Clinical trial NCT03181451
Conditions: Iron Deficiency, Anaemia in Children Iron-Deficiency
Sponsor: Shield Therapeutics
Start date: 2017-03-14; Completion date: 2018-03-28
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study has been designed to establish the pharmacokinetics (PK) and iron uptake of Ferric Maltol in children and adolescents aged 10-17 years using two (2) lower dose strengths in comparison to the EU-approved 30mg BID dose in adults with IDA in IBD.

Detailed description:
Phase I, open label, randomized, repeat dose, multicentre, pharmacokinetic study to assess the Safety and Tolerability of Ferric Maltol in 3 different dosages.

36 eligible patients will be randomized in a 1:1:1 ratio to one of the following 3 dosages for 9 days BID and a single dose on Day 10:

* 30mg ferric maltol capsules
* 16.6 mg ferric maltol capsules
* 7.8 mg ferric maltol capsules

Subject participation in the study will consist of 3 stages:

Screening: up to 14 days Treatment period: 10 days treatment period with 2 visits on Day 1 and Day 10 for PK blood sampling. Patients will be randomly allocated to one of the three Ferric Maltol dose groups according to centralized treatment allocation scheme.

Post-treatment Safety Follow-up:3-10 days following completion of the treatment period or premature discontinuation of study medication

Arms: arm 1: 12 subjects will receive 30 mg Ferric Maltol twice daily for 9 days (Days 1-9) plus a final 30mg dose on the morning of Day 10. PK study Day 1 \& Day 10. arm 2: 12 subjects will receive 16.6 mg Ferric Maltol twice daily for 9 days (Days 1-9) plus a final 16.6mg dose on the morning of Day 10. PK study Day 1 \& Day 10. arm 3: 12 subjects will receive 7.8 mg Ferric Maltol twice daily for 9 days (Days 1-9) plus a final 7.8mg dose on the morning of Day 10. PK study Day 1 \& Day 10.
Interventions: intervention 1: Ferric Maltol
Intervention descriptions: intervention 1: To assess the pharmacokinetics and iron uptake of Ferric Maltol through measurement of serum iron, transferrin saturation (TSAT) and plasma concentrations of maltol and maltol glucuronide.

Protocol documents:
Prot_000.pdf: 
 
  
CLINICAL STUDY PROTOCOL: A Phase 1, Open-Label, Randomised, Repeat Dose, Parallel Group 
Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Ferric Maltol at Three Dosage 
Levels in Paediatric Subjects Aged 10-17 Years of Age with Iron Deficiency (with or without 
Anaemia) 
Protocol Number: 
ST10-01-103  
Test Drug:  
 
Ferric Maltol  
EudraCT Number:  
2016-002192-10  
NCT Number:   
NCT03181451 
Study Name:   
AEGIS Kids PK 
Sponsor: 
Shield TX (UK) Limited, Northern Design Centre, Baltic Business Quarter, 
Gateshead Quays, NE8 3DF United Kingdom   
 
Version/Date: 
 Version 3.0, Final, 08 February 2017 
 
 
 
 
 
 
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. 


CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 1 of 59 
 
 
  
 
CLINICAL STUDY PROTOCOL 
A Phase 1, Open-Label, Randomised, Repeat Dose, Parallel Group Study to Evaluate the 
Pharmacokinetics, Safety and Tolerability of Ferric Maltol at Three Dosage Levels in 
Paediatric Subjects Aged 10-17 Years of Age with Iron Deficiency (with or without Anaemia) 
 
 
 
Protocol Number: 
ST10-01-103  
Test Drug:  
 
Ferric Maltol  
EudraCT Number:  
2016-002192-10  
Study Name:   
AEGIS Kids PK 
Sponsor: 
Shield TX (UK) Limited, Northern Design Centre, Baltic Business 
Quarter, Gateshead Quays, NE8 3DF United Kingdom   
 
Version/Date: 
 Version 3.0, Final, 08 February 2017 
 
 
 
 
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.




 
Protocol ST10-01-103, Version 3.0, Final, 08 February 2017 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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2 TABLE OF CONTENTS 
1 
PROTOCOL APPROVALS .................................................................................................................. 2 
2 
TABLE OF CONTENTS ....................................................................................................................... 3 
3 
ABBREVIATION INDEX ..................................................................................................................... 6 
4 
SYNOPSIS ......................................................................................................................................... 8 
5 
BACKGROUND INFORMATION ...................................................................................................... 16 
5.1 
OVERVIEW OF DISEASE ......................................................................................................... 16 
5.2 
CURRENT TREATMENT OF DISEASE ...................................................................................... 17 
5.3 
OVERVIEW OF TEST PRODUCT .............................................................................................. 20 
5.4 
DOSE SELECTION AND RESULTS OF PREVIOUS CLINICAL STUDIES ....................................... 21 
5.5 
RATIONALE FOR THE STUDY ................................................................................................. 23 
5.5.1 
Study Population ........................................................................................................... 23 
5.5.2 
Study Treatment Duration ............................................................................................ 23 
5.6 
RISK-BENEFIT EVALUATION ................................................................................................... 23 
6 
STUDY OBJECTIVES AND ENDPOINTS............................................................................................ 25 
6.1 
PRIMARY OBJECTIVE ............................................................................................................. 25 
6.2 
SECONDARY OBJECTIVES ...................................................................................................... 25 
6.3 
PRIMARY ENDPOINTS............................................................................................................ 25 
6.4 
SECONDARY ENDPOINTS ....................................................................................................... 26 
6.5 
EXPLORATORY ENDPOINTS ................................................................................................... 26 
7 
INVESTIGATIONAL PLAN ............................................................................................................... 27 
7.1 
STUDY OVERVIEW ................................................................................................................. 27 
7.2 
INVESTIGATIONAL SITES ....................................................................................................... 27 
7.3 
INCLUSION AND EXCLUSION CRITERIA ................................................................................. 28 
7.3.1 
Inclusion Criteria ........................................................................................................... 28 
7.3.2 
Exclusion criteria ........................................................................................................... 28 
7.4 
CONCOMITANT MEDICATION ............................................................................................... 29 
7.4.1 
Not Permitted ............................................................................................................... 29 
7.4.2 
Permitted ...................................................................................................................... 30 
7.4.3 
Potential Medication Interactions ................................................................................ 30 
7.5 
INDIVIDUAL DISCONTINUATION CRITERIA ............................................................................ 30 
7.6 
STUDY TERMINATION ........................................................................................................... 31 
8 
TREATMENT OF SUBJECTS ............................................................................................................ 32 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PRESENTATION ......................................... 32 
8.2 
PACKAGING ........................................................................................................................... 32 


