Randomised, Open-label, Active-controlled, Multicentre, Comparative Study to Evaluate the Safety and Efficacy of Ferric Maltol (Iron (III)-Maltol Complex) (ST10) Oral Suspension Compared to Ferrous Sulfate Oral Liquid in Children and Adolescents Aged 2 to 17 Years With Iron-deficiency Anaemia, Incorporating a Single Arm Study in Infants Aged 1 Month to Less Than 2 Years
Phase: PHASE3
Conditions: Anemia, Iron-deficiency
Sponsor: Shield Therapeutics

CONFIDENTIAL 
 
 
 
 
Page 1 of 80 
 
 
  
 
CLINICAL STUDY PROTOCOL 
Randomised, open-label, active-controlled, multicentre, comparative study to evaluate the 
safety and efficacy of ferric maltol (iron (III)-maltol complex) (ST10) oral suspension 
compared to ferrous sulfate oral liquid in children and adolescents aged 2 to 17 years with 
iron-deficiency anaemia, incorporating a single arm study in infants aged 1 month to less 
than 2 years 
 
 
Protocol Number: 
ST10-01-305  
Test Drug:  
 
Ferric Maltol (ST10) 
EudraCT Number:  
2018-000078-31 
IND Number:  
114832 
Study Name:   
FORTIS  
Sponsor: 
Shield TX (UK) Limited, Northern Design Centre, Baltic Business 
Quarter, Gateshead Quays, NE8 3DF United Kingdom   
 
Version/Date: 
 Version 4.1, Final, 06 July 2023 
 
 
 
Confidentiality Statement 
The information contained in this document is provided in confidence.  It is understood that 
this information will not be used, disclosed or published without written consent of Shield 
TX (UK) Limited.

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06-07-2023
17:43:57+01:00

 
Protocol ST10-01-305, Version 4.1 
Final, 06 July 2023 
 
 
CONFIDENTIAL 
 
 
 
 
Page 3 of 80 
 
2 TABLE OF CONTENTS 
1 
PROTOCOL APPROVALS .................................................................................................................. 2 
2 
TABLE OF CONTENTS ....................................................................................................................... 3 
3 
ABBREVIATION INDEX ..................................................................................................................... 7 
4 
SYNOPSIS ....................................................................................................................................... 10 
5 
BACKGROUND INFORMATION ...................................................................................................... 22 
5.1 
OVERVIEW OF DISEASE ......................................................................................................... 22 
5.2 
CURRENT TREATMENT OF DISEASE ...................................................................................... 23 
5.3 
OVERVIEW OF TEST PRODUCT .............................................................................................. 25 
5.4 
RESULTS OF PREVIOUS CLINICAL STUDIES ............................................................................ 25 
5.4.1 
Phase 3 studies in adults ............................................................................................... 25 
5.4.2 
Phase I studies in adults ................................................................................................ 26 
5.4.3 
Phase I study in children and adolescents .................................................................... 28 
5.5 
DOSE SELECTION AND RATIONALE FOR THE STUDY ............................................................. 29 
5.5.1 
Study Population ........................................................................................................... 35 
5.5.2 
Study Treatment and Duration ..................................................................................... 35 
5.6 
RISK-BENEFIT EVALUATION ................................................................................................... 36 
6 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 40 
6.1 
PRIMARY OBJECTIVES: .......................................................................................................... 40 
6.2 
SECONDARY OBJECTIVES: ..................................................................................................... 40 
6.3 
PRIMARY ENDPOINTS ............................................................................................................ 41 
6.4 
SECONDARY ENDPOINTS ....................................................................................................... 41 
6.5 
EXPLORATORY ENDPOINTS ................................................................................................... 41 
7 
INVESTIGATIONAL PLAN ............................................................................................................... 42 
7.1 
STUDY OVERVIEW ................................................................................................................. 42 
7.2 
INVESTIGATIONAL SITES........................................................................................................ 44 
7.3 
INCLUSION AND EXCLUSION CRITERIA ................................................................................. 44 
7.3.1 
Inclusion Criteria ........................................................................................................... 44 
7.3.2 
Exclusion criteria ........................................................................................................... 45 
7.4 
CONCOMITANT MEDICATION ............................................................................................... 46 
7.4.1 
Not Permitted ............................................................................................................... 46 
7.4.2 
Permitted ...................................................................................................................... 46 
7.4.3 
Potential Medication Interactions ................................................................................ 47 
7.5 
INDIVIDUAL DISCONTINUATION CRITERIA ............................................................................ 47 

 
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7.6 
STUDY TERMINATION ........................................................................................................... 48 
8 
TREATMENT OF SUBJECTS ............................................................................................................ 49 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PRESENTATION ......................................... 49 
8.2 
COMPARATOR ....................................................................................................................... 49 
8.3 
PACKAGING ........................................................................................................................... 49 
8.4 
STORAGE ............................................................................................................................... 49 
8.5 
LABELLING ............................................................................................................................. 49 
8.6 
TREATMENT ASSIGNMENT AND BLINDING .......................................................................... 50 
8.6.1 
TREATMENT ASSIGNMENT............................................................................................ 50 
8.7 
TREATMENT COMPLIANCE .................................................................................................... 51 
8.8 
CONTINUATION OF TREATMENT .......................................................................................... 51 
9 
ENROLMENT AND RANDOMISATION PROCEDURES ..................................................................... 52 
9.1 
SCREENING (Visit 1) ............................................................................................................... 52 
9.2 
RANDOMISATION (Visit 2) .................................................................................................... 52 
9.3 
REPLACEMENT POLICY .......................................................................................................... 53 
9.4 
BLINDING PROCEDURES ........................................................................................................ 53 
9.5 
EMERGENCY UNBLINDING .................................................................................................... 53 
10 STUDY PROCEDURES ..................................................................................................................... 54 
10.1 
COVID-19 IMPLICATIONS ON THE TRIAL ............................................................................... 54 
10.2 
DESIGN SCHEMATICS ............................................................................................................ 55 
10.3 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS AGED 2 YEARS-17 YEARS ............................... 56 
10.4 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS AGED 1 MONTH - < 2 YEARS .......................... 58 
10.5 
DEMOGRAPHICS AND MEDICAL HISTORY ............................................................................. 60 
10.6 
PHYSICAL EXAMINATION ...................................................................................................... 60 
10.7 
CONCOMITANT MEDICATIONS AND PROCEDURES .............................................................. 60 
10.8 
VITAL SIGNS ........................................................................................................................... 60 
10.9 
LABORATORY ASSESSMENTS ................................................................................................ 60 
10.9.1 
Haematology and Clinical Chemistry ............................................................................ 60 
10.9.2 
Pharmacokinetics .......................................................................................................... 61 
10.9.3 
Urine Pregnancy Test .................................................................................................... 63 
10.9.4 
Palatability and acceptability scoring............................................................................ 63 
10.9.5 
PK Days food intake ...................................................................................................... 64 
10.9.6 
Overall blood volume .................................................................................................... 64 
11 SAFETY ........................................................................................................................................... 65 

 
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11.1 
DEFINITIONS .......................................................................................................................... 65 
11.1.1 
ADVERSE EVENT (AE) .................................................................................................... 65 
11.1.2 
SERIOUS ADVERSE EVENT (SAE) .................................................................................... 66 
11.2 
REPORTING AND DOCUMENTATION .................................................................................... 67 
11.2.1 
Immediate Reporting .................................................................................................... 68 
11.2.2 
Non-Immediate Reporting ............................................................................................ 69 
11.3 
EVALUATION ......................................................................................................................... 69 
11.3.1 
Intensity ........................................................................................................................ 69 
11.3.2 
Causality ........................................................................................................................ 69 
11.3.3 
Outcome ....................................................................................................................... 70 
11.4 
RE-EXPOSURE ........................................................................................................................ 70 
12 STATISTICAL CONSIDERATIONS ..................................................................................................... 71 
12.1 
POWER CALCULATIONS ........................................................................................................ 71 
12.2 
STATISTICAL METHODS ......................................................................................................... 71 
12.2.1 
Primary Endpoint Analysis ............................................................................................ 71 
12.2.2 
Secondary Endpoint Analyses ....................................................................................... 72 
12.2.3 
Sensitivity Analyses ....................................................................................................... 72 
12.2.4 
Imputation of Missing Data .......................................................................................... 72 
12.3 
DEFINITION OF POPULATIONS .............................................................................................. 73 
12.3.1 
Randomised Population/ Intention to treat (ITT) ......................................................... 73 
12.3.2 
Safety Population .......................................................................................................... 73 
12.3.3 
Per Protocol population (PP)......................................................................................... 73 
12.3.4 
Pharmacokinetic (PK) Population (Full Analysis Set) .................................................... 73 
13 ETHICAL CONSIDERATIONS ........................................................................................................... 74 
13.1 
DECLARATION OF HELSINKI................................................................................................... 74 
13.2 
INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE ............................... 74 
13.3 
SUBJECT INFORMATION AND INFORMED CONSENT ............................................................ 74 
13.4 
SUBJECT DATA PROTECTION ................................................................................................. 75 
13.5 
SUBJECT INSURANCE ............................................................................................................. 75 
13.6 
CONFLICT OF INTEREST ......................................................................................................... 75 
13.7 
REGISTRATION OF STUDY AND DISCLOSURE OF RESULTS .................................................... 75 
14 STUDY MANAGEMENT .................................................................................................................. 76 
14.1 
SOURCE DATA ....................................................................................................................... 76 
14.2 
QUALITY ASSURANCE ............................................................................................................ 76 

 
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14.3 
MONITORING ........................................................................................................................ 76 
14.4 
STUDY FUNDING ................................................................................................................... 77 
14.5 
CONTRACT RESEARCH ORGANISATION (CRO) ...................................................................... 77 
14.6 
AMENDMENTS TO THE STUDY PROTOCOL ........................................................................... 77 
14.7 
STUDY STOPPING RULES ....................................................................................................... 77 
14.8 
END OF STUDY ....................................................................................................................... 78 
14.9 
RETENTION OF RECORDS ...................................................................................................... 78 
14.10 SECURITY AND PUBLICATIONS .............................................................................................. 78 
15 REFERENCES .................................................................................................................................. 79 

 
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3 ABBREVIATION INDEX  
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration Curve 
AUClast 
Area under the Plasma Concentration curve from 0 up to the last 
measurable concentration (non-below) quantification limit after 
dosing 
AUC(0-inf) 
Area Under the Plasma Concentration Curve for 0-infinity 
BID 
Twice Daily  
BNF 
British National Formulary 
BUN 
Blood Urea Nitrogen 
BP 
Blood pressure 
C 
Celsius 
CA 
Competent Authority 
CD 
Crohn’s Disease 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
Cmax 
Maximum Plasma Concentration 
CL/F 
Apparent Systemic Clearance 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract Research Organisation 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
dL 
Deciliter 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
ESA 
Erythropoiesis Stimulating Agent 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
Fe3+ 
Ferric iron 
FOCE 
First Order Conditional Estimation 
FO 
First Order Estimation 

 
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GCP 
Good Clinical Practice  
GDPR 
General Data Protection Regulation  
GGT 
Gamma-Glutamyl Transpeptidase  
GI 
Gastrointestinal  
GMP 
Good Manufacturing Practice  
h  
Hour 
Hrs 
Hours 
Hb 
Haemoglobin  
IBD 
Inflammatory Bowel Disease 
ICH 
International Conference on Harmonisation  
ID 
Iron Deficiency 
IDA 
Iron Deficiency Anaemia 
IEC 
Independent Ethics Committee 
IMP  
Investigational Medical Product  
IMPD 
Investigational Medicinal Product Dossier 
IND 
Investigational New Drug 
iPSP 
Initial Paediatric Study Plan 
IRB 
Institutional Review Board  
IRT 
Interactive Response Technology 
ISF 
Investigator Site File 
ITT 
Intention-To-Treat  
IUD 
Intrauterine Contraceptive Devices 
IV 
Intravenous  
m 
Month 
MAA 
Marketing Authorisation Application 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Millilitre  
NCA 
Non-compartmental analysis 
NCS 
Non-Clinically Significant 
NTBI 
Non-Transferrin Bound Iron 
OFP 
Oral Ferrous Product 
OTC 
Over-the-counter 
PHI 
Protected Health Information 
PI 
Prescribing Information 
PIP 
Paediatric Investigational Plan 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PSP 
Paediatric Study Plan 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 

 
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SD 
Standard Deviation 
TEAE 
Treatment-emergent Adverse event 
TESAE 
Treatment-emergent Serious Adverse event 
TIBC 
Total Iron Binding Capacity 
TLAG 
The delay between the time of dosing and time of appearance of 
concentration in the sampling compartment 
Tmax 
Time to Maximum Plasma Concentration 
TSAT 
Transferrin Saturation 
UC 
Ulcerative Colitis  
UIBC 
Unsaturated Iron Binding Capacity 
US 
United States 
V/F 
Apparent Volume of Distribution 
WHO 
World Health Organization  
yrs 
Years 
 

 
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4 SYNOPSIS 
Title  
Randomised, 
open-label, 
active-controlled, 
multicentre, 
comparative study to evaluate the safety and efficacy of ferric 
maltol (iron (III)-maltol complex) (ST10) oral suspension 
compared to ferrous sulfate oral liquid in children and 
adolescents aged 2 to 17 years with iron-deficiency anaemia, 
incorporating a single arm study in infants aged 1 month to less 
than 2 years 
 
Protocol Number  
ST10-01-305 
Study Name 
FORTIS 
Test Drug 
Ferric maltol oral suspension 
Comparator 
Ferrous sulfate oral liquid 
Phase  
Phase 3 
Sites 
Approximately 20 sites  
Study Rationale 
The existing scientific and clinical experience with ferric maltol in 
the treatment of IDA in patients with inflammatory bowel disease 
(IBD) and chronic kidney disease (CKD) supports its further 
investigation in the treatment of iron deficiency/IDA in children 
and adolescents, in line with the Paediatric Investigation Plan 
(PIP) for ferric maltol that has been reviewed and approved by 
the European Medicines Agency (PIP reference:  EMEA-001195-
PIP 01-11) and the Paediatric Study Plan (PSP) agreed with the US 
FDA (IND 114832). 
Ferric maltol makes iron available in the gastrointestinal tract, 
providing the iron in a biologically labile form for uptake across 
duodenal mucosal cells and ultimate haematopoiesis and storage 
on ferritin. 
Randomised 
Phase 
III 
studies 
(ST10-01-301/302) 
have 
demonstrated that ferric maltol over a 12-week period effectively 
increases Hb by over 2 g/dL compared to baseline in iron 
deficiency anaemic patients with inflammatory bowel disease 
(IBD). Ferric maltol was also demonstrated to be well tolerated 
(87% of adult subjects completing 12 weeks of study treatment) 
and with a side effect profile comparable to the placebo group. 
These data formed the basis of a Marketing Authorisation 

 
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Application (MAA) submission and subsequent EU centralised 
marketing authorisation.  
A randomised Phase III study (ST10-01-303) in 167 adult patients 
with IDA in Chronic Kidney Disease (CKD) over 16-week double 
blind phase and an open label 36-week treatment in 125 subjects 
demonstrated positive safety, efficacy and tolerability. Changes 
in TSAT, ferritin, and serum iron concentrations indicated an 
improvement in all iron parameters in the ferric maltol group 
compared to the placebo group and through the open-label 36-
week treatment period to Week 52. Overall, ferric maltol resulted 
in clinically and statistically significant increase in Hb compared 
to placebo.  These data, together with data from ST10-01-
301/302, formed the basis of a New Drug Application (NDA) 
submission and subsequent US marketing authorisation. 
Ferric maltol 30 mg capsules are approved for the treatment of 
Iron Deficiency in adults taken BID in the EU and Switzerland 
(Feraccru®) and in the US (Accrufer®). 
As part of the paediatric clinical development, two Phase I PK 
studies were performed. The first one was to understand the 
kinetics of the absorption of iron and absorption and the 
elimination of maltol in a paediatric subject group in order to 
establish a safe and effective dose in children and adolescents, 
aged 10-17 years. All 3 doses of ferric maltol (7.8 mg, 16.6 mg, 30 
mg) were well-tolerated and had a favourable safety profile over 
a 10-day period.  The results from this PK study support the 
proposed dosing regimen planned for this study.   
The second Phase I PK study was performed to compare 
therapeutic equivalence between the new oral ferric maltol 
suspension and the existing ferric maltol capsules in healthy 
adults under fed and fasted states. Both capsule and suspension 
were readily absorbed under both conditions with mean serum 
iron concentrations returning to baseline or slightly below at 24 
hrs.  As expected from the approved Prescribing Information, a 
food effect was observed for ferric maltol capsule with respect to 
Cmax but a definitive food effect was not observed with respect to 
AUClast and AUCinf (90% CIs span the 80.00-125.00 criteria). Ferric 
maltol suspension had similar serum iron PK when administered 
in fasted or fed conditions with respect to Cmax and AUClast. There 
were no apparent differences between the formulations 
(suspension versus capsule) in the number of AEs and no study 
drug-related TEAEs for either formulation. 
 

 
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Objectives 
Primary objective: 
1. To compare the safety and gastrointestinal tolerability of 
ferric maltol oral suspension and ferrous sulfate oral 
liquid in children and adolescents aged 2 years to 17 
years, and assess the safety and tolerability of ferric 
maltol oral suspension in children 1 month to less than 2 
years, in the treatment of iron deficiency anaemia during 
the 12 weeks treatment period. 
 
2. To assess the effect on haemoglobin (Hb) in children and 
adolescents aged 1 month to 17 years after twice daily 
ferric maltol oral suspension administration for 12 weeks. 
Secondary objectives: 
1. To assess the pharmacokinetics (PK) in children and 
adolescents aged 2 to 17 years after a single dose of ferric 
maltol oral suspension on Visit 2 (PK Day 1), and after twice 
daily administration for at least 6 days, on Visit 3 (PK Day 2) 
after a single morning dose, through measurement of serum 
iron, corrected serum iron, transferrin saturation (TSAT) and 
plasma 
maltol 
and 
maltol 
glucuronide.  
 
2. To assess the effect on iron markers in children and 
adolescents aged 1 month to 17 years after twice daily ferric 
maltol oral suspension administration for 12 weeks. 
 
