1 dated 02 Feb 2017 to the .lini.al trial protocol titled "Open label, muiti-centre,
parallel group study to compare the phamtacokinetics (PK), phammcodynamics (PD) and safeO,
of febuxostat between pediatric patients (>__6<18 years of age) and adults" - Final Version 1.0,
dated 12 Apr 2016- with regard to the execution of the study and the required documentatiolddata
collection. I agree to comply with this clinical trial protocol amendment in its entfl'ety and with the
ICH guidelines for Good Clinical Practice (GCP).
b) Anti-Corruption Statement
I agree to - I will and I will cause any of my collaborators to - perfonn any activity in accordance
with the pfinciples of any intemational anti-corruption legislations, such as OECD Convention on
Combating Bribery of Foreign Public Officials in International Business Transactions, UK Bribery
Act and US Foreign Con'upt Practices Act, including Italian Legislative Decree 231/2001. In
particular, along the performance of the study, I will not - and I will cause any of my collaborators
not to - directly or indirectly offer, pay, give, or promise to pay or give or receive any payment or
gift of any money or thing of value to or from any govermnent officer to influence any acts or
decisions or to induce such officer to use its influence to effect or infiuence the decision of the
relevant government body or any other decision maker. I accept to promptly inform the Sponsor in
wfiting in case of violations of or deviations fi'oro any of the above prescriptions in the conduct of
the study and I acknowledge and accept Sponsor's rights to conduct audits in order to verify
compliance with the above during or in comaection with the performance of the study. I agree and
accept that a violation of any of the above prescriptions may result in the tennination of the research
activities of the site I work in and/or the entire study.
Principal Investigator
Signature                        Date
e.eee.e....e..e.e.eo.iee.eeeoIe6ie..ieo.e.eooeoe.oe....oe....   .,.........,..,.... ,.., ..... «........,,......., i............ •   ............,.......,,...... 1.
(printed name)
Page 9 of 9


Clinical Trial Protocol Amendment No. 2
Only for Htmgary
EudraCT No.: 2016-001445-61
FLORET
Study Code FLO-02
Amendment Date 03 Feb 2017
MENARINI
RICERCHE
OPEN LABELÿ MULTI-CENTREÿ PARALLEL GROUP STUDY TO COMPARE
THE PHARMACOKINETICS (PK), PHARMACODYNAMICS (PD)
AND SAFETY OF FEBUXOSTAT BETWEEN
PEDIATRIC PATIENTS (>_6<18 YEARS OF AGE) AND ADULTS
Protocol Version(s)
Amendment
Previous Amendment(s)
Study code
Study Nick Name
EudraCT-Number
Invesfigafional Medicinal
Product
Final Version 1.0 dated 12 Apr 2016
Protocol Amendment No. 2, dated 03 Feb 2017
Protocol Aanendment No. 1, dated 02 Feb 2017
FLO-02
FLORET
2016-001445-61
FEBUXOSTAT
The contents ofthis Substantial Amendment No. 2 dated 03 Feb 2017 refers to changes made to
the Clinical Trial Protocol Final Version 1.0 dated 12 Apr 2016
and Amendment No. 1 dated 02 Feb 2017.
Submission for approval of this Arnendment No. 2 will be processed through the Competent
Authority, Ethical Colmnittees, and hwestigators involved in the study in Hungary.
Page 1 of 5


Clinical Trial Protocol Amendnlent No. 2
Only for Hungary
EudraCT No.: 2016-001445-61
FLQRET
Study Code FLO-02
Amendment Date 03 Feb 20 ! 7
1. Reasons for the Amendment
Glomerular Filtration Rate (GFR) is usually accepted as the best overall index of kidney function.
In clinical practice kidney function is evaluated by measuring the estimated Glomerular Filtration
Rate (eGFR) or Creatinine Clearance.
According to the linternational guidelines published in 2012 by KDIGO (Kidney Disease:
Improving Global Outcomes) severe renal insufficiency (grade 4) corresponds to creatinine
clearance <30 mL/nfin. For adult patients this classification is considered as the most appropriate
and is the same category considered for the use of Febuxostat as reported in its SmPC.
For the pediatric population a more conservative approach is commonly applied, and it considers
the corrected creatinine clearance with the cut off <60 mL/min/1.73 m2 as the indicator of kidney
damage.
As requested by the Hungarian National Institute of Phammcy and Nutrition Agency, the exclusion
of adult and paediatric patients with severe renal fimction will be based on the cut off of the
clearance creatinine < 30 mL/min and < 60 mL/min/1.73 m2, respectively. Therefore, the criteria
relative to kidney function making the patients eligible to take part to the study as well as for
treatment withdrawal because of severe renal failure will be accordingly specified along the
protocol.
IKidney Disease: hnproving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline
for the Evaluation and Management of Cluonic Kidney Disease. Kidney inter., Suppl. 2013; 3:1-150.; 2ADENURIC®
SnLPC, Appendix II:EU SmPCs for Adenuric®.
2. Protocol changes in detail
Report speci/ìc changes for relevant protocol section (including paragraph number and pageÿ),
additions shotdd be highlighted as tmderlined, whereas deletions as sb'i!ce o::t, reporting whenever
possible the full affected changes. AlternativeI); the tracked changes can be strictly limited to the
affected lines.
• Amendment to Protocol Section 2 and Section 8:
Currem version (page 4/18 and 45/72):
Section 2 Protocol Synopsis Exclusion Criteria (page 7) and Section 8.3.2 Exclusion Criteria
(page 49) is amended as described below:
•  patients with severe renal insufficiency-, as defined below calculated based on local clinical
prac,tice:
-  adult patients with a clearance creatinine < 30 mLhnin;
-  pediatric patients with eGFR <60 mL/milv'l.73 m2.
Section 8.3.3 Withdrawal of patients from therapy or assessment (page 49/50) is amended as
described below:
Page 2 of 5