 
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8.3 
STORAGE ............................................................................................................................... 32 
8.4 
LABELLING ............................................................................................................................. 32 
8.5 
DISPENSATION ...................................................................................................................... 33 
8.6 
ADMINISTRATION ................................................................................................................. 33 
8.7 
TREATMENT COMPLIANCE .................................................................................................... 33 
8.8 
CONTINUATION OF TREATMENT .......................................................................................... 34 
9 
ENROLMENT AND RANDOMISATION PROCEDURES ..................................................................... 35 
9.1 
SCREENING ............................................................................................................................ 35 
9.2 
RANDOMISATION .................................................................................................................. 35 
9.3 
REPLACEMENT POLICY .......................................................................................................... 35 
9.4 
BLINDING PROCEDURES ........................................................................................................ 36 
9.5 
EMERGENCY UNBLINDING .................................................................................................... 36 
10 STUDY PROCEDURES ..................................................................................................................... 37 
10.1 
DESIGN SCHEMATIC .............................................................................................................. 37 
10.2 
SCHEDULE OF ASSESSMENTS ................................................................................................ 38 
10.3 
DEMOGRAPHICS AND MEDICAL HISTORY ............................................................................. 40 
10.4 
PHYSICAL EXAMINATION ...................................................................................................... 40 
10.5 
CONCOMITANT MEDICATIONS AND PROCEDURES .............................................................. 40 
10.6 
VITAL SIGNS AND 12-LEAD ECG ............................................................................................ 40 
10.7 
LABORATORY ASSESSMENTS ................................................................................................ 40 
10.7.1 
Haematology and Clinical Chemistry ............................................................................ 40 
10.7.2 
Pharmacokinetics .......................................................................................................... 41 
10.7.3 
Urine Pregnancy Test .................................................................................................... 42 
10.7.4 
Summary table of sparse PK blood sampling schedule on Day 1 and Day 10 .............. 42 
10.7.5 
Overall blood volume .................................................................................................... 43 
11 SAFETY ........................................................................................................................................... 44 
11.1 
DEFINITIONS .......................................................................................................................... 44 
11.1.1 
ADVERSE EVENT (AE) .................................................................................................... 44 
11.1.2 
SERIOUS ADVERSE EVENT (SAE) .................................................................................... 45 
11.2 
REPORTING AND DOCUMENTATION .................................................................................... 46 
11.2.1 
Immediate Reporting .................................................................................................... 47 
11.2.2 
Non-Immediate Reporting ............................................................................................ 48 
11.3 
EVALUATION ......................................................................................................................... 48 
11.3.1 
Intensity ........................................................................................................................ 48 
11.3.2 
Causality ........................................................................................................................ 48 


 
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11.3.3 
Outcome ....................................................................................................................... 49 
11.4 
RE-EXPOSURE ........................................................................................................................ 49 
11.5 
SAFETY ENDPOINTS ............................................................................................................... 49 
12 STATISTICAL CONSIDERATIONS ..................................................................................................... 50 
12.1 
SAMPLE SIZE AND POWER CALCULATIONS........................................................................... 50 
12.2 
STATISTICAL METHODS ......................................................................................................... 50 
12.2.1 
Primary Endpoint Analysis ............................................................................................ 50 
12.2.2 
Secondary Endpoint Analyses ....................................................................................... 52 
12.2.3 
Sensitivity Analyses ....................................................................................................... 52 
12.2.4 
Imputation of Missing Data........................................................................................... 53 
12.3 
DEFINITION OF POPULATIONS .............................................................................................. 53 
12.3.1 
Randomised Population ................................................................................................ 53 
12.3.2 
Safety Population .......................................................................................................... 53 
12.3.3 
Intention- To-Treat (ITT) Population (Full Analysis Set) ................................................ 53 
13 ETHICAL CONSIDERATIONS ........................................................................................................... 54 
13.1 
DECLARATION OF HELSINKI .................................................................................................. 54 
13.2 
INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE ............................... 54 
13.3 
SUBJECT INFORMATION AND INFORMED CONSENT ............................................................ 54 
13.4 
SUBJECT DATA PROTECTION ................................................................................................. 55 
13.5 
SUBJECT INSURANCE ............................................................................................................. 55 
13.6 
CONFLICT OF INTEREST ......................................................................................................... 55 
13.7 
REGISTRATION OF STUDY AND DISCLOSURE OF RESULTS .................................................... 55 
14 STUDY MANAGEMENT .................................................................................................................. 56 
14.1 
SOURCE DATA ....................................................................................................................... 56 
14.2 
QUALITY ASSURANCE ............................................................................................................ 56 
14.3 
MONITORING ........................................................................................................................ 56 
14.4 
STUDY FUNDING ................................................................................................................... 57 
14.5 
CONTRACT RESEARCH ORGANISATION (CRO) ...................................................................... 57 
14.6 
AMENDMENTS TO THE STUDY PROTOCOL ........................................................................... 57 
14.7 
STUDY STOPPING RULES ....................................................................................................... 57 
14.8 
END OF STUDY....................................................................................................................... 57 
14.9 
RETENTION OF RECORDS ...................................................................................................... 58 
14.10 
SECURITY AND PUBLICATIONS .......................................................................................... 58 
15 REFERENCES .................................................................................................................................. 59 