3. To assess the PK in children aged 1 month to less than 2 years 
of age after a single dose of ferric maltol oral suspension (Pre-
assignment PK visit) and after twice daily administration for 
at least 6 days, on Visit 3 (PK Day 2) after a single morning 
dose, through measurement of serum iron, corrected serum 
iron, transferrin saturation (TSAT) (PK Day 2 only), plasma (PK 
Day 2 only) and urine concentration of maltol and maltol 
glucuronide. 
 
4. To assess the effect, in children aged 1 month to less than 2 
years of age after twice daily administration for at least 6 
days, on Visit 3 (PK Day 2) after a single morning dose, on 
serum transferrin, total and unsaturated iron binding capacity 
(TIBC, UIBC). 

 
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5. To assess the effect, in children aged 2 to 17 years   
after a single dose of ferric maltol suspension Visit 2 (PK Day 
1), and after twice daily administration for at least 6 days, on 
Visit 3 (PK Day 2) after a single morning dose, on serum 
transferrin, total and unsaturated iron binding capacity (TIBC, 
UIBC). 
  
6. To compare the palatability from age-appropriate scoring 
system of ferric maltol oral suspension and ferrous sulfate 
oral liquid. 
Endpoints  
Primary endpoints: 
- 
Safety and gastrointestinal tolerability  
o Treatment emergent Adverse Events (TEAEs)  
o Treatment-emergent Serious Adverse Events 
(TESAEs)  
- 
Treatment-emergent Adverse Events leading to 
premature 
discontinuation 
of 
study 
drug/PK 
assessments from baseline to Week 12 
- 
Change in Hb concentration from baseline to Week 12 
 
Secondary endpoints: 
- 
PK analysis of serum iron, corrected serum iron, TSAT, 
transferrin, TIBC, UIBC, maltol and maltol glucuronide 
in children and adolescents aged 1 month to 17 years 
in the ferric maltol group 
- 
Changes in iron markers from baseline to Week 12  
- 
Achieving Hb concentration within normal range at 
Week 12  
- 
Qualitative assessments from subject questionnaires 
that allow evaluation of the acceptability, palatability 
and ease of use  
- 
Age 1 month to less than 2 years; maltol and maltol 
glucuronide in urine from both PK days in children 
aged 1 month to less than 2 years 
 
 
Design 
The study will comprise of the following stages: 
• Screening: To determine subject eligibility for the study 

 
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(within 21 days prior to randomisation for each subject) 
• Pre-assignment PK phase: only applicable for subjects aged 1 
month to less than 2 years. Up to 28 days from Screening.  
All eligible subjects aged 1 month to less than 2 years will 
enter a Pre-assignment phase, 1-day Pharmacokinetic 
assessment day following a single dose of ferric maltol oral 
suspension.  After a baseline urine sample is collected, 
subjects will take a single dose of 0.1 ml/kg ferric maltol 
suspension under supervision and then further urine samples 
from three timepoints up to 12 hours.  
The PK samples will be analysed and if evidence of 
metabolism and elimination of maltol is shown, these 
subjects will enter the treatment phase and be assigned to 
the ferric maltol arm.  
Randomised treatment: 12 weeks open label treatment 
   
• Subjects aged 2-17 will be randomised 1:1 to receive ferric 
maltol oral suspension or ferrous sulfate oral liquid.  
The first 12 subjects randomised to ferric maltol in each 
age sub-group (2 – 9 yrs, 10 – 17 yrs, respectively) will 
enter a Pharmacokinetic phase from Visit 2 (PK Day 1) till 
Visit 3 (PK Day 2) with 2 PK days. Following baseline pre-
dose blood sample, subjects will take a single dose of 2.5 
ml (2 yrs- 11 yrs) or 5 ml (12 yrs - 17 yrs) ferric maltol oral 
suspension under supervision and then further 2 PK blood 
samples will be taken up to 6 hrs post dose. Following the 
last scheduled PK sample on PK Day 1 (Visit 2), subjects 
will be reminded to take their dose twice daily until PK 
Day 2 (between Day 7-Day 10). On PK Day 2 (Visit 3) 
subjects should withhold their morning dose until 
attending their next PK assessments. Same procedure will 
be repeated for PK assessment as on PK Day 1.  
Following PK Day 2 subjects will continue on treatment 
until Week 12.  
Once the 12 subjects in each age subgroup (2 - 9 yrs, 10-
17 yrs, respectively) have finished their PK visits, they will 
continue on treatment until week 12. They will not need 
to have further PK samples taken. 
Subjects randomised to ferrous sulfate oral liquid will not 
need to complete the PK period, they will remain on oral 
ferrous sulfate liquid until Week 12.  
 

 
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Ferrous sulfate 125 mg/ml (25 mg elemental iron) or 
equivalent dose will be used for all children/adolescents. 
To maximise the iron replenishment for subjects within 
this group as well; aged 2 - 17 yrs will be dosed 0.24ml 
(6mg elemental iron) per kg body weight per day, up to a 
maximum of 8ml given daily in two divided doses. 
 
• Assigned treatment phase: 12 weeks open label treatment for 
ferric maltol children aged 1 month to less than 2 years 
Once the PK samples collected from the pre-assignment 
phase have been analysed for subjects aged 1 month to 
less than 2 years and confirm they can enrol in the 
randomisation phase, they will be assigned to receive 
ferric maltol oral suspension and start the 0.1ml/kg/dose, 
BID (Maximum 2.5ml BID) dose on Visit 2 and continue for 
7-10 days. On Visit 3 (PK Day 2), following baseline pre-
dose blood sample and urine sample, subjects will take a 
single dose of 0.1 ml/kg ferric maltol suspension under 
supervision. Further three PK blood and urine samples will 
be collected up to 12 hours post dose. Subjects will 
continue until week 12. 
 
• End of study: Week 12 visit  
• Post-treatment safety follow-up: 10-14 days following study 
completion of the treatment period or premature 
discontinuation  
Number of Subjects 
Approximately 110 male and female children from 1 month to 17 
years of age, with iron deficiency anaemia. 
Subjects aged 2 to 17 years will be 1:1 randomised to ferric maltol 
and ferrous sulfate, with 49 subjects in each arm. Subjects then 
will be further divided into 2 age groups: 2 yrs – 9 yrs and 10 yrs 
-17 yrs. A minimum of 18 subjects must be recruited into the 2 
yrs - 9 yrs and 10 yrs – 17 yrs age groups and a minimum of 25% 
of either sex must be recruited.  
A maximum of 12 subjects will be recruited in the 1 month to less 
than 2 years age group. If less than 91 subjects in total have been 
randomized when 32 ferric maltol subjects have completed, then 
an interim analysis analysis of the primary effectiveness endpoint 
(change in Hb concentration from baseline to Week 12) will be 
conducted. If significant, the study will stop recruitment.  If not 
significant, the study will continue (all subjects will be assigned to 

 
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ferric maltol) until 54 subjects have been recruited in the ferric 
maltol arm. 
Inclusion Criteria 
1. Patient is willing and able to comply with the study 
requirements and to provide written informed consent. In 
the case of patients under the age of legal consent, the 
legal guardian(s) must provide informed consent and the 
patient should provide assent per local and national 
requirements. 
2. Age ≥1 month and ≤17 years at the time of informed 
consent  
3. Subjects must have iron deficiency anaemia defined by 
the following criteria, as measured by the central 
laboratory at the screening visit  
Haemoglobin thresholds define anaemia by age and gender: 
Children (1 m – < 5 yrs) <11.0 g/dl 
Children (5 yrs – < 12 yrs) <11.5 g/dl 
Children (12 yrs) <12.0 g/dl 
Female child (≥13 yrs) <12.0 g/dl 
Male child (≥13 yrs) <13.0 g/dl 
and 
Ferritin thresholds define anaemia by: 
ferritin <30 µg/L,  
or ferritin <50 µg/L with transferrin saturation (TSAT) 
<20%,  
4. Female subjects of childbearing potential must agree to 
use a highly effective method of contraception (which 
includes complete abstinence) until study completion and 
for at least 4 weeks following their final study visit.  Highly 
effective contraception is defined as a method which 
results in a low failure rate, i.e., less than 1% per year 
when used consistently and correctly, such as implants, 
injectables, some intrauterine contraceptive devices 
(IUDs), a vasectomised partner and oral contraceptive 
medications.  
The need for contraception and compliance with 
contraception requirements will be assessed at every visit 
for adolescent patients, and urine pregnancy testing will 
be performed at each visit for female subjects of 

 
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childbearing potential. 
Exclusion Criteria 
 
A subject who meets any of the following criteria is not eligible 
for participation in the study. 
1. Subject with anaemia due to any cause other than iron 
deficiency, including, but not limited to, 
a. Untreated or untreatable severe malabsorption 
syndrome  
2. Subjects who have received prior to Screening: 
a. Within 28 days intramuscular or intravenous (IV) 
injection or administration of depot iron preparation. 
b. Within 7 days single agent iron preparations and 
during the study. 
c. Within 12 weeks of blood transfusion or is scheduled 
to have blood transfusion or donation during the 
study period 
d. Within 28 days erythropoiesis stimulating agents and 
during the study period 
e. Within 14 days COVID-19 vaccination  
3. Subjects with vitamin B12 or folic acid deficiency as 
determined by the central laboratory screening results. 
Subjects may start vitamin B12 or folate replacement and 
rescreen after at least 2 weeks.  
4. Has 
concomitant 
disease 
that 
would 
significantly 
compromise iron absorption or absorbed iron utilization such 
as swallowing disorders and/or extensive small bowel 
resection. 
5. History of active peptic ulcer 
6. Has chronic renal disease (eGFR <60 mL/min/m2), as assessed 
at Screening based on serum creatinine. 
7. Known hypersensitivity or allergy to either the active 
substance or excipients of ferric maltol or ferrous sulfate. 
8. Has a known contraindication for treatment with iron 
preparations, e.g. haemochromatosis, chronic haemolytic 
disease, sideroblastic anaemia, thalassemia, or lead 
intoxication induced anaemia. 
9. Impaired 
liver 
function 
as 
indicated 
by 
alanine 
aminotransferase (ALT) or aspartate transaminase (AST)>2.0 

 
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times upper normal limit as measured at the Screening visit. 
10. Active acute inflammatory disease, including IBD flare or 
disease exacerbation, which in the opinion of the 
Investigator, is clinically significant. 
11. Active chronic or acute infectious diseases requiring 
antibiotic treatment. 
12. Pregnant or breast feeding. 
13. Concomitant medical conditions with extensive active 
bleeding, other than menstrual cycles; subjects who suffer 
from menorrhagia may be included at the Investigator’s 
discretion. 
14. Scheduled or expected hospitalisation and/or surgery during 
the course of the study  
15. Participation in any other interventional clinical study within 
28 days prior to Screening. 
16. Diagnosed to be COVID-19 positive by (SARS‐CoV‐2‐RT‐PCR 
positive) within 28 days prior to screening.  
17. Cardiovascular, 
liver, 
renal, 
hematologic, 
psychiatric, 
neurologic, 
gastrointestinal, 
immunologic, 
endocrine, 
metabolic, respiratory or central nervous system disease 
that, in the opinion of the Investigator, may adversely affect 
the safety of the subject and/or objectives of the study drug 
or severely limit the lifespan of the subject. 
18. Any other unspecified reason that, in the opinion of the 
Investigator or the Sponsor make the subject unsuitable for 
enrolment. 
Concomitant Medication 
Not Permitted: 
• Treatment with other single agent oral iron preparations 
(prescription and non-prescription) within 7 days prior to 
screening and throughout the study period.  
• Treatment with parenteral iron preparations within 28 days 
prior to screening and throughout the study period. 
• Blood transfusions within 12 weeks before screening and 
during the study. 
• Erythropoiesis stimulating agents within 28 days before 
screening and during the study. 
Permitted: 
• Immunosuppressants. 

 
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• Vitamin B12 and folic acid supplements/replacement are 
allowed during the study 
• Over the Counter (OTC) oral supplements/multivitamin type 
preparations (including those that contain iron) may be taken, 
however subjects should keep the same dose during the 
study 
• Oral contraceptives are allowed during the study 
• All other concomitant medications must remain stable from 
Screening and throughout the study 
 
Discontinuation Criteria 
Subjects may be discontinued prematurely during the study for 
the following reasons: 
• Withdrawal of informed consent 
• >1 g/dl Hb drop from baseline 
• Unwillingness or inability to comply with protocol 
requirements 
• Pregnancy or not using a reliable method of birth control 
(female subject of childbearing potential) 
• Use of prohibited concomitant medications 
• Serious adverse events that are judged by the Investigator to 
be related to study treatment 
• Blood transfusions for any cause during the study treatment 
period 
• Use of any other single agent prescribed iron medications 
 
The reason for study drug discontinuation and the date of last 
dose should be recorded in the eCRF.  Subjects who discontinue 
treatment prematurely must return for the Post-treatment safety 
visit, unless informed consent is withdrawn (and the subject 
and/or their parent or guardian do not agree to attend this 
follow-up visit). A subject who meets discontinuation criteria 
should be discussed on an individual basis with the Medical 
Monitor. 

 
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Investigational Medicinal 
Product  
 
Ferric maltol oral suspension: oral suspension containing 30 mg 
elemental iron, in the form of 231.5 mg ferric maltol, in 5 ml 
suspension.  
Ferric maltol oral suspension will be taken every morning and 
evening at least 30 minutes after a meal. Dosing will be 
supervised by the parent/legal guardian for children/adolescents 
throughout the treatment period and recorded on a dosing diary.  
Ferric maltol bottles will be labelled for clinical trials use and each 
bottle will have a unique bottle number which will be utilised in 
the randomisation procedure. 
A final eligibility evaluation must be conducted immediately prior 
to randomisation.  
Reference safety information will be the Investigator Brochure.  
Comparator Therapy 
Ferrous sulfate 125 mg/ml (25 mg/ml elemental iron) oral liquid 
or equivalent dose will be administered under this protocol. 
Dosing will be supervised by the parent/legal guardian for 
children/adolescents throughout the treatment period and 
recorded on a dosing diary. 
Reference safety information will be the currently approved 
summary of product characteristics. 
Statistical Methods 
 
Safety and gastrointestinal tolerability will be compared between 
ferric maltol oral suspension and ferrous sulfate oral liquid via 
summaries of treatment emergent adverse events (TEAEs), 
treatment emergent serious AEs (TESAEs) and treatment-
emergent AEs (TEAEs) leading to premature discontinuation of 
study drug. 
Efficacy of ferric maltol will be assessed via the change in Hb 
concentration from baseline to week 12. If no interim analysis is 
conducted it will be based on a 95% two-sided confidence 
interval; If an interim analysis is conducted, a Pocock spending 
function will be used; the interim analysis will be based on a (100 
– 3.45)% two sided confidence interval; if the study does not stop 
after the interim analysis, the final analysis will be based on a (100 
– 2.57)% two sided confidence interval. 
For the PK analysis, all analytes in serum will be summarised per 
PK day, for children and adolescents aged 1 month to 17 years 
receiving ferric maltol. 

 
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In addition, all analytes in urine will be summarised per PK day, 
for children aged 1 month to less than 2 years. 
Full details of the statistical analysis, including the analysis of PK 
endpoints, will be specified in the statistical analysis plan (SAP). 
 
 
 

 
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5 BACKGROUND INFORMATION 
5.1 
OVERVIEW OF DISEASE 
In children, iron deficiency anaemia (IDA) should be considered in the presence of tiredness, 
restlessness, attention-deficit/hyperactivity disorder, irritability, growth retardation, and 
cognitive and intellectual impairment.  
The gold standard for diagnosing IDA is an iron stain of the bone marrow aspirate. Because 
bone marrow aspiration is too invasive to be used on a regular basis, the accepted and reliable 
method of diagnosis is based on a combination of parameters, including haematological and 
iron metabolism indices. Typically, decreased serum concentrations of haemoglobin (Hb) and 
iron, mean corpuscular volume, ferritin concentration and transferrin saturation are 
accompanied by increased total iron-binding capacity, transferrin concentration, red blood 
cell distribution width and erythrocyte protoporphyrin in comparison to age-appropriate 
reference ranges. Additionally, hypochromasia (meant by an excess of 10% of hypochromic 
cells) is noted on the peripheral blood smear (Thayu & Mamula, 2005; Mamula et al, 2002). 
However, diagnosing IDA in the setting of inflammatory disease (e.g. Inflammatory Bowel 
Disease, IBD) may be complicated due to inflammation. In these circumstances, many of the 
laboratory measures of iron status may be unreliable, as inflammation influences parameters 
of iron metabolism (Thayu & Mamula, 2005). For instance, the elevation in transferrin levels 
typical of iron deficiency may not be found, as patients with low albumin tend also to have 
low transferrin concentrations. Similarly, serum iron, transferrin saturation (TSAT), total iron 
binding capacity (TIBC) and zinc protoporphyrin levels are often difficult to interpret in the 
presence of inflammation.  Finally, circulating concentrations of the iron storage protein 
ferritin, the most accessible and well-known measure of stored iron and the most powerful 
test for iron deficiency, can be normal or even increased in response to inflammation, as it is 
an acute phase reactant, even in the presence of severe iron deficiency. Therefore, this 
parameter may not provide adequate information about the storage compartment in the 
setting of inflammatory conditions such as IBD, making it a less reliable marker because it 
adds confusion to the clinical picture.  
Accordingly, it has been suggested that specific diagnostic criteria for IDA need to be adapted 
to the level of inflammation. Thus, in patients without biochemical (C-reactive protein, etc.) 
or clinical (diarrhoea, endoscopic findings, etc.) evidence of inflammation, the cut-off point 
for defining a low level of serum ferritin is <30 μg/L; however, in the presence of 
inflammation, the lower limit of this parameter consistent with normal iron stores should be 
increased up to 100 μg/L.  
The soluble transferrin receptor, a cell surface glycoprotein, is a truncated fragment of the 
membrane receptor whose levels are increased when the availability of bone marrow iron 
stores for erythropoiesis are low, as in IDA. As the circulating concentration is not affected by 
anaemia of chronic disease, increased concentration of soluble transferrin receptor and the 

 
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ratio of soluble transferrin receptor/log ferritin has been proposed for reliable differential 
diagnosis of these overlapping conditions (Gasche et al, 2004). However, this assay is used 
primarily as a secondary measure, because it is not yet widely available and published data 
exist only for paediatric IBD (Weiss & Gasche, 2010).  
Other aids to the differentiation between IDA and anaemia of chronic disease, essential in 
order to provide the appropriate treatment, include quantification of reticulocyte 
haemoglobin and the percentage of hypochromic red cells, which indicate the availability of 
iron for erythroid progenitors, as well as determination of hepcidin in serum (Weiss & Gasche, 
2010). While anaemia of chronic disease is mostly normochromic and normocytic, IDA more 
frequently presents as microcytic and hypochromic anaemia.  
5.2 
CURRENT TREATMENT OF DISEASE 
There is a clear unmet medical need for an alternative oral treatment for anaemic children, 
particularly those who are intolerant to ferrous products, to avoid the need for IV iron 
therapy, regardless of the cause of the iron deficiency.  The proposed paediatric indication to 
be developed for ferric maltol is the treatment of iron deficiency anaemia (IDA). 
The first approach to correct iron deficiencies is related to diet and lifestyle. Mild iron 
deficiency can be corrected by increasing the intake of iron-rich food (particularly that 
containing the better-absorbed haem iron), and by increasing the absorption of iron by 
avoiding concomitant intake of tea (for example) or by concomitant ingestion of vitamin C. 
Introduction of iron-rich food/formula should be considered for asymptomatic infants aged 
6-12 months who are at increased risk of IDA, but infants and toddlers with suspected or 
proven IDA should begin oral iron treatment  (British Columbia Guidelines, 2010). The 
ultimate goal of dietary changes or pharmacological treatment is the return of haemoglobin 
concentrations to the age-appropriate reference range. The duration of treatment should be 
sufficient to normalise not only the haemoglobin value but also the iron stores. In the case of 
individuals with underlying diseases associated with IDA, the primary disease must also be 
addressed, of course. 
The mainstay of treatment of iron-deficiency anaemia is oral iron supplements. Ferrous 
compounds (sulfate, fumarate and gluconate), which are available both in solid and liquid 
forms, are the most common due to the extremely low bioavailability of conventional ferric 
preparations. The usual adult dose is 180 mg of elemental iron/day in divided doses. 
Therapeutic doses can range from 100 to 200 mg of elemental iron/day, depending on 
severity of symptoms, ferritin levels, age of the patient, and gastrointestinal side effects. The 
daily recommended dose of elemental iron for infants and children is between 3 and 6 mg/kg 
separated in two to three intakes and up to a maximum daily dose of 180 mg (British Columbia 
Guidelines, 2010) or 200 mg (BNF for Children, 2012). 