Clinical Trial Protocol Amendment No. 2
Only for Hungary
EudraCT No.: 2016-001445-61
FL©RET
. .,.xa • -» ÿJ .ÿÿ-,..I, -«ÿ, .»
Study Code FLO-02
Amendment Date 03 Feb 2017
Patients should not receive fi.'ther study medication and will be withdrawn from the study (study
termination) ha case of medicai emergency or necessity including but not limited to:
,,  adverse events with a possible, probable or certain drug-causality as per Investigator's judgment
ofseverity grade >_3 CTCAE version 4.03;
appearance of skin rash or of any signs which may indicate allergic/hypersensitivity
reactions (NOTE: in case of severe allergic/hypersensitivity reactions, febuxostat must not
be re-started in patients at aw time; for guidance please refer to the EU SmPC, Appendix
II:TLS Risk Assesment);
severe hepatic insufficiency;
severe renal insufficiency;
NOTE: renal insufficiency defined as below:
-     adult patients with a clearance creatinine < 30 mL/min;
-     pediatrie patients with eGFR <60 mL/min/1.73 m2.
Page 3 of 5




Ciinical Trial Protocol Amendment No. 2
Only for HtmgaD'
EudraCT No.: 2016-001445-61
FL©RET
Study Code FLO-02
Amendment Date 03 Feb 2017
PRINCIPAL INVESTIGATOR'S STATEMENT
a) Clinical Statement
My signature below documents my agreement with the contents of this clinical trial protocol
amendment No. 2 dated 03 Feb 2017 to the clinical trial protocol titled "Open label, multi-centre,
parallei group study to contpare the pharmacokinetics (PK), pharmacodj,namics (PI)) attd safeO,
of febuxostat between pediatrie patients (>__6<18 j,ears of age) attd adults'- Final Version 1.0,
dated 12 Apr 2016 - with regard to the execution of the study and the required documentation/data
collection. I agree to comply with this clinical trial protocol alnendment in its entirety and with the
ICH guidelines for Good Clinical Practice (GCP).
b) Anti-Corruption Statement
I agree to - I will and I will cause any of my collaborators to - perform any activity in accordance
with the principles of any international anti-corruption legislations, such as OECD Convention Oh
Combating Bribery of Foreign Public Officials in International Business Transactions, UK Bribery
Act and US Foreign Con'upt Practices Act, including Italian Legislative Decree 231/2001. In
particular, along the performance of the study, I will not - and I will cause any of my collaborators
not to - directly or indirectly offer, pay, give, or promise to pay or give or receive any payment or
giri of any money or thing of value to or fi'oro any government officer to influence any acts or
decisions or to induce such officer to use its influence to effect or influence the decision of the
relevant government body or any other decision maker. I accept to promptly inform the Sponsor in
writing in case of violations of or deviations fi'oro any of the above prescriptions in the conduct of
the study and I acknowledge and accept Sponsor's fights to conduct audits in order to verify
compliance with the above during or in connection with the performance of the study. I agree and
accept that a violation of any of the above prescriptions may result in the termination of the research
activities of the site I work in and/or the entire study.
Principal Investigator
Signature                        Date
• e.o..oco  oo..eeeo.oeeo.e.oooeeo.oe....o.oo.o.oo..o...oo...o..   ..,.e,,...,,,,..,.,....,....,.,.,,.,,,,.., .. o,,..,,..,.,,,,,,   ..,.,.,,,,.,,.,,.,, .,,.,,,..,,
(printed name)
Page 5 of 5