 
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3 ABBREVIATION INDEX  
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration Curve 
AUC(0-6h) 
Area Under the Plasma Concentration Curve for 0-6h 
AUC(0-inf) 
Area Under the Plasma Concentration Curve for 0-infinity 
BID 
Twice Daily  
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CA 
Competent Authority 
Cave(0-6h) 
Average Steady State Plasma Concentration from 0-6h 
CD 
Crohn’s Disease 
CHr 
Reticulocyte Haemoglobin Concentration 
Cmax 
Maximum Plasma Concentration 
CL/F 
Apparent Systemic Clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CRP 
C-Reactive Protein 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
Ctrough 
Minimum Plasma Concentration 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
ESA 
Erythropoiesis Stimulating Agent 
FOCE 
First Order Conditional Estimation 
FO 
First Order Estimation 
GCP 
Good Clinical Practice  
GGT 
Gamma-Glutamyl Transpeptidase  
GI 
Gastrointestinal  
GMP 
Good Manufacturing Practice  
h  
Hour 
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 
IRB 
Institutional Review Board  


 
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ITT 
Intention-To-Treat  
IV 
Intravenous  
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin Concentration 
MCV 
Mean Cell Volume 
NCS 
Non-Clinically Significant 
NTBI 
Non-Transferrin Bound Iron 
OFP 
Oral Ferrous Product 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PPK 
Population Pharmacokinetics 
PP 
Per Protocol 
PR 
Electrocardiogram PR Interval 
QRS 
Electrocardiogram QRS Duration 
QT 
Electrocardiogram QT Interval 
RR 
Electrocardiogram RR Interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
t1/2 
Half-life 
TIBC 
Total Iron Binding Capacity 
Tmax 
Time to Maximum Plasma Concentration 
TNFα 
Tumor necrosis factor alpha 
TSAT 
Transferrin Saturation 
UC 
Ulcerative Colitis  
UIBC 
Unsaturated Iron Binding Capacity 
V/F 
Apparent Volume of Distribution 
WHO 
World Health Organisation  
yrs 
Years 
 


 
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4 SYNOPSIS 
Title  
A Phase 1, Open-Label, Randomised, Repeat Dose, Parallel Group Study 
to Evaluate the Pharmacokinetics, Safety and Tolerability of Ferric 
Maltol at Three Dosage Levels in Paediatric Subjects Aged 10-17 Years 
of Age with Iron Deficiency (with or without Anaemia) 
Protocol Number  
ST10-01-103 
Study Name 
AEGIS Kids-PK 
Test Drug 
Ferric Maltol (ST10) 
Comparator 
Not Applicable 
Phase  
Phase 1 
Sites 
Approximately 4-6 sites in the UK 
Study Rationale 
The existing scientific and clinical experience with ferric maltol in the 
treatment of IDA in patients with inflammatory bowel disorder (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-PIP01-11). 
This trial is the initial PIP specified clinical study, designed to establish 
the PK and iron uptake of Ferric Maltol in children and adolescents aged 
10-17 years using two (2) lower dose strengths in comparison to the 
approved 30mg BID dose in adults with IDA in IBD.  The data from this 
study will be used to select the dose(s) for a subsequent Phase 3 
paediatric study of Ferric Maltol in the treatment of IDA (per the EU 
PIP). 
Doses chosen for this paediatric pharmacokinetic study (ages 10 to 17 
years) are based on the daily elemental iron requirements of the study 
subjects and the broad range of weights likely to enrolled, with an aim 
of finding a minimum effective dose in this age group. With the 30mg 
BID adult dose chosen as the highest exposure, 16.6mg BID and 7.8mg 
BID were chosen as approximately ½ and ¼ of the adult dose. The exact 
doses coincide with full fill of available capsule shell sizes.  The lower 
strength formulations will be identical to the 30mg capsule 
formulation. 
Objectives 
Primary objective: 
To assess the pharmacokinetics (PK) and iron uptake of Ferric Maltol 
(ST10) in children and adolescents (aged 10-17 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. 


 
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Secondary objectives: 
1. To assess the effect of 7.8 mg, 16.6 mg or 30 mg Ferric Maltol in 
children and adolescents (aged 10-17 years) after twice daily oral 
doses for 9 days (Days 1 to 9) and a single morning dose on Day 10, 
on serum transferrin, total and unsaturated iron binding capacity 
(TIBC, UIBC), ferritin, non-transferrin bound iron (NTBI); routine 
haematology indices, including absolute reticulocyte count, in 
blood. 
 
2. To assess the safety and tolerability of 7.8 mg, 16.6 mg or 30 mg 
Ferric Maltol in children and adolescents (aged 10-17 years) after 
twice daily oral doses for 9 days (Days 1 to 9) and a single morning 
dose on Day 10, based upon vital signs, adverse events, 
concomitant medications, 12-lead ECG and clinical laboratory 
safety blood tests. 
 
Endpoints  
Primary endpoints: 
1. Population PK analysis of maltol and maltol glucuronide in plasma 
from PK samples collected on Day 1 (after first morning dose) and 
Day 10 (after last morning dose).  Parameters to be derived and 
reported for each Ferric Maltol dose will be:  
 
Cmax, Cave(0-6h), AUC(0-6h), AUC(0-inf) on Day 1 and Day 10, and 
ratios of Day 10/Day 1 for these parameters. 
 