 
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A wide range of iron supplements is available, both on prescription and over-the-counter.  
Table 1 displays examples of oral iron compounds that are indicated for the treatment of iron-
deficiency anaemia in paediatric patients.  
Table 1. Example of oral liquid ferrous sulfate for treatment of iron-deficiency states in paediatrics 
 
Product 
Iron content 
Indication(s) 
Paediatric dose 
Ironorm® Drops 
1 ml of syrup 
contains the 
active ingredient 
Ferrous Sulfate 
125 mg 
(equivalent to 25 
mg Iron per ml). 
Prevention and treatment 
of iron deficiency 
anaemia.  
Paediatric: 0.12 ml to 0.24 
ml (3 mg – 6 mg elemental 
iron) per kg body weight, 
up to a maximum of 8 ml 
(200 mg elemental iron) 
given daily in two or three 
divided doses. 
 
Ferrous sulfate 75 
mg/ml (Iron 15 
mg/ml) (US OTC 
Monograph) 
Iron 15 mg/ml (as 
sulfate 75 mg/ 1 
ml 
Prevention and treatment 
of iron deficiency 
anaemia.  
Paediatric: 3-6 mg/kg daily 
in 3 divided doses.  
 
Data sourced from: http://www.medicines.org.uk/EMC/ , Iron Preparations, Oral Monograph for Professionals - Drugs.com 
Intramuscular iron compounds are not widely used due to the multiple side effects and the 
existence of intravenous agents. 
Intravenous iron preparations are considered treatment options after the failure of oral 
therapy or in specific cases in which iron stores and the degree of anaemia warrant acute 
therapy.  They sometimes become necessary in the case of active IBD (flare-ups), for example, 
because chronic inflammation inhibits iron absorption in the duodenum because of the 
combined actions of hepcidin and TNF-α (Weiss & Gasche, 2010). The major drawback 
concerning intravenous iron is that tight physiological regulation of iron absorption is 
bypassed, so there is an important risk for potential iron overload and associated toxicity.  
Blood transfusions are widely used as an immediate intervention for rapid correction of 
severe or life-threatening anaemia. However, such transfusions do not correct the underlying 
pathology and do not have a lasting effect. The decision on whether to administer blood 
should not, therefore, be based only on the haemoglobin level, but should also take clinical 
symptoms and co-morbidity into account (Weiss & Gasche, 2010). 

 
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5.3 
OVERVIEW OF TEST PRODUCT 
In an effort to overcome the significant challenges of iron substitution with oral ferrous 
products (OFP), ferric maltol, a chemically stable complex formed between ferric iron (Fe3+) 
and maltol (3-hydroxy-2-methyl-4-pyrone) was developed.  Ferric maltol makes iron available 
in the GI tract, providing the iron in a biologically labile form for uptake onto transferrin and 
ferritin and ultimately haematopoiesis and storage on ferritin. European Commission 
marketing authorisation was granted for ferric maltol in February 2016 and FDA approval was 
granted on 25 July 2019.  The currently approved dose and indication is 30 mg capsule twice 
daily (BID), taken in the morning and evening on an empty stomach for the treatment of ID in 
adults. 
5.4 
RESULTS OF PREVIOUS CLINICAL STUDIES 
5.4.1  Phase 3 studies in adults  
ST10-01-301/302 study 
A Phase 3 study has been completed in adult subjects with IDA and IBD, who are intolerant of 
oral iron products or are unsuitable for treatment with them (ST10-01-301 and ST10-01-302; 
Gasche, 2015; Schmidt, 2016), using a dose of 30 mg BID ferric maltol, or 60 mg elemental 
iron total daily dose. 128 subjects were randomised to 12 weeks of blinded medication (30 
mg BID ferric maltol or matched placebo capsule) followed by a 52-week open-label extension 
period; during which all available subjects received ferric maltol at the same dose.  87% and 
82% Ferric Maltol and placebo treated subjects, respectively, completed the 12-week double 
blind period.  The difference between the treatment groups in mean Hb from baseline to 
week 12 was 2.25 g/dL (ANCOVA p<0.0001).  Hb increased to normal values at week 12 in 
65% of ferric maltol group and 10% of placebo subjects.  When the placebo subjects were 
transferred to ferric maltol treatment in the open-label phase, there was a sharp rise in Hb 
levels that mirrored the response in the ferric maltol group in the double-blind phase.  There 
were further increases in Hb up to 48 weeks of treatment and no indication of any reduction 
in efficacy over the full 64-week treatment period.  
 
ST10-01-303 study 
A double-blind, randomised, placebo-controlled study in 167 patients with Iron Deficiency 
Anaemia in Chronic Kidney Disease was performed in a 2:1 randomisation. Ferric maltol 30 
mg capsules or matching placebo were administered bid for 16 weeks followed by open-label 
treatment with ferric maltol 30 mg capsules for up to an additional 36 weeks.  
167 patients with IDA in Chronic Kidney Disease (CKD) over 16-week double blind phase and 
an open label 36-week treatment in 125 subjects demonstrated positive safety, efficacy and 
tolerability. Changes in TSAT, ferritin, and serum iron concentrations indicated an 

 
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improvement in all iron parameters in the ferric maltol group compared to the placebo group 
and through the open-label 36-week treatment period to Week 52.  
The efficacy parameters in subjects originally in the placebo group moving to the ferric maltol 
group during the open-label 36-week treatment period mirrored the changes seen in the 
ferric maltol group patients during the double-blind 16-week treatment period. No clinically 
significant accumulation was observed for either plasma maltol or plasma maltol glucuronide. 
The results indicated that subjects with eGFR >30 mL/min/1.73 m2 may experience a greater 
treatment effect. Indeed, this would be expected due to a likely lower erythropoietin 
response to anaemia in the subjects with more severe renal impairment. 
The most common system organ class of study drug related TEAEs during the double-blind 
and open-label period was GI disorders.  Only three subjects experienced study drug-related 
adverse events that led to discontinuation in the double-blind phase and 5 subjects in the 
open-label phase. Changes in laboratory values were mainly consistent with the disease 
progression and all of them were considered as not related to study drug. 
In general, ferric maltol was well tolerated with only minor differences in the safety profile 
and overall GI side effects compared to placebo. 
 
5.4.2 Phase I studies in adults 
ST10-01-101 study 
Another open-label, randomised Phase 1 study evaluated the pharmacokinetics of ferric 
maltol and its effect on iron indices in patients with iron deficiency (with or without anaemia). 
24 subjects received ferric maltol 30, 60, or 90 mg BID over an 8-day period. PK and iron 
uptake were assessed on Days 1 and 8. Ferric maltol showed predictable pharmacokinetics, 
no accumulation over 7 days, and improvements in iron uptake across the dose range 30–90 
mg BID (Bokemeyer, 2016).  
The PK data from this study are consistent with previous data indicating that maltol is rapidly 
glucuronidated and renally excreted after ferric maltol dosing, while iron is independently 
absorbed. Across the three dosing regimens investigated, exposure to maltol glucuronide 
increased dose proportionally. Serum iron concentrations and TSAT values generally 
increased with higher doses, but there was no clear relationship between these parameters 
and exposure to maltol or maltol glucuronide. Higher NTBI levels were detected in the higher 
dosing regimens. Although the frequency of AEs was also higher with these dosing regimens, 
there is no evidence that this was a consequence of elevated NTBI in these subjects. The 
reported AEs were consistent with the established safety profile of ST10. 
ST10-01-102 study 
The pharmacokinetics (PK) and iron uptake of 30 mg ferric maltol BID were confirmed in a 
cohort of 15 IBD patients participating in the open-label phase of studies ST10-01-301 and 
ST10-01-302 (Shield TX, data on file for sub-study ST10-01-102).  Plasma concentrations of 

 
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maltol above the limit of assay detection were transiently observed between 15 min and 4 h 
after dosing (mean Cmax 67.3 ng/mL; median Tmax 1.0 h; mean AUC 136 h*ng/mL; mean t 1/2 
term 0.8 h). However, consistent with earlier studies of ferric maltol, maltol glucuronide 
predominated in plasma (mean Cmax 4677 ng/mL; median Tmax 1.0 h; mean AUC 9651h*ng/mL 
and mean t ½ term 1.1 h).  Maximal change in serum iron and TSAT was observed 2 h after 
dosing, however in many subjects it was apparent from the TSAT rises that iron uptake was 
occurring from 30 minutes.  The inter-subject variability for AUC of both maltol and maltol-
glucuronide in this cohort was low (approximately 27%). 
ST10-01-104 study 
An open-label, Phase I, randomised, 4-way crossover study was completed to evaluate the PK 
and iron absorption after a single 30 mg dose of ferric maltol administered as a capsule or 
oral suspension (fasted and fed condition) via primary parameters Cmax and AUClast.   
Both capsule and suspension of ferric maltol in fasted and fed conditions were readily 
absorbed with mean serum iron concentrations returning to baseline or slightly below at 24 
hours. 
For the fasted condition, comparing the suspension versus the capsule, the ratios of Cmax, 
AUClast, and AUCinf geometric LS means (90% Confidence Interval (CI)) for serum iron findings 
indicated that, in the fasted condition, ferric maltol capsule and suspension had different PK 
with respect to Cmax but a definitive difference in PK was not observed with respect to AUClast 
and AUCinf.  
For the suspension formulation comparing fasted versus fed conditions, the ratios of Cmax, 
AUClast, and AUCinf geometric LS means (90% CI) findings indicate that the ferric maltol 
suspension had similar PK when administered in fasted or fed conditions with respect to Cmax 
and AUClast.  
For the fed condition, comparing the suspension versus capsule the ratios of Cmax, AUClast, and 
AUCinf geometric LS means (90% CI) for serum iron indicate that, in the fed condition, ferric 
maltol capsule and suspension had similar PK with respect to Cmax and AUClast and a definitive 
difference in PK was not observed for AUCinf. 
The baseline corrected serum iron and TSAT, were consistent with the primary endpoint 
findings, although the formulation effect and capsule food effect differences were more 
marked with baseline corrected serum iron. 
It is noted that the overall exposure of maltol and maltol glucuronide are less influenced by 
physiological iron status compared to the iron PK parameters. 
There were no apparent differences between the formulations (suspension versus capsule) in 
the number of AEs and no study drug-related TEAEs were reported for either formulation. 

 
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5.4.3 Phase I study in children and adolescents 
ST10-01-103 study 
An open-label, randomised, Phase I study was completed in 37 children and adolescents (aged 
10-17) after BID oral doses of 7.8 mg, 16.6 mg or 30 mg ferric maltol (ST10) over a 10 days 
treatment period. Of the 37 subjects, there were 12 subjects in the 7.8 mg dose group, 13 
subjects in the 16.6 mg dose group and 12 subjects in the 30 mg dose group. The primary 
objective of the study was to assess the PK and iron uptake of these 3 doses, through 
measurement of serum iron, TSAT and plasma concentrations of maltol and maltol 
glucuronide.  
A one-compartment model with first order absorption with TLAG and first order elimination 
kinetics describes plasma maltol glucuronide PK for ferric maltol according to the current 
data. No covariates tested in this analysis had an effect on KA, TLAG, CL/F, and Vz/F of maltol 
glucuronide. The exposure of maltol glucuronide (Cmax and AUCs) were estimated using the 
predicted maltol glucuronide concentrations from the PPK model and then the dose 
proportionality was assessed using a power model. The results showed that dose 
proportionality existed over the dose range tested in this study, although the predicted Cmax 
of plasma maltol glucuronide on Day 10 slightly deviated from dose proportionality.  
The exposure of iron (Cmax and AUCs) was estimated using the NCA method with the predicted 
iron concentrations and then dose proportionality was assessed using a power model. The 
results showed that dose proportionality for iron did not exist over the dose range tested in 
this study. The Day 1 iron exposure parameters increased less than dose proportionally 
probably because of the plateauing effect observed between the 16.6 mg and 30 mg doses, 
and the Day 10 iron exposure parameters were comparable across the 3 doses.  
A direct effect linear model without intercept fit serum TSAT according to the current data. 
The predicted response parameters of TSAT (Cmax, AUC Above_B, etc) were estimated using the 
NCA method with the predicted TSAT. The response-time profile had a similar pattern with 
iron-time profile. 
Safety was assessed by evaluating TEAEs, SAEs, physical examinations, vital signs, 12-lead 
ECGs, and laboratory parameters. In total, 20 (54.1%) subjects experienced a TEAE: 7 (58.3%) 
subjects in the 7.8 mg dose group, 6 (46.2%) subjects in the 16.6 mg dose group, and 7 (58.3%) 
subjects in the 30 mg dose group. Treatment-emergent adverse events were mostly mild and 
no subjects had a severe TEAE. One (7.7%) subject in the 16.6 mg dose group experienced a 
TEAE of tonsillitis that led to withdrawal of study drug and study discontinuation; this event 
was considered by the Investigator to be moderate in severity and not related to study drug. 
No subjects died or experienced an SAE during the study.  
No clinically meaningful differences in mean changes from baseline in haematology or clinical 
chemistry parameters were noted between dose groups. Overall, individual shifts from 

 
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normal to abnormal in haematology and clinical chemistry laboratory parameters were 
considered as not related to study drug and not clinically significant.  
No subjects had laboratory abnormalities that were considered as TEAEs, SAEs, or led to 
withdrawal of study drug or study discontinuation. There were no clinically meaningful mean 
changes from baseline in vital signs results or ECG parameters, and no subjects had clinically 
significant abnormal ECG results. There was 1 abnormal, clinically significant physical 
examination finding for the subject who had a TEAE of tonsillitis that led to withdrawal of 
study drug and study discontinuation. 
Overall, the study concludes that all 3 doses of ferric maltol (7.8 mg, 16.6 mg, and 30 mg BID) 
administered over a 10-day period were well tolerated and had a favourable safety profile in 
this paediatric population. 
Refer to the Investigator Brochure for further information. 
 