Tmax, half-life (t1/2). 
 
Apparent systemic clearance (CL/F), apparent volume of 
distribution (V/F) 
Descriptive statistics for plasma concentrations of maltol and 
maltol glucuronide by time of collection on Day 1 and Day 10 will 
also be presented, including Ctrough. 
2. Descriptive and population PK analysis of serum iron and TSAT from 
PK samples collected on Day 1 and Day 10.  Parameters to be 
derived and reported for each Ferric Maltol dose will be: 
 
Change from pre-dose (Ctrough) to maximum post-dose 
(Cmax) value for serum iron and TSAT; Cave(0-6h). 
 
Pre-dose adjusted Incremental AUC(0-6h) on Day 1 and Day 
10 from a population PK analysis approach, and 
percentage change from Day 1 to Day 10. 
 
Apparent systemic clearance (CL/F), apparent volume of 
distribution (V/F). 
Descriptive statistics for serum iron and TSAT by time of collection 
on Day 1 and Day 10 will also be presented. 
 


 
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Secondary endpoints: 
1. Descriptive analysis of transferrin, TIBC, UIBC and ferritin 
concentrations from PK samples collected on Day 1 and Day 10. 
2. Descriptive analysis of non-transferrin bound iron (NTBI) 
concentrations from PK samples collected on Day 1 and Day 10. 
3. Descriptive analysis of haemoglobin concentration and absolute 
reticulocyte count from haematology samples collected at 
Screening and Day 10.  
4. Treatment-emergent Adverse Events (AEs) will be summarised. 
5. Treatment-emergent Serious Adverse Events (SAEs) will be 
summarised. 
6. Treatment-emergent Adverse Events leading to premature 
discontinuation of study drug/PK assessments will be summarised.
7. Clinical laboratory safety blood results at Screening and Day 10 will 
be summarised. 
8. Changes in vital signs and 12-lead ECG will be summarised. 
9. Concomitant medications will be summarised. 
 
Design
The study will comprise of the following stages:
 
Screening: to determine subject eligibility for the study (within 14 
days prior to the planned Ferric Maltol dosing period for each 
subject). 
 
Randomised, Parallel Group, Open-Label Treatment Period: A 
treatment period of 10 days with 2 visits on Day 1 and Day 10 for 
PK blood sampling. 
Eligible subjects will be randomly allocated to one of the three 
Ferric Maltol dose groups according to a centralised treatment 
allocation scheme, as follows: 
1. Group 1 – 12 subjects will receive 30 mg Ferric Maltol twice 
daily for 9 days (Days 1-9) plus a final 30mg dose on the 
morning of Day 10.  PK study Day 1 & Day 10. 
2. Group 2 – 12 subjects will receive 16.6 mg Ferric Maltol 
twice daily for 9 days (Days 1-9) plus a final 16.6mg dose on 
the morning of Day 10.  PK study Day 1 & Day 10. 
3. Group 3 – 12 subjects will receive 7.8 mg Ferric Maltol 
twice daily for 9 days (Days 1-9) plus a final 7.8mg dose on 
the morning of Day 10.  PK study Day 1 & Day 10. 
 
Post-treatment Safety Follow-up: 3-10 days following completion 
of the treatment period or premature discontinuation of study 
medication. 
Number of Subjects 
Thirty-six (36) eligible subjects aged 10-17 years will be randomised at 
a ratio of 1:1:1 to one of three doses of Ferric Maltol (7.8 mg, 16.6 mg 
or 30 mg twice daily [BID]) for 9 days (Days 1 to 9); a final single dose 
will then be administered on the morning of Day 10.  


 
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The randomisation scheme will be stratified by co-variates for age 
(10-14y, 15-17y) and sex (M/F).  This will ensure that a minimum of 25% 
of each gender and at least 3 children per age group (15-17 yrs and 10 
to 14 yrs) are enrolled in each Ferric Maltol dose group. 
Inclusion Criteria 
1. 
Ability to understand the information given in the Independent 
Ethics Committee (IEC) approved Information Sheet and Consent 
form. The parent or guardian of the study subject must sign and 
date the informed consent and authorisation to use protected 
health information (PHI) in accordance with national and local 
subject privacy regulations prior to any study mandated 
procedure.  The study participant will be asked to provide their 
assent to participate in the study using the IEC approved Assent 
form. 
2. 
Willing and able to comply with study requirements. 
3. 
Age ≥10 to ≤17 years at the time of informed consent and 
throughout duration of the study. 
4. 
A current diagnosis of iron deficiency (with or without anaemia); 
iron deficiency defined by ferritin <30 µg/L, or ferritin <50 µg/L 
with transferrin saturation (TSAT) <20%, as measured by the 
central laboratory at the Screening visit (subjects with or without 
anaemia may be enrolled providing Hb is 8.5 g/dL as measured 
at the Screening visit). 
5. 
Where appropriate, female subjects of childbearing potential 
must agree to use a reliable method of contraception until study 
completion and for at least 4 weeks following their final study visit.  
Reliable 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), complete sexual abstinence, a 
vasectomized partner and oral contraceptive medications.   
 
Exclusion Criteria 
 
A subject who meets any of the following criteria is not eligible for 
participation in the study. 
1. Has untreated or untreatable severe malabsorption syndrome e.g., 
untreated coeliac disease 
2. Has received within 28 days prior to Screening intramuscular or 
intravenous (IV) injection or administration of depot iron 
preparation. 
3. Has received oral iron supplementation within 7 days prior to 
Screening  
4. Has received blood transfusion within 12 weeks prior to Screening 
or is scheduled to have blood transfusion or donations during the 


 
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study period. 
5. Has concomitant disease that would significantly compromise iron 
absorption or absorbed iron utilisation such as swallowing 
disorders and/or extensive small bowel resection. 
6. Has chronic renal disease (eGFR <30mL/min), as assessed at 
Screening based on serum creatinine. 
7. Known hypersensitivity or allergy to either the active substance or 
excipients of Ferric Maltol capsules. 
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. 
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. 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. 
17. Any other unspecified reason that, in the opinion of the 
Investigator or the Sponsor make the subject unsuitable for 
enrolment. 


 
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Concomitant Medication 
Not Permitted: 
 
Treatment with other oral iron preparations (prescription and non-
prescription) within 7 days prior to Screening and throughout the 
study period. Over the Counter (OTC) multivitamins containing iron 
are permitted provided the dose remains stable throughout the 
study (from Screening to Post-Study visit). 
 
Treatment with parenteral iron preparations within 28 days prior 
to Screening and throughout the study period. 
 
Antibiotics, which are prohibited at screening and during the study.
 
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 taken at a stable dose for 12 weeks prior to 
randomisation and likely to stay stable throughout the study 
treatment period are permitted so long as there is no clinical 
evidence or suspicion of the immunosuppressant contributing to 
the subject’s anaemia (if relevant). 
 
Vitamin B12 and folic acid supplements/replacement are allowed 
during the study 
 
Over the Counter (OTC) oral supplements/multivitamin type 
preparations may be taken, however subjects are encouraged to 
keep the same dose during the course of the study. 
 
Oral contraceptives are permitted, provided that the subject has 
been on a stable dose for at least 12 weeks prior to the Screening 
visit and dosage changes are not anticipated 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. 
 
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 Ferric Maltol. 
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-study visit, unless informed 


 
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consent is withdrawn (and the subject and/or their parent or guardian 
do not agree to attend this visit follow-up visit). 
Investigational Medicinal 
Product  
Ferric Maltol, presented as hard, gelatine, red capsules. For the 
purposes of this study capsules containing three different doses of iron 
and associated excipients will be provided: 
 
30 mg capsule: Each capsule contains 30 mg iron and the 
following excipient(s) with known effect: lactose, Allura Red AC 
(E129) and Sunset Yellow FCF (E110).  
 
16.6 mg capsule: Each capsule contains 16.6 mg iron and the 
following excipient(s) with known effect: lactose, Allura Red AC 
(E129) and Sunset Yellow FCF (E110). 
 
7.8 mg capsule: Each capsule contains 7.8 mg iron and the 
following excipient(s) with known effect: lactose, Allura Red AC 
(E129) and Sunset Yellow FCF (E110). 
Eligible subjects will be randomly allocated to one of the three Ferric 
Maltol dose groups according to a centralised treatment allocation 
scheme using the eCRF, and treated as follows: 
1. Group 1 – 12 subjects will receive 30 mg Ferric Maltol twice 
daily for 9 days (Days 1-9) plus a final 30mg dose on the 
morning of Day 10.  PK study Day 1 & Day 10. 
2. Group 2 – 12 subjects will receive 16.6 mg Ferric Maltol twice 
daily for 9 days (Days 1-9) plus a final 16.6mg dose on the 
morning of Day 10.  PK study Day 1 & Day 10. 
3. Group 3 – 12 subjects will receive 7.8 mg Ferric Maltol twice 
daily for 9 days (Days 1-9) plus a final 7.8mg dose on the 
morning of Day 10.  PK study Day 1 & Day 10. 
Subjects will be instructed to take Ferric Maltol with a glass of water on 
an empty stomach (one hour before eating, or two hours after eating), 
as the absorption of iron is reduced when taken with food.  The 
capsules should be swallowed whole only.  The first capsule of Ferric 
Maltol will be administered in the presence of the site staff on Day 1.  
For subsequent doses, depending upon the age of the subject, capsules 
may need to be administered under the supervision of the child’s 
parent or guardian.  Subjects will be instructed to withhold their final 
dose of Ferric Maltol on the morning of Day 10 until pre-dose PK blood 
samples have first been collected at the site. 
Statistical Methods 
The primary endpoints for this study are PK parameters, which will be 
analysed using a Population PK (PPK) approach.   PPK models will be 
built using a nonlinear mixed effects modelling technique with 
NONMEM® software. It is planned that the first order conditional 
estimation (FOCE) method will be used for model development. If this 
is not feasible (i.e. the model will fail to converge), the first order (FO) 
method will be used instead. Different models will be attempted to fit 


 
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the PK concentration-time data. The models will include but not 
limited to one-compartment linear model, one-compartment linear 
model with first order absorption, two-compartment linear 
mammillary model, two-compartment linear mammillary model with 
first order absorption, three- compartment linear model, and three-
compartment linear model with first order absorption. 
For each individual model, model stability will be assessed with the 
following: 
 
Model parameter estimates not close to a boundary; 
 
Shrinkage for interindividual variability terms (ETA) and 
residual unknown variability (EPS) < 30%; 
 
Condition number (ratio of the largest to the smallest 
eigenvalues) <100; and 
 
Correlation less than 0.95 between any two parameter 
estimates. 
For the final PPK model, diagnostic plots will be presented. 
The plasma maltol and maltol glucuronide concentration-time profile 
at steady state will be predicted using the PPK parameters estimates 
in the final model.  
The pre-dose adjusted incremental AUC(0-6h) on Day 1 and Day 10 in 
serum iron and TSAT will be calculated with non-compartmental 
methods using a population approach. Ratio between Day 10 and 
Day 1 will be calculated. 
Full details of the planned primary and secondary endpoint analyses 
will be documented in the Statistical Analysis Plan (SAP) for the study 
prior to database lock. 
 