5.5 
DOSE SELECTION AND RATIONALE FOR THE STUDY 
Clinical studies conducted to date provide evidence for the therapeutic potential of ferric 
maltol in adult patients with IDA in IBD, CKD and other causes of IDA. The performed Phase 1 
and Phase 3 studies demonstrate that ferric maltol is effective and well-tolerated in patients 
who are intolerant of OFPs or are unsuitable for other treatments as well at a dose of 30 mg 
(elemental iron) BID in adults aged 18 and over. Additional data has shown increased 
absorption from 60 mg dosing, but no additional increase at 90 mg, suggesting a saturable 
absorption mechanism. (Study ST10-01-101).  
The existing scientific and clinical experience with ferric maltol in the treatment of IDA in 
patients with IBD supports its further investigation in the treatment of iron deficiency/IDA in 
children and adolescents, in line with the Paediatric Investigation Plan (PIP) for ferric maltol 
that has been reviewed and approved by the European Medicines Agency (PIP reference:  
EMEA-001195-PIP 01-11) and FDA (IND 114832). 
The initial PIP specified clinical study ST10-01-103 assessed the pharmacokinetics (PK) and 
iron uptake of ferric maltol (ST10) in children and adolescents (aged 10 to 17 years) after twice 
daily (BID) oral doses of 7.8 mg, 16.6 mg, or 30 mg for 9 days (Days 1 to 9) and a single morning 
dose on Day 10 through measurement of serum iron, transferrin saturation (TSAT), and 
plasma concentrations of maltol and maltol glucuronide.  
Figure 1. presents a plot of mean serum iron concentrations change from baseline by dose 
group on linear and semi-logarithmic scales on Day 10 for the FAS/ITT Population 

 
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The scheduled time was chosen from the intermediate time point of the particular window. 
For example, pre-dose was deemed as 0 h, and '0.5 - 1 h' was deemed as 0.75 h. Baseline was 
defined as the last value observed before the first dose.Lower limit of quantitation for serum 
iron = 1.8 µmol/L. 
Figure 2. Plot of Predicted Mean Serum Iron Concentrations (mg/L) by Dose Group on Linear 
and Semi-Logarithmic Scales on Day 1 – Full Analysis Set/Intent-to-Treat Population 
 
Lower limit of quantitation for serum iron = 0.1 mg/L 
Figure 3. Plot of Predicted Mean Serum Iron Concentrations (mg/L) Change from Baseline by 
Dose Group on Linear and Semi-Logarithmic Scales on Day 1 – Full Analysis Set/Intent-to-Treat 
Population 

 
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Baseline was defined as the predicted Day 1 pre-dose concentration.  
Lower limit of quantitation for serum iron = 0.1 mg/L 
The predicted iron concentration PK parameters showed that iron uptake increases with 
dosage but under proportionally at Day 1, while the predicted maltol glucuronide PK 
parameter results showed dose proportionality exists. The dissociation of ferric maltol 
complexes may explain the different PK profiles of iron and maltol glucuronide. 
The most recent PK study has shown comparing the ferric maltol suspension and capsule in 
fed and fasted that serum iron concentration has returned to baseline or slightly below at 24 
hours. After 2 hours post-dose, the mean serum iron concentration of the ferric maltol 
capsule/fasted condition was higher than all other treatments studied,  
Figure 4 Plot of Mean Serum Iron Concentration (µg/dL) by Formulation/Condition Group on 
Linear Scale and Semi-Log Scale – FAS Population 

 
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To assess the impact of formulation of ferric maltol on the PK of serum iron, an ANOVA model 
was performed on the ln-transformed PK parameters (Cmax, AUClast, and AUCinf) of the 
2 formulations 
including 
terms 
for 
sequence 
(treatment 
sequence), 
treatment 
(formulation/condition), and period as fixed effects, and subjects nested within a sequence 
as a random effect.  
For the fasted condition, the ratios of Cmax, AUClast, and AUCinf geometric LS means (90% CI) 
for serum iron were 69.94% (61.75, 79.23), 77.54% (70.38, 85.42), and 78.16% (65.64, 93.06), 
respectively, comparing the suspension versus capsule. The geometric LS mean of Cmax in the 
ferric maltol suspension/fasted group was lower than in the ferric maltol capsule/fasted 
group and the 90% CI was below 80%. These findings indicate that, in the fasted condition, 
ferric maltol capsule and suspension had different PK with respect to Cmax but a definitive 
difference in PK was not observed with respect to AUClast and AUCinf.  
For the fed condition, the ratios of Cmax, AUClast, and AUCinf geometric LS means (90% CI) for 
serum iron were 99.11% (87.50, 112.27), 96.99% (88.04, 106.86), and 111.86% (87.36, 
143.23), respectively, comparing the suspension versus capsule. These findings indicate that, 
in the fed condition, ferric maltol capsule and suspension had similar PK with respect to Cmax 
and AUClast and a definitive difference in PK was not observed for AUCinf. 
To assess the impact of a test meal on the PK of ferric maltol, an ANOVA model was performed 
on the ln-transformed PK parameters (Cmax, AUClast, and AUCinf) of the 2 formulations including 
terms for sequence (treatment sequence), treatment (formulation/condition), and period as 
fixed effects, and subjects nested within a sequence as a random effect. 

 
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For the capsule formulation, the ratios of Cmax, AUClast, and AUCinf geometric LS means (90% 
CI) were 147.27% (130.01, 166.81), 134.25% (121.86, 147.91), and 137.53% (114.45, 165.26), 
respectively, comparing fasted versus fed conditions. These findings indicate that a food 
effect was observed for ferric maltol capsule with respect to Cmax but a definitive food effect 
was not observed with respect to AUClast and AUCinf. 
For the suspension formulation, the ratios of Cmax, AUClast, and AUCinf geometric LS means 
(90% CI) were 103.93% (91.75, 117.72), 107.32% (97.41, 118.24), and 96.10% (76.45, 120.79), 
respectively, comparing fasted versus fed conditions. These findings indicate that the ferric 
maltol suspension had similar PK when administered in fasted or fed conditions with respect 
to Cmax and AUClast. 
This Phase 3 open-label, comparative study is in the Paediatric Investigational Plan (PIP), 
designed to evaluate the safety, efficacy and tolerability of ferric maltol oral suspension 
compared to ferrous sulfate oral liquid over a 12 weeks treatment period in children and 
adolescents aged between 2 and 17 years. In order to comply with the iPSP agreed with FDA, 
children from 1 month to less than 2 years will be included in only the ferric maltol group. 
Due to the isoform of the glucuronidation enzyme, infants will initially receive only a single 
dose of ferric maltol. If the data from the single dose in this age group shows evidence of 
absorption of serum iron and elimination of maltol, subjects will enter a Treatment phase and 
be assigned to the ferric maltol arm. Subjects will be eligible to enter the treatment phase if 
the maltol level returns to baseline, or to a low level, confirming there is no accumulation of 
maltol or maltol glucuronide and there is evidence of iron absorption. 
During early infancy, iron requirements are met by the little iron contained in the human milk. 
(FAO/WHO, 2004). The need for iron rises markedly 4-6 months after birth and amounts to 
about 0.7-0.9 mg/day during the remaining part of the first year. Between 1 and 6 years of 
age, the body iron content is again doubled.  Iron requirements are also very high in 
adolescents, particularly during the period of growth spurt. Girls usually have their growth 
spurt before menarche, but growth is not finished at that time. In boys there is a marked 
increase in haemoglobin mass and concentration during puberty. In this stage, iron 
requirements increase to a level above the average iron requirements in menstruating 
women. 

 
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Iron requirements of 97.5% of individuals in terms of absorbed iron, by age group and sex 
(World Health Organization, 1989). 
The average adult stores about 1-3 g of iron in his or her body. A fine balance between dietary 
uptake and loss maintains this balance. About 1 mg of iron is lost each day through sloughing 
of cells from skin and mucosal surfaces, including the lining of the gastrointestinal tract (Cook 
et al, 1986). Menstruation increases the average daily iron loss to about 2 mg per day in 
premenopausal female adults (Bothwell, 1982). The augmentation of body mass during 
neonatal and childhood growth spurts transiently and boosts iron requirements (Gibson, 
1988). Many disease states increase the daily iron requirement by causing increased blood 
loss, reduced iron absorption or by affecting iron utilization. 
Physiologically, iron stores are managed through active absorption of dietary iron that 
matches loss. Any additional iron in the gastrointestinal tract that is not required is passed in 
the faeces.  This ensures that there is no iron overload, which can be potentially toxic. 
As the physiological mechanisms of absorption of iron ensure that only the required amount 
of iron is absorbed and the fact that this required amount changes with disease state and 
level of iron deficiency, the principles of dosing choice are to ensure sufficient iron levels to 
address the physiological need and to minimise the gastrointestinal effects that are 
frequently a challenge to adherence.  
Available iron salts for children are dosed at up to 200 mg of elemental iron from 1 year of 
age up to 17 years (BNF for Children, 2012) with higher exposure than in adults. However, the 

 
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availability of iron salt preparations can be less than 10% of the ingested dose (Harvey et al, 
1998). 
As the basal iron requirement for adolescents/children are raised, it is proposed that ferric 
maltol is dosed at the adult dose level of 30 mg BID from ages 12 to 17 years. For those aged 
2 - 11 years, a lower dose of 15 mg BID will provide approximately 7.2 mg of potential iron 
available for absorption (based on 24% availability) which will ensure that the basal 
requirements plus additional disease related needs are available.   
For infants under 2 years of age, dosing by weight is proposed at a level of 0.6 mg of elemental 
iron per kg BID. 
Ferrous sulfate oral liquid 125 mg/ml (25 mg/ml elemental iron) or equivalent dose will be 
administered under this protocol. To maximise the iron replenishment for subjects within the 
ferrous sulfate group as well; aged 2-17 years will be dosed 0.24ml (6mg elemental iron) per 
kg body weight, up to a maximum of 8ml given daily in two divided doses. 
This Phase 3 study will generate data to provide an alternative to existing oral ferrous 
products in treating children with IDA both from a patient/physician perspective but also 
wider healthcare decision making.  
5.5.1 Study Population 
The study population will be males and females, aged 1 month - 17 years at time of screening.  
5.5.2 Study Treatment and Duration 
Ferric maltol group:  
Subjects aged 1 month to 17 years randomised or assigned to oral ferric maltol will receive 
the following dosing for the duration of the study (12 weeks), including 2 PK days: 
Age 
Dose 
Suspension equivalent 
1 month to < 2 years 
0.6 mg/kg/dose, BID 
0.1 ml/kg/dose, BID  
2 years to 11 years 
15 mg per dose, BID 
2.5 ml per dose, BID 
12 years to 17 years 
30 mg per dose, BID 
5 ml per dose, BID 
 
In the event of an administered dose not being consumed or partially consumed by the 
patient this will be noted as a missed dose and will not be repeated. Clear instructions will be 
provided to the parents/guardians who are supervising the drug administration and dosing 
diary. 
To give the right dose of study treatment to the infant, the adaptor and oral syringe provided 
must be used. The parents/guardians should be instructed to gently invert the bottle 
(maximum 5 times) prior to preparing the dose. 

 
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After drawing up the required dose from the bottle using the oral syringe, the 
parents/guardians should put the tip of the syringe into the infant’s mouth and push the 
plunger to slowly push small amounts of the study product into the infant’s mouth at a time. 
The parents/guardians should allow the infant to swallow the study product before they push 
the syringe again. This step should be repeated until the whole dose has been administered. 
Patient weight should be recorded at each clinic visit and drug dosing administered as per last 
clinic visit weight. 
Ferrous sulfate group: 
Subjects aged 2 years to 17 years randomised to oral ferrous sulfate will receive the following 
dosing for the duration of the study (12 weeks):  
- 
2 yrs -17 yrs: 0.24ml per kg body weight, up to a maximum of 8ml given daily in 
two divided doses. 
Age 
Dose 
Liquid equivalent 
2 years to 17 years 
3 mg/kg/dose, BID 
0.12 ml/kg/dose, BID  
 
In the event of an administered dose not being consumed or partially consumed by the 
patient this will be noted as a missed dose and will not be repeated. Clear instructions will be 
provided to the parents/guardians who are supervising the drug administration and dosing 
diary. 
Patient weight should be recorded at each clinic visit and drug dosing administered as per last 
clinic visit weight. 
5.6 
RISK-BENEFIT EVALUATION 
The safety of ferric maltol in adult subjects with IDA and IBD has been established in a well-
controlled Phase 3 clinical study with data having been collected over 12 weeks on 128 
subjects in the double-blind phase and for over 12 months in some subjects in open-label 
follow-up (Gasche, 2015; Schmidt, 2016).  IBD patients are reported as being very sensitive 
and largely intolerant to oral ferrous products, and so if non-IBD paediatric subjects are 
recruited into this Phase 3 study, it is anticipated their tolerability to ferric maltol will be 
comparable to the existing adult data.  The safety and tolerability of ferric maltol in adults 
with IDA in IBD study was positive, with the overall AE rate in ferric maltol being comparable 
to the placebo group over a 12-week period; 87% of ferric maltol subjects remained in the 
study.  This data is supported by smaller published clinical studies using higher doses of ferric 
maltol and by preclinical studies testing ferric maltol in rodents (see Investigator’s Brochure).  

 
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The safety and tolerability study with ferric maltol in 167 subjects with CKD and IDA have been 
positive with data collected over the 52 weeks period. The most common system organ class 
of study drug related TEAEs during the double-blind and open-label period was GI disorders.  
Only three subjects experienced study drug-related adverse events that led to discontinuation 
in the double-blind phase and 5 subjects in the open-label phase. Changes in laboratory values 
were mainly consistent with the disease progression and all of them were considered as not 
related to study drug. In general, ferric maltol was well tolerated with only minor differences 
in the safety profile and overall GI side effects compared to placebo. 
In the Phase 1 paediatric PK study, children and adolescents aged 10 to 17 years were 
administered up to the adult dose of 30 mg BID. Given physiological control of intestinal 
absorption of iron uptake through the hepcidin pathway and considering a total daily dose of 
60 mg iron is within the approved dosage regimen for oral ferrous products in older children, 
iron overload in a 10-day exposure was considered not to be a risk. Furthermore, in children 
the metabolism of maltol through glucuronidation in the liver was similar to adults. There was 
not any great individual clinical benefit over 10 days of ferric maltol therapy, although the 
information gathered was very important in establishing the doses to be studied in this 
subsequent Phase 3 paediatric efficacy and safety study in IDA subjects. 
Doses chosen for this phase 3 study were based on the first Paediatric PK study and a new 
age-appropriate formulation has been developed. The study population will recruit subjects 
with iron deficiency anaemia who are otherwise generally well. The study population will 
include both female and male subjects aged 1 month - 17 years age range.  
From the Phase I PK adult study comparing the ferric maltol suspension and ferric maltol 
capsule under fed and fasted condition, information was gathered that in the fed condition, 
ferric maltol capsule and suspension had similar PK with respect to serum iron Cmax and 
AUClast. 
The Cmax data suggest that there might be a formulation effect in the fasted state in favor of 
the capsule with respect to serum iron levels but this was not definitively supported by AUClast 
and AUCinf comparisons, nor was this supported by the maltol and maltol glucuronide PK.  
Ferric maltol suspension had similar PK when administered in fasted or fed conditions with 
respect to Cmax and AUClast.  Nevertheless, we advise ferric maltol should be taken at least 
30 mins after meal.  
PK assessments will take place for the first 12 subjects in age group 2 yrs -17 yrs) and all 1 m 
- < 2 yrs assigned to ferric maltol to assess the efficacy, the safety and tolerability of ferric 
maltol.  
This study`s procedures risks are related to IV cannulation and blood sampling, with fainting, 
minor bleeding and bruising regarded as the main risks. Total blood loss as a result of 
phlebotomy will be approximately 33.8 ml in subject group 1 m to less than 2 years and 40 ml 
in the 2 to 17 yrs age group.   

 
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There is no appreciable risk from urine collection. 
If the subject`s Hb drops by >1 g/dl from baseline, each individual case will be discussed with 
the Medical Monitor prior to study discontinuation.  
Pregnancy testing will ensure that pregnant female subjects do not enter the study, and that 
any subjects who become pregnant during the study are detected.  
The comparator product, ferrous sulfate liquid, is available as various proprietary and generic 
formulations in the EU, UK and US for the treatment of ID/IDA. The proposed dosage is in 
accordance with the US OTC monograph and UK Prescribing Information for oral iron 
preparations. According to UK Prescribing Information and the US OTC monograph, the 
recommended dosage for the therapeutic use of ferrous sulfate is 3-6 mg/kg with maximum 
daily dose of up to 8 ml.   
Assessment of Patient Safety and Benefit conducting this study during coronavirus (COVID-
19) Pandemic 
The start of this study will be after the vaccination programme for COVID-19 has started in all 
countries being considered for clinical study investigational sites. Patients with a significant 
underlying health condition that could also be eligible for this study will be prioritised to 
receive a vaccination; as have healthcare staff.  For patients that are unable to be vaccinated 
for health or other reasons, we would expect the Investigator to make a judgement with the 
patient/carer about the benefits and added risks of participation. Mandating COVID-19 
vaccination as an eligibility criteria could act to systematically exclude some groups of patients 
from this study.  Visits by patients and carers to healthcare facilities should always have a 
purpose and benefit to the patient, and with the introduction of additional sanitation and 
infection control practices at study sites the risks of cross-infection have not been eliminated 
completely but are considered to be very low. 
The oral iron replacement treatments in this study are not contraindicated or cautioned 
against in the prescribing information for currently available vaccines; however we do advise 
that a 14 day period has elapsed from the last COVID-19 vaccination before a patients starts 
participation in this study (to avoid side effects overlapping with study participation). 
This is a randomised study, with two active treatments, both with known benefit and side-
effect profile in adults and children; and monitoring of clinical effect on iron deficiency 
anaemia. As all participants in this study are receiving active treatment, the risk to the patient 
is that one treatment is less effective than correcting IDA compared to the other, or that rate 
and seriousness of side effects are not the same.  Infection with COVID-19 during participation 
in this study would have minimal additional risk, compared to infection out with the study  
The number and frequency of site visits in this study has been reviewed and reduced to what 
is considered a safe minimum; based on collection of clinical samples, clinical evaluation, 
collection of adverse events and distribution/collection of study drug.  As this is also a PK 

 
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study it is unavoidable that patients have to visit the clinic for blood samples – phlebotomy in 
these paediatric subjects at home has been considered and was not thought appropriate. 
Some aspects of patient care are being managed through telephone calls (i.e. end of study 
visit/follow up). 
Summary 
There is considered to be a good balance of risks and potential benefits in either treatment 
arm, justifying randomisation of subjects within this open‐label clinical study. 
The risk to the subject related to study procedures has been assessed as very low and 
considered positive.  
Refer to the Investigator’s Brochure for further details on risk/benefit assessment. 

 
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6 STUDY OBJECTIVES AND ENDPOINTS 
6.1 
PRIMARY OBJECTIVES: 
1. To compare the safety and gastrointestinal tolerability of ferric maltol oral suspension 
and ferrous sulfate oral liquid in children and adolescents aged 2 years to 17 years and 
assess the safety and tolerability of ferric maltol oral suspension in children 1 month 
to less than 2 years, in the treatment of iron deficiency anaemia during the 12 weeks 
treatment period. 
 
2. To assess the effect on haemoglobin in children and adolescents aged 1 month to 17 
years after twice daily ferric maltol oral suspension administration for 12 weeks 
 
 
6.2 
SECONDARY OBJECTIVES: 
1. To assess the pharmacokinetics (PK) in children and adolescents aged 2 to 17 years after 
a single dose of ferric maltol oral suspension on Visit 2 (PK Day 1), and after twice daily 
administration for at least 6 days, on Visit 3 (PK Day 2), after a single morning dose, 
through measurement of serum iron, corrected serum iron, transferrin saturation (TSAT) 
and plasma maltol and maltol glucuronide 
 
2. To assess the effect on iron markers in children and adolescents aged 1 month to 17 years 
after twice daily ferric maltol oral suspension administration for 12 weeks 
 
3. To assess the PK, in children aged 1 month to less than 2 years of age after a single dose 
of ferric maltol oral suspension (Pre-assignment PK visit) and after twice daily 
administration for at least 6 days, on Visit 3 (PK Day 2), after a single morning dose, 
through measurement of serum iron, corrected serum iron, transferrin saturation (TSAT) 
(PK Day 2 only), plasma (PK Day 2 only) and urine concentration of maltol and maltol 
glucuronide 
 
4. To assess the effect, in children aged 1 month to less than 2 years of age after twice daily 
administration for at least 6 days, on Visit 3 (PK Day 2) after a single morning dose, on 
serum transferrin, total and unsaturated iron binding capacity (TIBC, UIBC) 
 
5. To assess the effect, in children aged 2 to 17 after a single dose of ferric maltol suspension 
Visit 2 (PK Day 1), and after twice daily administration for at least 6 days, on Visit 3 (PK 
Day 2) after a single morning dose, on serum transferrin, total and unsaturated iron 
binding capacity (TIBC, UIBC). 
  
6. To compare the palatability from age-appropriate scoring system of ferric maltol oral 
suspension and ferrous sulfate oral liquid  

 
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6.3 
PRIMARY ENDPOINTS 
- 
Safety and gastrointestinal tolerability  
o Treatment emergent Adverse Events (TEAE)  
o Treatment-emergent Serious Adverse Events (TESAEs) Treatment-emergent 
Adverse Events leading to premature discontinuation of study drug/PK 
assessments from baseline to Week 12 
- 
- Change in Hb concentration from baseline to Week 12 
 
6.4 
SECONDARY ENDPOINTS 
- 
PK analysis of serum iron, corrected serum iron, TSAT, TIBC, transferrin UIBC, 
maltol and maltol glucuronide in children and adolescents aged 1 month to 17 
years in the ferric maltol group 
 
- 
Changes in iron markers from baseline to Week 12 
 
- 
Achieving Hb concentration within normal range at Week 12  
 
- 
Qualitative assessments from subject questionnaires that allow evaluation of the 
acceptability, palatability and ease of use  
 
- 
Age 1 month to less than 2 years; maltol and maltol glucuronide in urine from both 
PK days in children aged 1 month to less than 2 years 
 
6.5 
EXPLORATORY ENDPOINTS 
Not Applicable

 
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7 INVESTIGATIONAL PLAN 
7.1 
STUDY OVERVIEW 
This is a Phase 3, randomised, open-label, active controlled, multicentre, comparative study 
between ferric maltol oral suspension and ferrous sulfate oral liquid. 98 eligible subjects aged 
2 to 17 years will be randomised at a ratio of 1:1 to ferric maltol or ferrous sulfate for a 12 
weeks treatment period and a maximum of 12 subjects aged 1 month to < 2 years will be 
assigned to the ferric maltol group. 
The study will comprise of the following stages: 
• Screening: To determine subject eligibility for the study (within 21 days prior to the 
randomisation for each subject) 
• Pre-assignment PK phase: only applicable for subjects aged 1 month to less than 2 years. 
Up to 28 days from Screening visit.  
All eligible subjects aged 1 month to less than 2 years will enter a Pre-assignment phase, 
1-day Pharmacokinetic assessment day following a single dose of ferric maltol oral 
suspension.  After a baseline pre-dose urine sample, subjects will take a single dose of 0.1 
ml/kg ferric maltol suspension under supervision and then further  urine samples from 
three timepoints up to 12 hours.  
 
The PK samples will be analysed and if evidence of metabolism and elimination of maltol 
is shown, these subjects will enter the treatment phase and be assigned to the ferric 
maltol arm. Subjects will be eligible to enter the treatment phase if the maltol level 
returns to baseline, or to a level confirming there is no accumulation of maltol or maltol 
glucuronide. 
• Randomised treatment: 12 weeks open label treatment 
Subjects aged 2-17 will be randomised 1:1 to receive ferric maltol oral suspension or 
ferrous sulfate oral liquid. The first 12 subjects randomised to ferric maltol in each age 
sub-groups (2 – 9 yrs, 10 – 17 yrs, respectively) will enter a Pharmacokinetic phase from 
Visit 2 (PK Day 1) till Visit 3 (PK Day 2) with 2 PK days. Following baseline pre-dose blood 
sample, subjects will take a single dose of 2.5 ml (2 yrs -11 yrs) or 5 ml (12 yrs - 17 yrs) 
ferric maltol oral suspension under supervision and then a further 2 PK blood samples will 
be taken up to 6 hours.  Following the last scheduled PK sample on PK Day 1 (Visit 2), 
subjects will be reminded to take their dose twice daily until PK Day 2 (between Day 7-
Day 10). On PK Day 2 (Visit 3) subjects should withhold their morning dose until attending 
their second PK assessment day. Same procedure will be repeated for PK assessment as 
on PK Day 1. Following PK Day 2, subjects will continue treatment until Week 12.  
 

 
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Once the 12 subjects in each age subgroup (2 - 9 yrs, 10-17 yrs, respectively) have 
finished their PK visits, they will continue on treatment until week 12. Further subjects 
will not need to have PK samples taken. 
 
Subjects randomised to ferrous sulfate oral liquid will not need to complete the PK 
period, they will remain on oral ferrous sulfate until Week 12. Ferrous sulfate 125 
mg/ml (25 mg/ml elemental iron) or equivalent dose will be used for all 
children/adolescents. To maximise the iron replenishment for subjects within this 
group as well; aged 2 - 17 yrs will be dosed 0.24ml (6mg elemental iron) per kg body 
weight, up to a maximum of 8ml given daily in two divided doses. 
 
• Assigned treatment phase: 12 weeks open label treatment for ferric maltol children 
aged 1 month to less than 2 years 
 
Once the PK samples have been analysed for subjects aged 1 month to less than 2 
years and they can enrol in the randomisation phase, they will be assigned to receive 
ferric maltol oral suspension and start the 0.1 ml/kg/dose, BID on Visit 2 for 7-10 days. 
On Visit 3 (PK Day 2), following baseline pre-dose blood sample and urine sample, 
subjects will take a single dose of 0.1 ml/kg ferric maltol suspension under supervision 
and then a further three PK blood samples and urine samples will be taken at three 
timepoints up to 12 hours. Subjects will continue treatment until week 12. 
 
• End of study: Week 12 visit 
 
• 
Post-treatment safety follow-up: 10-14 days following study completion of the treatment 
period or premature discontinuation 
 
The randomisation scheme will be stratified by co-variates for age (2 yrs – 9 yrs, 10 yrs – 17 
yrs) and sex (M/F). A minimum of 18 subjects must be recruited into each age group with 25% 
of either sex.  
A maximum of 12 subjects will be recruited in the 1 months to < 2 years age group and they 
will only be assigned to ferric maltol. Once there is evidence of metabolism and  elimination 
of maltol from Pre-assignment PK samples, they will continue to the Treatment Phase and be 
assigned to the ferric maltol arm. Subjects will be eligible to enter the treatment phase if their 
maltol level returns to baseline, or to a level confirming there is no accumulation of maltol or 
maltol glucuronide. 
 
Where applicable country and local regulations and infrastructure for home healthcare allow, 
home healthcare may take place at a location other than the clinical trial site to perform study 

 
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assessments, which may include but are not limited to collection of blood and urine samples, 
measurement of vital signs, length/height, and weight. 
 
7.2 
INVESTIGATIONAL SITES 
Approximately 20 sites 
7.3 
INCLUSION AND EXCLUSION CRITERIA 
No deviations to the inclusion or exclusion criteria are permitted.   
7.3.1 Inclusion Criteria 
1. Patient is willing and able to comply with the study requirements and to provide 
written informed consent. In the case of patients under the age of legal consent, the 
legal guardian(s) must provide informed consent and the patient should provide 
assent per local and national requirements. 
2. Age ≥1 month and ≤17 years at the time of informed consent  
3. Subjects must have iron deficiency anaemia defined by the following criteria, as 
measured by the central laboratory at the screening visit  
Haemoglobin thresholds define anaemia by age and gender: 
• Children (1 m – < 5 yrs) < 11.0 g/dl 
• Children (5 yrs – < 12 yrs) <11.5 g/dl 
• Children (12 yrs) <12.0 g/dl 
• Female child (≥13 yrs) <12.0 g/dl 
• Male child (≥13 yrs) <13.0 g/dl 
And  
Ferritin thresholds define anaemia by: 
• ferritin <30 µg/L,  
• or ferritin <50 µg/L with transferrin saturation (TSAT) <20%,  
4. Female subjects of childbearing potential must agree to use a highly effective method 
of contraception (which includes complete abstinence) until study completion and for 
at least 4 weeks following their final study visit.  Highly effective contraception is 
defined as a method which results in a low failure rate, i.e., less than 1% per year when 
used consistently and correctly, such as implants, injectables, some intrauterine 
contraceptive devices (IUDs), a vasectomised partner and oral contraceptive 
medications.  
The need for contraception and compliance with contraception requirements will be 

 
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assessed at every visit for adolescent patients, and urine pregnancy testing will be 
performed at each visit for female subjects of childbearing potential. 
7.3.2 Exclusion criteria 
A subject who meets any of the following criteria is not eligible for participation in the study. 
1. Subject with anaemia due to any cause other than iron deficiency, including, but not 
limited to, 
a. Untreated or untreatable severe malabsorption syndrome  
2. Subjects who have received prior to Screening: 
a. Within 28 days intramuscular or intravenous (IV) injection or administration of 
depot iron preparation. 
b. Within 7 days single agent iron preparations. 
c. Within 12 weeks of blood transfusion or is scheduled to have blood transfusion or 
donation during the study period 
d. Within 28 days erythropoiesis stimulating agents and during the study 
e. Within 14 days COVID-19 vaccination  
3. Subjects with vitamin B12 or folic acid deficiency as determined by the central laboratory 
screening results. Subjects may start vitamin B12 or folate replacement and rescreen after 
at least 2 weeks.  
4. Has concomitant disease that would significantly compromise iron absorption or 
absorbed iron utilization such as swallowing disorders and/or extensive small bowel 
resection. 
5. History of active peptic ulcer 
6. Has chronic renal disease (eGFR <60 mL/min/m2), as assessed at Screening based on 
serum creatinine. 
7. Known hypersensitivity or allergy to either the active substance or excipients of ferric 
maltol or ferrous sulfate. 
8. Has a known contraindication for treatment with iron preparations, e.g., 
haemochromatosis, chronic haemolytic disease, sideroblastic anaemia, thalassemia, or 
lead intoxication induced anaemia. 
9. Impaired liver function as indicated by alanine aminotransferase (ALT) or aspartate 
transaminase (AST)>2.0 times upper normal limit as measured at the Screening visit. 
10.  Active acute inflammatory disease, including IBD flare or disease exacerbation, which in 
the opinion of the Investigator, is clinically significant. 

 
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11. Active chronic or acute infectious diseases requiring antibiotic treatment. 
12. Pregnant or breast feeding. 
13. Concomitant medical conditions with extensive active bleeding, other than menstrual 
cycles; subjects who suffer from menorrhagia may be included at the Investigator’s 
discretion. 
14. Scheduled or expected hospitalization and/or surgery during the course of the study. 
15. Participation in any other interventional clinical study within 28 days prior to Screening. 
16. Diagnosed to be COVID-19 positive by (SARS‐CoV‐2‐RT‐PCR positive) within 28 days prior 
to screening.  
17. Cardiovascular, liver, renal, hematologic, psychiatric, neurologic, gastrointestinal, 
immunologic, endocrine, metabolic, respiratory or central nervous system disease that, 
in the opinion of the Investigator, may adversely affect the safety of the subject and/or 
objectives of the study drug or severely limit the lifespan of the subject. 
18. Any other unspecified reason that, in the opinion of the Investigator or the Sponsor make 
the subject unsuitable for enrolment. 
 
7.4 
CONCOMITANT MEDICATION 
7.4.1 Not Permitted 
• Treatment with single agent oral iron preparation (prescription and non-prescription) 
within 7 days prior to screening and throughout the study period.  
• Treatment with parenteral iron preparations within 28 days prior to screening and 
throughout the study period. 
• Blood transfusions within 12 weeks before screening and during the study. 
• Erythropoiesis stimulating agents within 28 days before screening and during the 
study. 
 
7.4.2 Permitted 
• Immunosuppressants 
• Vitamin B12 and folic acid supplements/replacement are allowed during the study. 
• Over the Counter (OTC) oral supplements/multivitamin type preparations (including 
those that contain iron) may be taken, however subjects should keep the same dose 
during the study. 
• Oral contraceptives are allowed during the study. 

 
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• All other concomitant medications must remain stable from Screening and throughout 
the study. 
7.4.3 Potential Medication Interactions 
Iron-drug interactions of clinical significance have been reported to occur with a large number 
of concomitant therapies. Concurrent ingestion of oral iron causes marked decrease in the 
bioavailability of a number of drugs due to the formation of iron-drug complexes (chelation 
or binding of iron by the second drug). Examples of affected drugs are: penicillamine, 
bisphosphonates, 
ciprofloxacin, 
entacapone, 
levodopa, 
levofloxacin, 
levothyroxine 
(thyroxine) moxifloxacin, mycophenolate, norfloxacin, ofloxacin, tetracyclines, calcium and 
magnesium salts, dimercaprol, chloramphenicol and methyldopa.  
Based on the recent Phase I study finding, ferric maltol oral suspension can be taken at least 
30 mins after a meal. To minimise the potential for drug interactions, patients should wait at 
least 4 hours before taking other concomitant medications and/or supplements. The exact 
timing of any concomitant medication and its iron content should be recorded in the eCRF. 
 
7.5 
INDIVIDUAL DISCONTINUATION CRITERIA 
Subjects and/or their parents or guardians have the right to withdraw consent without 
prejudice at any time during the study.  If a subject withdraws consent, the Investigator should 
make a reasonable effort to determine the cause. All withdrawn subjects should have a Post-
Treatment Safety Visit within 10-14 days after the last dose of study drug (if the subject agrees 
in the case of withdrawn consent). 
If there is any sign of accumulation of maltol or glucuronide in the pre-assignment phase PK 
day for subject population aged 1 month to less than 2 years, the recruitment to this age 
group will be suspended and they will not enter the treatment phase until the risk has been 
assessed and approved via a substantial amendment to the protocol.  
Subjects may be discontinued prematurely during the study for the following reasons: 
• Withdrawal of informed consent 
• A drop of >1 g/dl in Hb from baseline 
• Unwillingness or inability to comply with protocol requirements 
• Pregnancy or not using a reliable method of birth control (female subject of 
childbearing potential) 
• Use of prohibited concomitant medications 
• Serious adverse events that are judged by the Investigator to be related to study 
treatment 

 
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• Blood transfusions for any cause during the study treatment period 
• Use of any other single agent prescribed iron medications 
• Occurrence of any condition that, in the opinion of the Investigator, significantly 
jeopardizes the wellbeing and safety of the patient, including any intolerable toxicity 
related to study treatment determined by the investigator to be unacceptable given 
the severity of the event 
 
The reason for study drug discontinuation and the date of last dose should be recorded in the 
eCRF.  Subjects who discontinue treatment prematurely must return for the Post-Treatment 
Safety Visit, unless informed consent is withdrawn (and the subject and/or their parents or 
guardians do not agree to attend this follow-up visit). A subject who meets discontinuation 
criteria should be discussed on an individual basis with the Medical Monitor. 
7.6 
STUDY TERMINATION 
The Sponsor reserves the right to temporarily halt and/or terminate the study (or if 
appropriate, individual treatment dose groups) at any time for safety, scientific or ethical 
reasons including, but not limited to:  
- 
Emerging safety concerns from this study, other ongoing studies with ferric maltol, or 
new and relevant scientific information, which result in the risk-benefit ratio for this 
study becoming unfavorable, in the Sponsor’s opinion. 
- 
If the total number of dropouts is so high or the number of included subjects is so low 
that completion of the trial will not realistically be expected within a reasonable 
timeframe. 
- 
If the Sponsor determines the study will no longer reveal new knowledge and 
consequently is ethically no longer justifiable. 
In case of an early termination of the study or temporary halt by the Sponsor, the IEC and CA 
will be notified within 15 calendar days, including a detailed written explanation of the 
reasons for the termination/halt.  
In all circumstances connected with temporary halt and/or termination of the study, the 
following principles will apply: 
- 
All affected parties (such as the IEC, CA, Investigators, heads of study centers /clinic 
directors) must be informed as applicable according to local law. 
- 
All study materials and supplies (except documentation that should remain stored at 
site) must be returned to the Sponsor/designee.  
 

 
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8 TREATMENT OF SUBJECTS 
Ferric maltol oral suspension will be supplied to study sites on behalf of Shield TX (UK) Ltd by 
Quay Pharma, Deeside Ind. Park, Flintshire. The drug substance and drug product are 
manufactured, tested and controlled in accordance with Good Manufacturing Practice (GMP).  
Full details are documented in the Investigational Medicinal Product Dossier (IMPD) and 
current Investigator’s Brochure. Sites must arrange storage of Investigational Medicinal 
Product in a temperature monitored, secure location which is accessible to authorised 
individuals only. 
Ferrous sulfate oral liquid 125 mg/ml (25 mg/ml elemental iron) or equivalent dose will be 
used for all children/adolescents randomised to this group.  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PRESENTATION 
• 150 ml amber glass bottle with graduated syringe and adaptor. Oral suspension 
containing 30 mg elemental iron, in the form of 231.5 mg ferric maltol, in 5 ml 
suspension 
 
A full list of excipients can be found in the Investigator’s Brochure. 
8.2 
COMPARATOR 
• Ferrous sulfate 125 mg/ml (25 mg/ml elemental iron) oral liquid or equivalent dose 
will be administered under this protocol.  
 
8.3 
PACKAGING 
Oral suspension: Ferric maltol oral suspension will be supplied in an amber glass bottle with 
graduated syringes and adaptor. 
8.4 
STORAGE 
IMP must be stored below 25 °C and must not be frozen.  In the event that the drug is exposed 
to temperatures greater than or equal to 25°C, or to freezing, the CRA/Sponsor should be 
contacted for review and further instruction. 
Ferrous sulfate oral liquid to be handled and stored according to SPC/PI. 
8.5 
LABELLING  
All bottles will be identified by a unique Bottle ID number. Bottles will be clearly labelled as 
ferric maltol with the dose indicated.  Labels of the IMP will contain information according to 
European Directives 2003/94/EC, 2001/20/EC and US 21 CFR 312.6.  