 
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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 sulphate, 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 (sulphate, 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 prophylaxis 
and/or treatment of iron-deficiency anaemia in paediatric patients.  
Table 1. Examples of oral iron compounds for treatment of iron-deficiency states in paediatrics 
 
Product 
Iron content 
Indication(s) 
Paediatric dose 
Ferrous gluconate 
tablets 
300 mg 
ferrous 
gluconate 
Prevention and treatment 
of iron deficiency states. 
Children (aged 6-12 years) 
Prophylactic: 1 or 2 tablets 
daily. Therapeutic: 3 tablets 
daily in divided doses. 
Ferrous sulphate 
tablets 
Each 200mg ferrous 
sulphate tablet is 
equivalent to 65mg 
of ferrous iron. 
Prevention and treatment of 
iron- deficiency anaemia 
Children 6-12 
years: 
Treatment:  
> 22kg – one tablet daily; 
 < 44kg – one tablet twice 
daily;  
> 66kg – one tablet three 
times daily. 
A liquid preparation maybe 
more appropriate for 
children. 
Fersamal (syrup) 
Ferrous fumarate 
approx 140 mg/5 mL 
(45 mg elemental 
iron) 
Prophylaxis and treatment 
of iron- deficiency states 
for prophylaxis during 
pregnancy, a combination 
of iron and folic acid is 
usually recommended. 
Full-term infants and young 
children: half to one 5 mL 
spoonful twice a day.  
Premature infants: 0.6 
mL/kg/day to 2.4 mL/kg/day. 
Feospan Spansule 
Capsules 
Dried ferrous 
sulphate 150 mg 
(elemental iron 47 
mg) 
Prevention and treatment 
of iron deficiency 
Children over one year: one 
capsules a day. The capsule 
may be opened and the 
pellets mixed with soft, cool 
food, but they must not be 
chewed. 


 
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Product 
Iron content 
Indication(s) 
Paediatric dose 
Galfer capsules 
Ferrous fumarate 
305.0 mg (equivalent 
to 100 mg elemental 
iron) 
Treatment and prophylaxis of 
uncomplicated iron-
deficiency anaemia 
Children over 12 years; 
prophylaxis = one capsule 
daily; treatment = one 
capsule twice daily. 
Galfer syrup 
Ferrous fumarate 
150 mg/5 mL 
(equivalent to 45 mg 
elemental iron) 
Prophylaxis and treatment of 
iron- deficiency anaemia 
Full-term infants and young 
children> 0.5 mL/kg/day 
administered in 2-3 divided 
doses daily. Max total daily 
dose should not exceed 20 mL.
Premature infants: 0.5 mL/day 
in infants weighting up to 3 kg. 
Iron supplementation in 
premature infants is only 
recommended in those of low 
birth weight who are solely 
breastfed and in these cases 
supplementation should be 
commenced 4-6 weeks after 
the birth and continued until 
mixed feeding is established, 
Niferex100 mg 
gastro-resistant 
capsules, hard 
Ferrous (II) glycine- 
sulphate complex 
equivalent to Fe 2+ 
100 mg. 
Iron deficiency 
Adults and children from age 6:
1 capsule per day. 
In case of pronounced iron 
deficiency anaemia, adults and 
adolescents from age 15 or 
from at least 50 kg bodyweight 
can increase dosage to 1 
capsule 2-3 times daily at the 
beginning of therapy. A daily 
dose of 5 mg Fe 2+ / kg should 
not be exceeded. 
Capsules contain gastro-
resistant granules, which can 
be emptied from the capsule 
shell and swallowed together 
h
ff
f


 
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Product 
Iron content 
Indication(s) 
Paediatric dose 
Sytron (oral 
solution) 
Sodium feredetate 
190 mg (equivalent to 
27.5 mg of iron/5 mL 
Iron-deficiency anaemias, 
notably in paediatrics 
In pregnancy when other forms 
of oral iron may not be well 
absorbed 
Anaemias secondary to 
rheumatoid arthritis 
Infant (including premature 
infants) up to 1 year: 2.5 mL 
twice daily, somewhat smaller 
doses should be used initially  
1 to 5 years: 2.5 mL three times 
daily 
6 to 12 years 5 mL three times
daily 
Data sourced from: http://www.medicines.org.uk/EMC/ and http://www.drugs.com/uk/ 
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). 
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.  The approved dose 
and indication is 30mg twice daily (BID), taken in the morning and evening on an empty 
stomach for the treatment of IDA in IBD in adults. 
Unlike OFPs, which are often given with food in order to reduce side effects, Ferric Maltol 
should, be given on an empty stomach to maximise bioavailability.  Oral ferric iron chelated 


 
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with maltol can be administered with improved tolerability and the total dose exposure of 
unabsorbed iron within the GI tract is significantly reduced. 
In early human studies, maltol was not detected in the systemic circulation following oral 
intake of Ferric Maltol.  This suggests that following absorption, maltol undergoes rapid and 
complete first pass metabolism, is bio transformed to maltol-glucuronide, and excreted in the 
urine. This is consistent with the known metabolism and excretion of maltol absorbed 
naturally from the diet (WHO, 1980; WHO, 2006; Barrand, 1991a,b). 
5.4 
DOSE SELECTION AND RESULTS OF PREVIOUS CLINICAL STUDIES 
Ferric maltol is not absorbed systemically as an intact complex and traditional PK studies may 
not provide the relevant information (Barrand 1991a,b). Therefore, a model was developed 
to determine the optimal dose.  Data from 6 previous studies of Ferric Maltol in subjects with 
IBD and IDA were used to estimate absorption rates in the study population.  Using these 
data, the model suggested that in a compliant adult study population, 30 mg Ferric Maltol 
twice daily would result in correction of baseline anaemia in the majority of subjects. 
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 (30mg 
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 2.25g/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.  
The pharmacokinetics (PK) and iron uptake of 30mg 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 
maltol above the limit of assay detection were transiently observed between 15min and 4h 
after dosing (mean Cmax 67.3ng/mL; median Tmax 1.0h; mean AUC 136h*ng/mL; mean 
t1/2term 0.8h). However, consistent with earlier studies of Ferric Maltol, maltol glucuronide 
predominated in plasma (mean Cmax 4677ng/mL; median Tmax 1.0h; mean AUC 
9651h*ng/mL and mean t1/2term 1.1h).  Maximal change in serum iron and TSAT was 
observed 2h 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%). 