 
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Individual supplies packaging and labelling will be checked by the Investigator/designee 
before the subject (aged 2-17 yrs) takes their first dose of study medication at site on Day 1 
(Visit 2).  
Packaging and labelling will be checked by the Investigator/Designee before the subject (aged 
1 m - < 2 yrs) takes their single dose on the Pre-assignment PK visit. 
8.6 
TREATMENT ASSIGNMENT AND BLINDING 
At randomisation, the Interactive Response Technology (IRT) will assign children aged 2 yrs to 
17 yrs to either the ferric maltol or ferrous sulfate treatment group.  The site will dispense the 
appropriate number of open-label ferric maltol bottles or ferrous sulfate at each scheduled 
study visit according to the schedule of assessments. Study Treatment and duration is 
specified in section 5.5.2 of this protocol.  
Children aged 1 m - < 2 yrs: all subjects will receive ferric maltol oral suspension following 
satisfactory completion of the pre-assignment phase.  
This is an open label study and treatment assignment is not blinded. 
8.6.1 TREATMENT ASSIGNMENT 
Subjects aged 2 yrs to 17 yrs will be randomised 1:1 to either treatment. Randomisation will 
be centrally controlled and stratified by age and gender as well.  
The subject will be instructed to administer the first dose of ferric maltol oral suspension in 
the presence of the site staff on Visit 2 (infant age group Pre-assignment PK Day).  Subsequent 
doses may need to be administered under the supervision of the child’s parent or legal 
guardian and recorded on a dosing diary. The first 12 subjects in each age group (2 yrs – 9 yrs, 
10 yrs – 17 yrs, respectively) will be instructed to withhold their morning dose of ferric maltol 
on PK Day 2 until pre-dose PK blood samples have been collected at the site. 
If a subject forgets to take a dose, he/she should take the next dose as normal.  The subject 
should not take a double dose to make up for a forgotten dose.  
In the event of an administered dose not being consumed or partially consumed by the 
patient this will be noted as a missed dose and will not be repeated. Clear instructions will be 
provided by the Investigator to the parents/guardians who are supervising the drug 
administration and dosing diary. 
Patient weight should be recorded at each clinic visit and drug dosing administered as per last 
clinic visit weight. 
During the PK days: 

 
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- if the administered dose is not consumed or partially consumed by the patient this will be 
noted as a missed dose and will not be repeated. The PK sampling will be cancelled. 
 -the site staff will record the timing of each meal, concomitant medication and its iron 
content within the eCRF. 
8.7 
TREATMENT COMPLIANCE 
Subjects will be instructed to take the study drug as described in detail on the drug labels and 
by the Investigator/designee.   
Subjects (ferric maltol and ferrous sulfate) will be instructed on Visit 2 to complete a dosing 
diary from the evening of Visit 2 until the next visit, in order to document the day and time 
that they took their morning and evening doses on those treatment days whilst at home.  
Subjects will be instructed to return all unused supplies medication packaging on their visits, 
having withheld their dose of ferric maltol on PK Day 2 morning.  Compliance will be assessed 
from the dosing diary entries and reconciled using the drug accountability form. 
If a subject is found to be non‐compliant with the study medication (defined as less than 80% 
or more than 120% compliant with the dosage schedule), the subject/parent/legal guardian 
will be counselled and trained on the importance of maintaining adherence to study 
medication. If the subject is repeatedly non‐adherent, a decision will be made by the medical 
monitor and/or Sponsor as to whether the subject should be withdrawn from the study 
treatment. 
If the subject discontinues the study due to intolerance to either ferrous sulfate or ferric 
maltol, this should be documented in the eCRF.  
Subjects who do not attend their visits may be withdrawn from the study.  A copy of the 
relevant local SPC/PI for ferrous sulfate will be available in the Investigator Site File (ISF). 
Special safety information and warnings/precautions relating to the drug will be highlighted 
to the Investigator during the Site Initiation Visit (SIV). 
The delivery of medication to the site, its use and return, as well as subject-specific 
compliance, will be reconciled and documented using a Drug Accountability Form in order to 
monitor compliance with the medication schedule.  All opened containers, together with 
remaining contents, and unopened containers will be kept by the Investigator in a secure, 
locked area until return to the drug supplier by the monitor or destruction by the site if agreed 
with the Sponsor/designee.  The Investigator will use the IMP only within the framework of 
this clinical study and in accordance with the current, approved study protocol. 
8.8 
CONTINUATION OF TREATMENT 
No further provisions are made for access to the study treatment under this protocol 
following Day 84/Visit 6.  

 
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9 ENROLMENT AND RANDOMISATION PROCEDURES 
Full details of procedures will be provided in the Investigator Site File and eCRF Completion 
Guidelines. 
9.1 
SCREENING (Visit 1) 
Subjects will be evaluated according to the inclusion and exclusion criteria (Sections 7.3.1 
and 7.3.2). Subjects will be deemed eligible for randomisation if all inclusion criteria and 
no exclusion criteria are met. The Investigator is required to document all screened 
candidates considered for inclusion in this study. If excluded prior to enrolment, the 
reasons for exclusion will be documented in the subject’s eCRF, medical notes and on the 
study screening log. 
A subject may be retested once for screening laboratory criteria that do not meet protocol 
in/exclusion criteria initially, so long as randomisation occurs no more than 21 days from 
the initial Screening visit date (if eligible based on retest results). 
A subject may be re-screened after an initial screening and screening failure once it is 
assessed by the investigator the reason for the screening failure was resolved e.g.: Subject 
screening failure due to folates outside of protocol range, receives folates replacement 
therapy can be re-screened. 
9.2 
RANDOMISATION (Visit 2) 
Subjects will be registered into the study at the Screening visit and assigned a unique 
subject identification number in the IRT.  Subjects will be categorised during the screening 
process based upon their age (2 to ≤ 9 years of age and 10 to ≤ 17 years of age) and their 
gender. Age and gender will be incorporated into the randomisation as stratification 
factors.  A minimum of 18 subjects must be recruited into the 2-9 and 10-17 age group and 
a minimum of 25% of either sex must be recruited. Maximum of 12 subjects will be 
recruited in the 1 m – 2 yrs cohort. In the event of a subject having a birthday whilst on 
study and they move to a different age cohort -they will remain in the baseline cohort for 
the duration of the study. 
A final eligibility evaluation must be conducted by the Investigator/designee prior to 
randomisation/pre-assignment PK visit via IRT, once the results of all Screening 
assessments are available.   
Subjects aged 1 month to < 2 years: 
Following the eligibility evaluation, a maximum of 12 subjects will enter a Pre-assignment 
phase: 1-day Pharmacokinetic assessment day following a single dose of 0.1 ml/kg ferric 
maltol oral suspension.  Once the PK samples have been analysed and evidence is showing 
metabolism and elimination of maltol, subjects will be assigned to ferric maltol oral 
suspension treatment phase. Subjects will be eligible to enter the treatment phase if their 
maltol level returns to baseline, or to a level confirming there is no accumulation of maltol 

 
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or maltol glucuronide. The sample results will be analysed on an individual basis. The 
Sponsor’s Medical Monitor will make a recommendation to the investigator based on pre-
assignment results. The investigator will make the final decision if subjects aged 1 month 
to < 2 years are eligible to enter the treatment phase. 
Subjects aged 2 years to 17 years: 
No subject may begin treatment prior to being randomised in the IRT. The randomisation 
procedure (created using a computer-generated random permutation procedure) will 
assign the subject to one of the treatment arms.   
Initial dosing with ferric maltol and ferrous sulfate must occur on the same day of 
randomisation. The date of Visit 2 is the date of first dose with ferric maltol or ferrous 
sulfate. 
9.3 
REPLACEMENT POLICY 
Discontinuations after randomisation due to adverse events will not be replaced.  
Discontinuations after randomisation for any other reasons may be replaced at the 
discretion of the Sponsor, in order to reach the agreed number of evaluable subjects for 
pharmacokinetic endpoints. 
9.4 
BLINDING PROCEDURES 
Not applicable as this is an open label study.  
9.5 
EMERGENCY UNBLINDING 
Not applicable as this is an open label study. 

 
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10 STUDY PROCEDURES 
10.1  COVID-19 IMPLICATIONS ON THE TRIAL 
All efforts will be made by the Investigational sites to avoid screenings of any subjects who 
might have a known exposure to SARS‐CoV‐2 or any symptoms suggestive of any infection 
with it by following the local guidelines provided for evaluating patients for COVID‐19.  
 
If there is a confirmed COVID-19 positive case (SARS‐CoV‐2‐RT‐PCR) in a subject after 
randomization, the subject will be assessed by the investigator to determine if their 
participation in the trial is suitable. Positive cases will be recorded as an adverse event in 
the CRF, and authorised medication will be recorded as concomitant medication in the CRF. 
Every attempt will be made to follow up with the adverse events via phone call to the 
subject until known resolution or stabilization of the disease. 
 
During periods of time when a pandemic impedes the ability of patients to travel to the 
study site 
• Study assessments and visit window may be expanded up to 14 days (Visit 4, 5, 6) 
• Study assessments by a healthcare professional may occur at an offsite location 
such as the patient`s home.  
 
Where applicable country and local regulations and infrastructure for home healthcare 
allow, home healthcare may take place at a location other than the clinical trial site to 
perform study assessments, which may include but are not limited to collection of blood 
and urine samples, measurement of vital signs, length/height, and weight. 
 
 
 

 
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10.2 DESIGN SCHEMATICS 
 
 
 
1: Only applicable if subjects aged 1 month to < 2 years continues to the assigned treatment phase. 
2: Visit 3 will only be performed for the first 12 subjects in age group 2-17 years  
 

 
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10.3 SCHEDULE OF ASSESSMENTS FOR SUBJECTS AGED 2 YEARS-17 YEARS 
 
 
 
 
 
 
 
SCREENING 
TREATMENT 
FOLLOW-UP 
Duration 
Up to 21 days 
12 WEEKS  
(equivalent of 84 days) 
10-14 days 
Day 
 
1 
7-10 
28 
56 
84 
94-98 
Visit 11 
1 
2 
33 
4 
5 
6 
79,10 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility 1,8 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
X 
 
Vital Signs 2 
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy Test 4 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory tests 5 
X 
 
 
 
 
X 
 
Haematology 6 
X 
 
 
X 
 
X 
 
Iron markers 6 
X 
 
 
X 
 
X 
 
PK assessment –PK Blood 
Sampling for maltol/maltol 
glucuronide and iron markers 7 
 
X 
X 
 
 
 
 
Randomisation 8 
 
X 
 
 
 
 
 
Dispense Study Drug 
 
X 
X 
X 
X 
 
 
Return Study Drug for 
Accountability 
 
 
X 
X 
X 
X 
 
Palatability questionnaire  
 
X 
 
X 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications and 
Procedures 
X 
X 
X 
X 
X 
X 
X 
Compliance reminder 
 
X 
X 
X 
X 
X 
 
Compliance assessment 
 
 
X 
X 
X 
X 
 

 
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1. 
A subject may be retested once for laboratory criteria that do not meet protocol criteria so long as randomisation 
occurs no more than 21 days from the initial screening visit date (if eligible). 
2. 
Vital Signs – body weight, height, systolic/diastolic blood pressure, pulse, and body temperature at each visit. 
Patient weight should be recorded at each clinic visit and drug dosing administered as per last clinic visit weight. 
3. 
Visit 3 (PK Day 2) only applicable for the first 12 subjects randomised to ferric maltol group in each age group (2 
yrs -9 yrs, 10 yrs-17 yrs).  
4. 
Urine pregnancy test for female subjects of childbearing potential only. 
5. 
Clinical Laboratory tests including:  
a. 
Clinical Chemistry: Vitamin B12, folate, ALT, AST, alkaline phosphatase, gamma-glutamyl transpeptidase 
(GGT), total bilirubin, creatinine, amylase, blood urea nitrogen (BUN), phosphorous, sodium, potassium, 
chloride, calcium, total cholesterol, uric acid, glucose, total protein, albumin 
6. 
Haematology and Iron markers: 
a. 
Haematology:  Red blood cell count, haemoglobin, haematocrit, mean cell volume (MCV), white blood 
cell count (total and differential (% and absolute), absolute reticulocyte count and platelet count. 
b. 
 Iron Markers:  serum iron, transferrin, transferrin saturation (TSAT), total and unsaturated iron binding 
capacity (TIBC, UIBC) and ferritin. 
7. 
On PK study Day 1 (Visit 2) and PK study Day 2 (Visit 3) for the first 12 subjects in each age group (2 yrs – 9 yrs, 10 
yrs-17 yrs, respectively) who have been randomised to ferric maltol groups have baseline PK blood samples 
collected immediately prior to ferric maltol dosing (0 hr).  Subjects will then have further PK blood samples collected 
at two (2) additional times between 0.5 hr and 6 hrs after dosing on Visit 2 and 3; the post-dose PK sample time 
collection windows will be 0.5-1h, 1.0-2.0 hrs, 2.0-3.0 hrs, 3.0-4.0 hrs and 4.0-6.0 hrs. For each individual subject, 
the post-dose PK blood sampling schedule will be the same on PK Day 1 and PK Day 2.  Post-dose blood samples 
should be collected within the time windows allocated only. N.B: samples should be taken at least 1.0 hr apart.  
In the event of an administered dose not being consumed or partially consumed by the patient this will be noted as 
a missed dose and will not be repeated. 
8. 
Eligibility laboratory sampling/assessments must be completed before the subject is randomised and before the 
first dose of study treatment taken. A minimum number of 18 subjects must be recruited into each age group (2 
yrs -9 yrs, 10 yrs-17 yrs) and a minimum of 25% of either sex must be recruited and at least 49 subjects per arm.   
9. 
Subjects who have at least one dose of study medication and withdraw earlier from the study undergo Visit 7 (Day 
94-98) assessments (excluding those who have withdrawn consent). 
10. Visit 7 is conducted by telephone, unless the Subject has an ongoing AE that requires physical examination or 
investigations for assessment/management.  Visit 7 will take place 10-14 days after Visit 6 (Week 12) unless subject 
discontinued treatment early. All withdrawn subjects should undergo Visit 7 within 10-14 days after the last dose 
of study drug (if the subject agrees in the case of withdrawn consent).  
11. Visit Windows: Maximum of 21 days between screening and randomisation.  The Subject must visit to complete: 
a. 
Visit 2 and Visit 3: must be 6-9 days between the scheduled PK days.  
b. 
Visit 4: +/- 5 days relative to date of Visit 2/first dose administered 
c. 
Visits 5 to 6: +/- 5 days relative to date of Visit 2/first dose administered  
d. 
Visit 7: 10-14 days after Visit 6 (unless subject discontinued treatment early - see Note 10  
 
 
 
 
 

 
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10.4 SCHEDULE OF ASSESSMENTS FOR SUBJECTS AGED 1 MONTH - < 2 YEARS 
 
 
 
 
 
 
SCREENING 
PRE-ASSIGNMENT 
TREATMENT 
FOLLOW-UP 
Duration 
Up to 21 days 
Up to 28 days from 
Screening 
12 WEEKS  
(equivalent of 84 days) 
10-14 days 
Day 
 
 
1 
7-10 
28 
56 
84 
94-98 
Visit9 
1 
Pre-assigned6 
2 
33 
4 
5 
6 
78,9 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility 1,7 
X 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
X 
 
Vital Signs 2 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory tests 4 
X 
 
 
 
 
 
X 
 
Haematology, Iron markers 5 
X 
 
X10 
 
 
 
X 
 
PK assessment: Blood 
Sampling for iron markers, 
maltol and maltol glucuronide6  
 
 
 
X6 
 
 
 
 
PK assessment: Urine sampling 
for maltol/maltol glucuronide6 
 
X6 
 
X6 
 
 
 
 
Treatment Assignment 7 
 
 
X 
 
 
 
 
 
Dispense Study Drug 
 
X 
X 
X 
X 
X 
 
 
Return Study Drug for 
Accountability 
 
 
 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications and 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance reminder 
 
 
X 
X 
X 
X 
X 
 
Compliance assessment 
 
 
 
X 
X 
X 
X 
 

 
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1. 
A subject may be retested once for laboratory criteria that do not meet protocol criteria so long as pre-assignment 
visit occurs no more than 28 days from the initial screening visit date (if eligible). 
2. 
Vital Signs – body weight, length, systolic/diastolic blood pressure, pulse, and body temperature at each visit. 
Patient weight should be recorded at each clinic visit and drug dosing administered as per last clinic visit weight. 
3. 
Visit 3 (PK Day 2) this visit will be the second PK day following the pre-assignment PK assessment. 
4. 
Clinical Laboratory tests: including  
a. 
Clinical Chemistry:  Vitamin B12, folate, ALT, AST, alkaline phosphatase, gamma-glutamyl transpeptidase 
(GGT), total bilirubin, creatinine, amylase, blood urea nitrogen (BUN), phosphorous, sodium, potassium, 
chloride, calcium, total cholesterol, uric acid, glucose, total protein, albumin 
5. 
Haematology and Iron markers: 
a. 
Haematology:  Red blood cell count, haemoglobin, haematocrit, mean cell volume (MCV), white blood cell 
count (total and differential (% and absolute), absolute reticulocyte count and platelet count. 
b. 
Iron Markers:  serum iron, transferrin, transferrin saturation (TSAT), total and unsaturated iron binding 
capacity (TIBC, UIBC) and ferritin. 
6. 
Pre-assignment phase: All subjects in 1 m-< 2 yrs age group will enter a 1-day PK assessment day prior to entering 
the treatment phase. Pre-assignment PK Day, each subject has baseline PK urine samples collected immediately 
prior to ferric maltol dosing (0 h). Following this, subjects will take a single dose of 0.1 ml/kg ferric maltol under 
supervision. Three (3) PK urine samples will be taken between 0.5 hr -3 hrs, 3 hrs -6 hrs, and 7 hrs -12 hrs post dose. 
N.B: samples should be taken at least 1.0 h apart.  Urine collections instructions are detailed in the study’s 
Laboratory Manual. 
PK Day 2 (Visit 3), each subject has baseline PK blood and urine samples collected immediately prior to ferric maltol 
dosing (0 h). Following this, subjects will take a single dose of 0.1 ml/kg ferric maltol under supervision. Three PK 
Post-dose blood samples will be collected at the following windows 1.0-2.0 hrs, 3.0-4.0 hrs and 10.0-12.0 hrs; post-
dose urine samples will be taken between 0.5 hr -3 hrs, 3 hrs -6 hrs and 7 hrs -12hrs post dose. 
In the event of an administered dose not being consumed or partially consumed by the patient this will be noted as a 
missed dose and will not be repeated.   
7. 
Eligibility laboratory sampling/assessments must be completed before the subject is assigned to ferric maltol. The 
PK samples will be analysed and if evidence of metabolism and elimination of maltol is shown, these subjects will 
enter the ferric maltol treatment phase Visit 2.  
8. 
Subjects who have at least one dose of study medication and withdraw early from the study undergo Visit 7 (Day 
94-98) assessments (excluding those who have withdrawn consent). 
9. 
Visit 7 is conducted by telephone, unless the subject has an ongoing AE that requires physical examination or 
investigations for assessment/management.  Visit 7 will take place 10-14 days after Visit 6 (Week 12) unless subject 
discontinued treatment early. All withdrawn subjects should undergo Visit 7 within 10-14 days after the last dose 
of study drug (if the subject agrees in the case of withdrawn consent). 
10. Visit Windows: Maximum of 28 days between screening and pre-assignment phase. The Subject must visit to 
complete: 
a. 
Visit 3: must be 7-10 days from Visit 2   
b. 
Visit 4: +/- 5 days relative to date of Visit 2/first dose administered 
c. 
Visits 5 to 6: +/- 5 days relative to date of Visit 2/first dose administered  
d. 
Visit 7: 10-14 days after Visit 6 (unless subject discontinued treatment - see Note 10  
11.  Baseline Haematology and Iron markers: to be performed after urine PK assessment and prior to assignment 
a. 
Haematology:  haemoglobin 
b. 
Iron Markers:  serum iron, transferrin, transferrin saturation (TSAT), total and unsaturated iron binding 
capacity (TIBC, UIBC), ferritin 

 
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10.5 DEMOGRAPHICS AND MEDICAL HISTORY 
The following will be documented at Screening and updated (if required) prior to 
randomisation: Date of Birth, race and ethnicity, gender, all current medical conditions, all 
medical history relevant to iron deficiency anaemia diagnosis regardless of onset, all clinically 
significant medical history from the past 5 years (age dependant) including all malignancies, 
sterilisations, hospitalisations and surgeries; the method of contraception for female subjects 
of childbearing potential, if applicable. Body weight (Kg), height/length (m/cm) should be 
recorded at each clinic visit and drug dosing administered as per last clinic visit weight. 
PHYSICAL EXAMINATION 
A brief physical examination is to be conducted to assess safety. The examination should 
include an assessment of general appearance, skin, head, eyes, ears, nose and throat, 
cardiovascular, respiratory, abdominal, gastrointestinal, and musculoskeletal systems. 
10.6 CONCOMITANT MEDICATIONS AND PROCEDURES 
The following will be documented at Screening and updated (if required) prior to 
randomisation:  all current medications at the time of Screening or stopped within 3 months 
of screening and any medical procedure performed within 3 months prior to Screening.  
The following will be documented throughout the study: any medications initiated stopped 
or dose and/or frequency changes throughout the study. Any medical procedure performed 
throughout the study. 
Medical procedures to be documented are any therapeutic intervention such as 
surgery/biopsy, physical therapy or diagnostic assessment (e.g. blood gas measurement). 
The exact timing and iron content of any concomitant medications taken on any PK days will 
be recorded in the eCRF. 
10.7 VITAL SIGNS  
Body temperature (°C), blood pressure, body weight (Kg), height/length (m/cm) and pulse 
rate will be assessed. Blood pressure and pulse rate should be measured after the subject has 
been sitting for at least 5 minutes. 
10.8 LABORATORY ASSESSMENTS 
10.8.1 Haematology and Clinical Chemistry 
Routine clinical laboratory safety bloods for haematology and clinical chemistry/iron markers 
evaluations will be collected at Screening to assess eligibility.  Additional testing may be 
required if any abnormal value is reported and this must be followed until it is resolved (other 

 
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than iron indices and low haemoglobin due to ongoing iron deficiency/anaemia, or abnormal 
results due to other pre-existing conditions). 
All analyses will be conducted by a central laboratory. Procedures for the collection, 
processing, storing, and transporting of samples to the laboratory will be fully described in 
the study-specific Laboratory Manual. 
Investigators will review, sign and date all lab results upon receipt from the central laboratory.  
If a value is flagged as outside of the normal range, the Investigator must document the 
abnormality as ‘clinically significant’ (CS) or ‘non-clinically significant’ (NCS).  Any lab 
abnormality assessed as ‘CS’ must be recorded as an AE if not explained by a pre-existing 
condition (documented in the medical history).  
The signed paper copy of the laboratory report is retained at the investigational site.  The 
electronic data transferred from the central laboratory database to the clinical study database 
will be considered source data for the derivation of summary data and listings presented in 
the clinical study report. 
10.8.1.1 Haematology test parameters 
Red blood cell count, haemoglobin, haematocrit, mean cell volume (MCV), white blood cell 
count (total and differential (% and absolute), absolute reticulocyte count and platelet count. 
10.8.1.2 Clinical Chemistry and Screening Iron Markers test parameters 
Clinical Chemistry: Vitamin B12, folate, ALT, AST, alkaline phosphatase, gamma-glutamyl 
transpeptidase (GGT), total bilirubin, creatinine, amylase, blood urea nitrogen (BUN), 
phosphorous, sodium, potassium, chloride, calcium, total cholesterol, uric acid, glucose, total 
protein, albumin 
Iron Markers: serum iron, transferrin, transferrin saturation (TSAT), total and unsaturated iron 
binding capacity (TIBC, UIBC) and ferritin. 
10.8.2 Pharmacokinetics 
Blood samples for maltol and maltol glucuronide on each PK day  
Blood samples will be collected at the required times on the PK assessment days relative to 
the time of ferric maltol morning dosing:  pre-dose then two further times between 0.5-10 
hours post-dose in the 2-17 years age group and pre-dose then three further times between 
1-12 hours post-dose in the 1 m to less than 2 years age group  (see Section 10.3 and section 
10.4). 
Following collection and mixing, blood samples will be centrifuged, and the resultant plasma 
samples separated and stored at -20°C at the study site, prior to collection and onward 
shipping to the central laboratory on dry ice for subsequent assay of maltol and maltol 
glucuronide plasma concentrations using appropriately validated bioanalytical methods.  Full 

 
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details of the required sample collection, processing and handling logistics will be specified in 
the study specific Laboratory Manual.  Samples will be destroyed at the end of the study, once 
all analyses are complete. 
Blood samples for iron markers on each PK day 
Blood samples will be collected at the required times on the PK assessment days, relative to 
the time of ferric maltol dosing:  pre-dose then two further times between 0.5-6 hours post-
dose in the 2-17 yrs age group. Same times as blood samples for maltol/maltol glucuronide 
for each individual (see Section 10.3 and section 10.4.). 
Following collection and mixing, blood samples will be centrifuged, and the resultant serum 
samples separated and split into 2 aliquots at each timepoint.  Ambient serum samples will 
be shipped to the central laboratory for subsequent assay of serum iron, transferrin, 
transferrin saturation (TSAT), total and unsaturated iron binding capacity (TIBC, UIBC.  Frozen 
serum aliquot will be stored at site (-20°C) for later onward shipping on dry ice to the central 
laboratory.  Full details of the required sample collection, processing and handling logistics 
will be specified in the study specific Laboratory Manual.  Samples will be destroyed at the 
end of the study, once all analyses are complete. 
PK blood sample scheduling in the 2-17 yrs age groups: 
3 subjects will be assigned to the required post dose PK blood sampling schedule in sequential 
order at the time of randomisation, based on current subject enrolment across all study sites. 
The PK sampling schedule is not the same for each patient, the scheme in the table below has 
been produced to reduce sampling burden.  
 
 
 
 
 
 
 
 
 
 
 
PK Sample 
Schedule  
PK Day 1 and 
PK Day 2 
PK Sample 
Schedule 
Group 1 
(N=3) 
PK Sample 
Schedule 
Group 2 
(N=3) 
PK Sample 
Schedule 
Group 3 
(N=3) 
PK Sample 
Schedule 
Group 4 
(N=3) 
Pre-dose (0h) 
X 
X 
X 
X 
0.5 – 1 hour 
X 
X 
 
 
1 – 2 hours 
X 
 
X 
 
2 – 3 hours 
 
X 
 
X 
3 – 4 hours 
 
 
X 
 
4 – 6 hours 
 
 
 
X 

 
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PK blood sample scheduling in the 1 m - < 2 yrs age groups: 
Pre-assignment PK Day, each subject has baseline PK urine samples collected immediately 
prior to ferric maltol dosing (0 h). Following this, subjects will take a single dose of 0.1 
ml/kg ferric maltol under supervision. Three PK urine samples will be taken between 0.5 
hr -3 hrs, 3 hrs -6 hrs and 7 hrs -12hrs post dose.  
Note: samples should be taken at least 1.0 h apart. The PK samples will be analysed and 
if evidence of metabolism and elimination of maltol is shown, these subjects will enter 
the treatment phase and be assigned to the ferric maltol arm.  
PK Day 2 (Visit 3), each subject has baseline PK blood and urine samples collected 
immediately prior to ferric maltol dosing (0 h). Following this, subjects will take a single 
dose of 0.1 ml/kg ferric maltol under supervision. Three PK Post-dose blood samples will 
be collected at the following windows 1.0-2.0 hrs, 3.0-4.0 hrs and 10.0-12.0 hrs; post-dose 
urine samples will be taken between 0.5 hr -3 hrs, 3 hrs -6 hrs and 7 hrs -12hrs post dose. 
Urine samples for maltol and maltol glucuronide 
Urine samples will only be collected from subjects aged 1 month to less than 2 years. 
Full details of the required sample collection, processing and handling logistics will be 
specified in the study specific Laboratory Manual.  Samples will be destroyed at the end of 
the study, once all analyses are complete. 
10.8.3 Urine Pregnancy Test 
Females of childbearing potential only.  A urine pregnancy test should be conducted at the 
Screening visit to assess eligibility using the test kits provided by the central laboratory.  A 
repeat urine pregnancy test will be conducted prior to first dosing on Day 1; the result of this 
test must be negative for dosing with ferric maltol or ferrous sulfate to commence on Day 1.  
Repeat urine pregnancy testing will also be conducted at Visit 2, Visit 3, Visit 4, Visit 5, Visit 6. 
Full details of the required sample collection and processing procedures will be described in 
the study-specific Laboratory Manual. 
10.8.4 Palatability and acceptability scoring 
Subjects aged 2 yrs to 17 yrs on Visit 2 and Visit 4 will receive a 5-point Facial Hedonic scale 
which will be completed immediately after the administration of ferric maltol oral suspension 
or ferrous sulfate oral liquid. Subjects are free to ask for support in completing the 
questionnaires from parents/legal guardian and site staff.  
Subjects will complete Visit 2 Facial Hedonic Scale on site, immediately after dosing. 

 
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Subjects can complete Visit 4 Facial Hedonic Scale on site or at home after visit on site and 
dispensation of Visit 4 treatment, immediately after dosing. If subjects require support in 
completing the questionnaires from site staff, it is recommended the dosing and subsequent 
questionnaire completion occur on site. 
Questionnaires should be completed immediately after dosing, once a day (morning or 
evening dose). 
Hedonic expression will be converted to scores of 1-5 with 1 being the most positive 
expression and 5 the most negative. The data from the scales will be transformed into 
numbers for descriptive statistics. 
10.8.5 PK Days food intake 
 
On each PK day: the approximate amount of iron content for any food consumed after ferric 
maltol and before the end of the PK sampling will be recorded in the eCRF.  
10.8.6 Overall blood volume  
The individual volume of blood collected throughout the study will be: 
- 
Subjects aged 1 m to less than 2 yrs: up to 24ml (including PK days) 
- 
First 12 subjects aged 2 yrs to 17 yrs in the ferric maltol oral suspension group: up to 
27 ml (including PK days) 
- 
ferric maltol oral suspension group without PK sampling (2-17 years): 13 ml 
- 
ferrous sulfate oral liquid group: 13 ml 
Blood samples on PK days 
Subjects aged 2 yrs to 17 yrs; total number of blood samples on each PK day: 3 timepoints, 1 
pre-dose and 2 post doses. Total blood volume at each PK timepoint: 4.5 ml. 
Subjects aged 1 month to less than 2 yrs: total number of blood samples on PK blood day: 4 
timepoints, 1 pre-dose and 3 post doses. The total blood volume at each PK timepoint: 3.2 ml. 
 
 
 

 
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11 SAFETY  
11.1 DEFINITIONS 
11.1.1 ADVERSE EVENT (AE) 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavourable or unintended sign or symptom, intercurrent illness, injury, or 
any concomitant impairment of the subject’s health, temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.   
A treatment-emergent AE is any AE temporally associated with the use of a study drug, 
whether or not considered related to the study drug.  
AEs include: 
• 
Exacerbation of a chronic or intermittent pre-existing condition/disease/symptom 
present at baseline that worsen during the study including either an increase in 
frequency and/or intensity. 
• 
Disease or medical condition detected or diagnosed after study drug administration 
even though it may have been present prior to the start of the study. 
• 
Events considered by the Investigator to be related to study-mandated procedures.  
• 
Abnormal safety assessments, e.g. laboratory test abnormalities, physical exam 
findings or vital sign measurements must be reported as AEs if they represent a 
clinically significant finding in the medical and scientific judgment of the Investigator, 
symptomatic or not, which was not present at baseline or if present at baseline, 
worsened during the course of the study or led to dose reduction, interruption or 
permanent discontinuation of study drug.  However, if an abnormal laboratory or 
other safety-related test result is associated with clinical signs or symptoms, the signs 
or symptoms should be recorded as an AE.  If signs and symptoms are part of a 
diagnosis, then the diagnosis should be recorded as AE. 
• 
Signs, symptoms of a suspected drug interaction. 
• 
Signs, symptoms of a suspected overdose of either the study drug or a concomitant 
medication (overdose per se will not be reported as AE/SAE). 
AEs do not include: 
• 
Medical or surgical procedure, e.g., surgery, appendectomy, endoscopy, tooth 
extraction, transfusion (as these are treatments for an AE).  However, the event 
resulting in the procedure is the AE (e.g. appendicitis, abdominal pain).  

 
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• 
Pre-existing disease or medical condition documented at baseline that does not 
worsen. 
• 
Situations in which an adverse change did not occur, e.g., hospitalisations for 
cosmetic elective surgery or for social and/or convenience reasons. 
• 
Anticipated day-to-day fluctuations or seasonal fluctuations (e.g. allergic rhinitis) of 
pre-existing disease(s) or condition(s) documented at baseline. 
• 
The disease/disorder being studied, or the expected progression, signs or symptoms 
(including laboratory values) of the disease/disorder being studied, unless it is more 
severe than expected for the subject’s condition. 
• 
Overdose of either study drug or concomitant medication without any signs or 
symptoms.  
11.1.2 SERIOUS ADVERSE EVENT (SAE) 
An SAE is any untoward medical occurrence between the time of consent and the subject’s 
final visit that: 
• 
is fatal, 
• 
is life-threatening, 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation, 
• 
results in persistent or significant disability/incapacity, 
• 
results in a congenital anomaly/birth defect or 
• 
is otherwise judged as medically significant (may jeopardise the subject). 
The following guidelines should be used: 
Life-threatening: Refers to an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe. 
Inpatient hospitalisation: Subject has to stay in hospital at least overnight. The following 
reasons for hospitalisations are not considered AEs, and therefore not SAEs:  
• Hospitalisations for cosmetic elective surgery, social and/or convenience reasons. 
Standard monitoring of a pre-existing disease or medical condition that did not 
worsen, e.g., hospitalisation for coronary angiography in a subject with stable angina 
pectoris. 
• Elective treatment of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalisation for chemotherapy for cancer, elective hip replacement for 
arthritis, vein stripping for preventive and/or cosmetic purpose. 

 
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Prolongation of hospitalisation: Complications that occur during hospitalisation are AEs.  
However, if a complication prolongs hospitalisation or would have required hospitalisation or 
fulfils any other serious criteria, that complication is considered an SAE.  In any case, 
admission to an intensive care unit is considered a prolongation of hospitalisation.  When in 
doubt as to whether “prolongation of hospitalisation” was necessary, the AE should be 
considered serious. 
Significant disability: The term significant disability means that there is a substantial 
disruption of a person’s ability to conduct normal life functions.  This definition is not intended 
to include experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, accidental trauma (e.g. sprained ankle) or uncomplicated 
chronic diseases which may interfere or prevent everyday life functions but do not constitute 
a substantial disruption. 
Medically significant:  Medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious such as important medical events that 
might not be immediately life-threatening or result in death or hospitalisation but might/may 
jeopardise the subject or might/may require intervention to prevent one of the other 
outcomes listed in the definition above.  Examples of such events are invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse. 
SAE related to study-mandated procedures: Such SAEs are defined as SAEs that appear to 
have a reasonable possibility of causal relationship (i.e., a relationship cannot be ruled out) 
to study-mandated procedures (excluding administration of study drug) or complication of a 
mandated invasive procedure (e.g., blood sampling, heart catheterisation), or car accident on 
the way to the hospital for a study visit, etc. 
11.2 REPORTING AND DOCUMENTATION 
AEs should be documented in terms of a medical diagnosis.  When this is not possible, the AE 
should be documented in terms of signs and/or symptoms observed by the Investigator or 
reported by the subject at each study visit. 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start 
of the study should be recorded on the Medical History CRF.  
All SAEs that occur after informed consent through to study completion (Follow-up visit) or 
premature discontinuation must be reported on the SAE form in the CRF and reported within 
24 hours to the Sponsor using the Shield SAE form.  All AEs occurring from the time of the first 
dose of study treatment through study completion (Follow-up visit) or premature 

 
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discontinuation must be reported on the AE form in the CRF. For AEs related to COVID‐19 
testing, see section 10.1. 
Any SAE that occurs during the clinical study or within two weeks of receiving the last dose of 
study drug, whether or not related to the study drug, must be reported to the Sponsor. 
Deaths or congenital abnormalities if brought to the attention of the Investigator AT ANY 
TIME after cessation of study drug AND considered by the Investigator to be possibly related 
to study drug, should be reported to the Sponsor.  
At each visit AEs will be solicited. The nature of each event should be established.  Details of 
changes to study drug dosing or any subsequent treatment should be recorded on the 
appropriate pages of the CRF. 
AEs already documented in the CRF (i.e., at a previous assessment) and designated as 
'ongoing' should be reviewed at subsequent visits as necessary.  Upon resolution, the date of 
resolution should be recorded in the CRF.  If an AE increases in frequency or severity during a 
study period, a new record of the event should be started.  If the AE lessens in intensity, no 
change in the intensity is required as only the worst intensity must be reported. 
All AEs and SAEs, including those that are ongoing at the end of the study or at premature 
discontinuation, will be followed up until resolution or stabilisation or until the event is 
otherwise explained. 
11.2.1 Immediate Reporting 
The following AEs must be reported within 24 hours to the Sponsor or designee: 
• 
SAEs 
• 
Pregnancy (not considered as an AE, but must be reported immediately) 
For immediate reporting, the Investigator must fill out the SAE form or the Pregnancy form 
for pregnancies and send to the Sponsor within 24 hours after awareness. 
 