 
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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). 
Twenty-four subjects received Ferric Maltol 30, 60, or 90 mg BID over an 8-day period. 
Pharmacokinetics 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).  Maximum serum concentrations of 
total iron were reached between 2 and 3 hours’ post-dose. Initially a slight decline in serum 
total iron concentrations was observed, followed by an increase to on average 32.3, 49.1 and 
48.7 µmol/L on Day 1 for the 30 mg, 60 mg and 90 mg BID dose groups, respectively. Serum 
total iron concentrations gradually declined after reaching Tmax and mean serum 
concentrations were 11.8, 33.0 and 24.3 µmol/L above baseline at 6 hours’ post-dose on 
Day 1 for the 30 mg, 60 mg and 90 mg BID dose groups, respectively. Comparable serum 
concentrations were measured on Day 8. Plots comparing total iron and the exposure to 
maltol and maltol glucuronide showed no clear relationship. 
Maximum serum values of TSAT were reached between 2 and 3 hours’ post-dose.  TSAT values 
gradually increased up to an average value of 45.6, 69.8 and 67.3% on Day 1 for the 30 mg, 
60 mg and 90 mg BID dose groups, respectively. TSAT gradually declined after reaching Tmax 
and serum values were 17.0, 47.3 and 33.3% above baseline at 6 hours’ post-dose on Day 1 
for the 30 mg, 60 mg and 90 mg BID dose groups, respectively. Similar TSAT serum values 
were measured on Day 8.  Plots comparing TSAT and the exposure to maltol and maltol 
glucuronide showed no clear relationship. 
Both serum iron concentration and TSAT increased after dosing, with maximum values 
between 1.5 and 3 hours’ post dose.  Iron absorption appeared to plateau at 60mg BID. There 
was no clear relationship between either total serum iron or TSAT and exposure to maltol or 
maltol glucuronide.  Total serum iron concentrations and TSAT values were generally higher 
with increasing ferric maltol doses and were comparable after a single dose and at steady-
state. 
Plasma concentrations of both maltol and maltol glucuronide increased rapidly after dosing, 
reaching Cmax in around 1 to 1.5 hours’ post dose, before declining to baseline levels 
between 3 and 6 hours. Exposure to maltol glucuronide was considerably higher than 
exposure to maltol for all ferric maltol dosing regimens. The mean amount of unchanged 
maltol excreted in urine over 6 hours (Ae0-6h) on Day 1 was very low: 0.1, 0.2 and 0.4 mcg 
for the 30 mg, 60 mg and 90 mg dose groups, respectively, representing approximately 0.05, 
0.04 and 0.07% of the administered dose.  The mean renal clearance ranged between 2.5 and 
15 L/hour.  Urine PK parameters were generally comparable between Day 1 and Day 8.  The 
mean amount of maltol glucuronide excreted in urine over 6 hours on Day 1 was 197, 403 and 
870  mg for the 30 mg, 60 mg and 90 mg BID dose groups, respectively, representing 
approximately 40.8, 41.7 and 60.6% of the administered dose.  The mean renal clearance 
ranged between approximately 20 to 27 L/hour for the different dose groups.  Urine PK 
parameters were generally comparable between Day 1 and Day 8. 


 
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Unlike serum iron, maltol absorption appeared to be dose proportional. These data are 
consistent with the iron and maltol absorption profiles reported in the early 
unpublished/published clinical data and the published non-clinical data. 
Refer to the Investigator Brochure for further information. 
5.5 
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 and other causes of IDA.  A Phase 3 study in 128 
subjects with IDA and IBD, who are intolerant of OFPs or are unsuitable for treatment with 
them (ST10-01-301 and ST10-01-302; Gasche, 2015) demonstrated ferric maltol to be 
effective and well-tolerated. 
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-PIP01-11). 
This trial is the initial PIP specified clinical study, designed to establish the PK and iron uptake 
of Ferric Maltol in children and adolescents aged 10-17 years using two (2) lower dose 
strengths in comparison to the approved 30mg BID dose in adults with IDA in IBD.  The data 
from this study will be used to select the dose(s) for a subsequent Phase 3 paediatric study of 
Ferric Maltol in the treatment of IDA (per the agreed EU PIP). 
Doses chosen for this paediatric pharmacokinetic study (in ages 10 to 17 years) are based on 
the daily elemental iron requirements of the study subjects and the broad range of weights 
likely to enrolled, with an aim of finding a minimum effective dose in this age group. With the 
30mg BID adult dose chosen as the highest exposure, 16.6mg BID and 7.8mg BID were chosen 
as approximately ½ and ¼ of the adult dose. The exact doses coincide with full fill of available 
capsule shell sizes.  The lower strength formulations will be based on the 30mg capsule 
formulation.  Fixed dosing with 7.8, 16.6 or 30mg Ferric Maltol BID is considered sufficient to 
meet the objectives of this study for a population PK analysis approach.  
5.5.1 Study Population 
The study population (per the PIP) will be male and females, aged 10-17 years. 
5.5.2 Study Treatment Duration 
Subjects will receive twice daily (morning and evening) Ferric Maltol (7.8mg, 16.6mg or 30mg) 
for 9 days (Days 1 to 9) and final single dose on the morning of Day 10. 
5.6 
RISK-BENEFIT EVALUATION 
The safety of Ferric Maltol in 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 