SAFETY CONTACT DETAILS 
Primevigilance Limited has been contracted by the Sponsor for safety reporting 
Email SAE reports to shieldpv@primevigilance.com or fax to +44 800 781 6187 
Contact details for safety questions will be provided in the Investigator Site File 
 
If the site obtains relevant follow-up information, this information needs to be forwarded to 
the Sponsor within 24 h of awareness using a new SAE form.  

 
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Other documents must be submitted upon request.  All documents must be blinded with 
respect to the subject’s personal identification to meet data protection requirements, e.g., 
on the discharge summary this data must be blinded, and the subject number added.  
As soon as the Sponsor is informed about an SAE, an evaluation and potential reporting to 
central IRBs/IECs, Competent Authorities (CA) and other concerned parties will occur as 
required. The Investigator will be responsible for reporting to any local IRB/IEC as required. 
11.2.2 Non-Immediate Reporting 
AEs that do not qualify for immediate reporting will be documented in the eCRF and reported 
in the Clinical Study Report (CSR). 
11.3 EVALUATION 
AEs and the corresponding entries in the eCRF will be reviewed by the Investigator or qualified 
member of the study staff. Adverse events, toxicities and medical surgery/history will be 
categorized by primary system organ class (SOC) and preferred term using the MedDRA 
dictionary. Toxicities will also be graded as mild, moderate or severe. 
11.3.1 Intensity 
The intensity will be rated by the Investigator as “mild”, “moderate” or “severe”: 
Mild: Symptoms barely noticeable to the subject or does not make the subject uncomfortable; 
does not influence performance or functioning. 
Moderate: Symptoms of a sufficient severity to make the subject uncomfortable; 
performance of daily activity is influenced; subject is able to continue in study. 
Severe: Symptoms cause significant discomfort; incapacitation or significant impact on the 
subject’s daily life; may cause cessation of study treatment. 
A mild, moderate or severe AE may or may not be serious.  These terms are used to describe 
the intensity of a specific event (as in mild, moderate, or severe myocardial infarction).  A 
severe event may be of relatively minor medical significance (such as severe headache) and 
is not necessarily serious.  For example, nausea lasting several hours may be rated as severe, 
but may not meet the definition of seriousness.  Fever of 39 °C that is not considered severe 
may become serious if it prolongs hospitalisation. 
11.3.2 Causality 
The following should be considered when evaluating the relationship of AEs and SAEs to the 
study treatment: 
Not related: There is not a possibility that the event has been caused by the product under 
investigation. Consideration should be given to factors, including but not limited to, a lack of 
reasonable temporal relationship between administration of the drug and the event, the 

 
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presence of a biologically implausible relationship between the product and the AE (e.g. the 
event occurred before administration of drug), or the presence of a more likely alternative 
explanation for the AE. 
Related: There is a possibility that the event may have been caused by the product under 
investigation. Consideration should be given to factors, including but not limited to a positive 
re-challenge, a reasonable temporal sequence between administration of the drug and the 
event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug and 
the AE or a lack of an alternative explanation for the AE.  
11.3.3 Outcome 
The outcome of each AE has to be assessed as follows: 
• 
Fatal:  The AE resulted in death (“Death” is recorded as an outcome, not as the AE) 
• 
Ongoing/Not resolved: The AE has not resolved 
• 
Recovered with sequelae:  Resolution of the AE has occurred, but the subject retains 
some sequelae 
• 
Recovered: The AE fully resolved with no observable residual effects 
• 
Unknown:  The outcome of the AE is not known as the subject did not return for 
follow-up and attempts to locate the subject and/or to obtain follow-up information 
were unsuccessful (lost to follow-up). 
11.4 RE-EXPOSURE 
If an AE requires discontinuation of IMP and is judged to be treatment-related by the 
Investigator or by the Sponsor, re-exposure is not allowed.  If an AE requires dose reduction 
or discontinuation of IMP and is judged by the Investigator or by the Sponsor to be unrelated 
to investigational products, the decision to re-introduce the medication or to increase the 
dose of the medication requires prior approval of the Sponsor or designee. 

 
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12 STATISTICAL CONSIDERATIONS 
12.1 POWER CALCULATIONS 
The study will be analysed by descriptive statistics only. As such, there is no formal power 
calculation. 
The aim is to recruit up to 49 subjects in each treatment group in the 2 – 17 years cohort.  At 
least 12 subjects in each age group (i.e. 36 subjects in total) will be included in the PK model 
in the ferric maltol oral suspension group. A sample size of 49 in the Ferric Maltol group 
provides at least 80% power to demonstrate that the lower bound of the 95% confidence 
interval for increase in Hb at 12 weeks, compared with baseline, is above zero. This assumes 
that the SD of the change from baseline is 1.2 g/dL or lower and the true mean change is at 
least 0.5 g/dL. 
Every effort will be made to recruit up to 12 subjects in the under 2`s age group but in case of 
reasons of feasibility it cannot be completed, then the study may be completed without that 
cohort.  
If less than 91 subjects in total have been randomized when 32 ferric maltol subjects have 
completed, then an interim analysis of the primary effectiveness endpoint (change in Hb 
concentration from baseline to Week 12) will be conducted.  Less than 91 subjects recruited 
would indicate that the study will not complete in the near future. 
The interim analysis will test for significance of the increase in Hb in the ferric maltol arm 
(from Baseline to Week 12). If significant, the study will stop recruitment.  If not significant, 
the study will continue (all subjects will be assigned to ferric maltol) until 54 subjects have 
been recruited in the ferric maltol arm. 
12.2 STATISTICAL METHODS 
Full details of the statistical analysis, including the analysis of PK endpoints, will be specified 
in the statistical analysis plan. 
 
12.2.1 Primary Endpoint Analysis 
- 
Safety and gastrointestinal tolerability will be compared between ferric maltol oral 
suspension and ferrous sulfate oral liquid via the incidence of treatment emergent 
adverse events (TEAEs), treatment emergent serious AEs (TESAEs) and treatment-
emergent AEs (TEAEs) leading to premature discontinuation of study drug, estimated 
as the number of subjects with at least one event divided by the number of subjects 
in the safety population. 

 
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- 
AEs will be categorised by primary system organ class and MedDRA preferred term as 
coded using the MedDRA dictionary.  The number, intensity, relation to study 
medication and action taken will be described by incidence tables.  SAEs will be 
discussed separately.  
- 
Efficacy of ferric maltol will be assessed via the change in Hb concentration from 
baseline to week 12. 
o If no interim analysis is conducted it will be based on a 95% two-sided 
confidence interval;  
o If an interim analysis is conducted, a Pocock spending function will be used;  
the interim analysis will be based on a (100 – 3.45) % two sided confidence 
interval;  
o if the study does not stop after the interim analysis, the final analysis will be 
based on a (100 – 2.57)% two sided confidence interval 
 
12.2.2 Secondary Endpoint Analyses 
The following endpoints will be reported for each treatment group using descriptive statistics 
summarised by mean, median, and range, and 95% CIs where applicable, split by age group: 
- 
PK analysis of serum iron, TSAT, transferrin, TIBC, UIBC, maltol and maltol 
glucuronide in children and adolescents aged 1 month to 17 years in the ferric 
maltol group 
- 
Changes in iron markers from baseline to Week 12 
- 
Achieving Hb concentration within normal range at Week 12  
- 
Qualitative assessments from subject questionnaires that allow evaluation of the 
acceptability, palatability and ease of use  
- 
For subjects aged 1 month to < 2 years; Maltol and maltol glucuronide in urine: 
Ae0-6h, Ae0-3h, Ae3-6h, Durine0-6h, Durine0-3h, Durine3-6h, CLR; Pre-assignment and PK Day 2 
Categorical variables will be summarised for each treatment group via number and 
percentage in each category, split by age group: 
- 
Achieving Hb concentration within normal range at Week 12  
Qualitative assessments from subject questionnaires that allow evaluation of the 
acceptability, palatability and ease of use will be summarised appropriately.  
12.2.3 Sensitivity Analyses 
Change in Hb concentration from baseline to Week 12, will be summarized for subjects 
randomized when the endpoint was designated as secondary and for subjects randomized 
after the endpoint was changed to a primary endpoint. 
12.2.4 Imputation of Missing Data 
All data will be used according to availability, with no imputation for missing data. 

 
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12.3 DEFINITION OF POPULATIONS  
12.3.1 Randomised Population/ Intention to treat (ITT) 
All subjects who are randomised/assigned to treatment arms.  
12.3.2 Safety Population 
All subjects who have had at least one dose of study drug will be analysed for safety.  
12.3.3 Per Protocol Population (PP) 
The PP population will consist of those randomised/assigned subjects who do not have major 
protocol deviation during the study.  
12.3.4 Pharmacokinetic (PK) Population (Full Analysis Set) 
All subjects who have had at least one dose of study drug and who have at least one evaluable 
post-dose PK sample (applicable only for ferric maltol group) will be included in the PK 
analysis.   
 

 
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13 ETHICAL CONSIDERATIONS 
The Sponsor and Investigator must comply with this protocol, all applicable national and local 
regulations including International Conference on Harmonisation (ICH) and Good Clinical 
Practice (GCP). 
13.1 DECLARATION OF HELSINKI 
The Sponsor and the Investigator must comply with the principles set forth by the Declaration 
of Helsinki dated October 2008. 
13.2 INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE 
The Investigator must ensure that the IRB/IEC has approved the protocol, the Information 
Sheet and Consent/Assent Form and any other required study documents prior to starting 
the study. The Sponsor must approve any changes to the Information Sheet and 
Consent/Assent Form before submission to the IRB/IEC.  
Prior to activation of a site and provision of IMP, the Sponsor must receive documentation to 
demonstrate IRB/IEC approval of the required study documents and must have completed a 
comprehensive site initiation training with the Investigator and site staff.  
A progress report must be submitted to the IRB/IEC at least annually and more frequently if 
required by the IRB/IEC. 
On completion or termination of the study the Investigator or Sponsor must submit a closeout 
letter to the IRB/IEC (as required). A copy of the CSR synopsis will also be sent in accordance 
with local laws. 
13.3 SUBJECT INFORMATION AND INFORMED CONSENT 
IRB/IEC approval of the written information sheet and consent/assent form must be obtained 
prior to use. The Information Sheet will provide the subject/legal guardian with a complete 
and comprehensive explanation of the study including the study rationale, the procedures, 
the benefits and risks, that participation is voluntary and that the subject may withdraw from 
the study at any time without any negative consequences.  In addition, a physician will discuss 
this information with the subject/legal guardian who will be given sufficient time and 
opportunity to have any questions answered and to make a decision of whether to participate 
in the study.   
Written informed consent must be obtained from the subject/legal guardian in accordance 
with local practice and regulations prior to any study assessment or test being conducted. 
Written consent will be obtained by signing and dating the IRB/EC approved consent/assent 
forms.  
Each consent form must also contain an authorisation for the Sponsor and Investigators to 
use and disclose Protected Health Information (PHI) in compliance with local law.  

 
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No study assessments or procedures should be conducted until written informed 
consent/assent has been provided. 
A copy of the information sheet and consent/assent form signed and dated by the 
subject/legal guardian must be given to the subject/legal guardian. The signed consent and 
assent form(s) will be retained with the study records at site. A description of the 
consent/assent process must be documented in the subject’s medical record. 
13.4 SUBJECT DATA PROTECTION 
Prior to any study test being conducted, including Screening tests, the subject/legal guardian 
must provide authorisation as required by local law to use and disclose PHI. Subjects will not 
be identified by name (or initials) in the eCRF or any study reports. Data will be used for 
research purposes only. Every effort will be made to keep the subject’s personal medical data 
confidential. All data will be used for research purposes only. 
13.5 SUBJECT INSURANCE 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws. 
13.6 CONFLICT OF INTEREST 
Investigators should address any potential conflicts of interest (e.g. financial interest in the 
Sponsor) with the subject before the subject makes a decision to participate in the study. 
13.7 REGISTRATION OF STUDY AND DISCLOSURE OF RESULTS 
The Sponsor will register the study on all required registries (e.g. clinicaltrials.gov) and will 
post study results regardless of outcome on publicly accessible websites in accordance with 
the applicable laws and regulations. 

 
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14 STUDY MANAGEMENT 
14.1 SOURCE DATA 
The Investigator must ensure that all source documents (i.e., medical records) and eCRF pages 
are completed and maintained according to the study protocol and are available at the site. 
The Investigator should ensure clear records are maintained that demonstrate the integrity 
of the data reported to the Sponsor via the eCRF. This includes all original records, certified 
copies of clinical findings, observations or other activities necessary for reconstruction and 
evaluation of the study. This includes, but is not limited to, Investigator signed/dated 
laboratory reports and medical notes. Source data must not be changed without clear and 
documented rationale. Any changes should be confirmed with the originator. A full audit trail 
should always be available to identify the person making the entry and/or amendments, the 
original entry/result, the amendment and rationale. The Investigator must ensure that source 
data is always attributable, legible, contemporaneous, original and accurate.  
For this study, key data reported on eCRFs will be verified against source documents.  The 
eCRF will not act as source except in the instance of laboratory data which will be transferred 
directly to the Sponsor/designee responsible to Data Management.   
14.2 QUALITY ASSURANCE 
During and/or after study completion, Sponsor quality assurance officers, IRB/IEC or 
regulatory authorities may perform on-site audits. The Investigator will be expected to 
cooperate with any audit by providing assistance and access to all requested study-related 
records. 
14.3 MONITORING 
The Investigator must permit study-related monitoring by providing direct access to source 
data and to the subjects’ medical records. The Monitor(s) will visit the Investigator at regular 
intervals during the course of the study and after completion of the study if needed. 
During the monitoring visits, eCRFs, source records and other documentation relating to the 
study will be made available for review. The Investigator will ensure any discrepancies or 
omissions are resolved. 
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, data quality, IMP accountability, compliance with 
IRB/IEC/regulatory requirements and continued adequacy of the investigational site, 
resources and its facilities to conduct the study. 
Frequency and scope of the monitoring visits will be defined in the Clinical Monitoring Plan 
which will also define the extent of source data verification to be conducted.  

 
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14.4 STUDY FUNDING 
Shield TX (UK) Limited is the Sponsor and provides funding for the conduct of this study. All 
financial details are provided in clinical trial agreements between the institution, Investigator 
and Sponsor. 
14.5 CONTRACT RESEARCH ORGANISATION (CRO) 
A CRO (Medpace Inc.) will be contracted to be responsible for administrative aspects of the 
study including, but not limited to, site selection and qualification, study set-up, site initiation, 
monitoring, data management including clinical database and electronic CRF provisioning, 
statistics and programming and study reporting. Vendors will also be contracted to cover 
supportive services such as a central laboratory, bioanalysis of PK samples and IMP 
production/labelling, distribution. 
14.6 AMENDMENTS TO THE STUDY PROTOCOL 
The study will be conducted in compliance with this Protocol, as approved by all relevant 
parties.  Should any amendments to the protocol be deemed necessary, this will be resolved 
by mutual written agreement between the Principal Investigator and the Sponsor. 
Any significant changes to the protocol shall be submitted to the IRB/IEC and Regulatory 
Authorities and must be approved prior to implementation as required by local law. 
However, the Sponsor may, at any time, amend this protocol to eliminate an apparent 
immediate hazard to a subject. In this case, appropriate communications and notifications to 
the IRB/IEC and Regulatory Authorities will occur as required by local law. 
Amendments to the Information Sheet and Consent/Assent Form will be made if impacted by 
an amendment to the study protocol which will also be submitted and approved to the 
IRB/IEC as required by local law.  
14.7 STUDY STOPPING RULES 
The Sponsor may terminate this study at any time.  In consultation with the Investigator, it is 
normal procedure to review the emerging clinical and safety data (see Section 7.6). As a result 
of this review, it may be necessary to stop the study before all subjects have completed the 
study.  In this case, all subjects will be followed-up for safety assessments. 
If less than 91 subjects in total have been randomized when 32 ferric maltol subjects have 
completed, then an interim analysis will be conducted. The interim analysis will test for 
significance of the increase in Hb in the ferric maltol arm.   If significant, the study will stop 
recruitment.  If not significant, the study will continue until 54 subjects have been recruited 
in the ferric maltol arm. 
 

 
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The Sponsor will notify the IRB/IEC of discontinuation of the study and the reason for doing 
so. 
14.8 END OF STUDY 
The end of study is the date of the last subject, last visit for final collection of data. 
14.9 RETENTION OF RECORDS 
The Investigator must retain the informed consent/assent documentation, disposition of the 
IMP, hard-copy eCRFs, medical records and other source data at least 25 years after 
completion or discontinuation of the trial or for at least 2 years after the granting of the last 
marketing authorisation in the EC (when there are no pending or contemplated marketing 
applications in the EC) or for at least 2 years after formal discontinuation of clinical 
development of the investigational product. Prior to proceeding with destruction of records, 
the Investigator must notify the Sponsor in writing and receive written authorisation from the 
Sponsor to destroy study records.  
The Investigator must also notify the Sponsor of any changes in the archival arrangements 
including, but not limited to, archival at an off-site facility or transfer of ownership if the 
Investigator leaves the site. 
In addition, the Sponsor will retain copies / originals (as appropriate) of any study-related 
documents in the Trial Master File for at least 25 years after completion or discontinuation of 
the trial or for at least 2 years after the last approval of a marketing application in an ICH 
region, until there are no pending or contemplated marketing applications in an ICH region 
or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. 
14.10 SECURITY AND PUBLICATIONS 
This study protocol remains the Sponsor’s property until the final fulfilment of the contract 
and may only be passed on to registration authorities and license partners with the Sponsor’s 
/ Applicant’s approval.  The study site will treat all knowledge about the study product and/or 
its manufacturer with strictest confidentiality. 
The Sponsor ensures that substances used in the manufacture of the IMP are generally known 
in pharmaceutical science and have been released by the appropriate national authorities for 
use in medications, cosmetics or food.   
Publication rights will be described in the Investigator contract.  The study site’s agreement 
is not required for using the study results for discussions with regulatory/governmental 
authorities or for other purposes such as presentation at conferences, discussion with 
potential licencing partners or specialist groups. 

 
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15 REFERENCES 
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