 
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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 PK 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).  
In this paediatric PK study, children aged 10 to 17 years will be 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 
is considered not to be a risk. Furthermore, the metabolism of maltol through glucuronidation 
in the liver will be similar to adults.  There is unlikely to be any great individual clinical benefit 
over 10 days of Ferric Maltol therapy, although the information gathered will be very 
important in establishing the dose(s) to be studied in the subsequent Phase 3 paediatric 
efficacy and safety study in IDA subjects.  The risk to the subject related to study procedures 
has been assessed as very low.  The study population will recruit subjects with iron deficiency 
or low-normal iron and who are otherwise generally well.  The study population will include 
both female and male children and adolescents aged 10-17 age range.  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 main study procedure risk is related to 
IV cannulation and blood sampling, with fainting, minor bleeding and bruising regarded as the 
main risks.  Overall the benefit-risk of this study is 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 OBJECTIVE 
 To assess the pharmacokinetics (PK) and iron uptake of Ferric Maltol (ST10) in children 
and adolescents (aged 10-17 years) after twice daily [BID] oral doses of 7.8 mg, 
16.6 mg or 30 mg for 9 days (Days 1-9) and single morning dose on Day 10 through 
measurement of serum iron, transferrin saturation (TSAT) and plasma concentrations 
of maltol and maltol glucuronide. 
6.2 
SECONDARY OBJECTIVES 
 
To assess the effect of 7.8 mg, 16.6 mg or 30 mg Ferric Maltol in children and 
adolescents (aged 10-17 years) after twice daily oral doses for 9 days (Days 1 to 9) and 
a single morning dose on Day 10, on serum transferrin, total and unsaturated iron 
binding capacity (TIBC, UIBC), ferritin, non-transferrin bound iron (NTBI); routine 
haematology indices, including absolute reticulocyte count, in blood. 
 To assess the safety and tolerability of 7.8 mg, 16.6 mg or 30 mg Ferric Maltol in 
children and adolescents (aged 10-17 years) after twice daily oral doses for 9 days 
(Days 1 to 9) and a single morning dose on Day 10, based upon vital signs, adverse 
events, concomitant medications, 12-lead ECG and clinical laboratory safety blood 
tests. 
6.3 
PRIMARY ENDPOINTS 
1. Population PK analysis of maltol and maltol glucuronide in plasma from PK samples 
collected on Day 1 (after first morning dose) and Day 10 (after last morning dose).  
Parameters to be derived and reported for each Ferric Maltol dose will be:  
 
Cmax, Cave(0-6h), AUC(0-6h), AUC(0-inf) on Day 1 and Day 10, and ratios of 
Day 10/Day 1 for these parameters. 
 
Tmax, half-life (t1/2). 
 
Apparent systemic clearance (CL/F), apparent volume of distribution (V/F). 
Descriptive statistics for plasma concentrations of maltol and maltol glucuronide by 
time of collection on Day 1 and Day 10 will also be presented, including Ctrough. 
2. Descriptive and population PK analysis of serum iron and TSAT from PK samples 
collected on Day 1 and Day 10.  Parameters to be derived and reported for each Ferric 
Maltol dose will be: 
 
Change from pre-dose (Ctrough) to maximum post-dose (Cmax) value for serum 
iron and TSAT; Cave(0-6h). 
 
Pre-dose adjusted Incremental AUC(0-6h) on Day 1 and Day 10 from a 
population PK analysis approach, and percentage change from Day 1 to Day 
10.  
 
Apparent systemic clearance (CL/F), apparent volume of distribution (V/F). 


 
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Descriptive statistics for serum iron and TSAT by time of collection on Day 1 and Day 10 
will also be presented. 
 
6.4 
SECONDARY ENDPOINTS 
1. Descriptive analysis of transferrin, TIBC, UIBC and ferritin concentrations from PK samples 
collected on Day 1 and Day 10. 
2. Descriptive analysis of non-transferrin bound iron (NTBI) concentrations from PK samples 
collected on Day 1 and Day 10. 
3. Descriptive analysis of haemoglobin concentration and absolute reticulocyte count from 
haematology samples collected at Screening and Day 10.  
4. Treatment-emergent Adverse Events (AEs) will be summarised. 
5. Treatment-emergent Serious Adverse Events (SAEs) will be summarised. 
6. Treatment-emergent Adverse Events leading to premature discontinuation of study 
drug/PK assessments will be summarised. 
7. Clinical laboratory safety blood results at Screening and Day 10 will be summarised. 
8. Changes in vital signs and 12-lead ECG will be summarised. 
9. Concomitant medications will be summarised. 
 
6.5 
EXPLORATORY ENDPOINTS 
Not Applicable


 
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7 INVESTIGATIONAL PLAN 
7.1 
STUDY OVERVIEW 
This is a Phase 1, randomised, open-label, parallel group, multicentre paediatrics 
pharmacokinetic (PK) study. Thirty-six (36) eligible subjects aged 10-17 years will be 
randomised at a ratio of 1:1:1 to one of three doses of Ferric Maltol (7.8 mg, 16.6 mg or 30 mg 
twice daily [BID]) for 9 days (Days 1 to 9); a final dose will then be administered on the morning 
of Day 10.  During the treatment period (Days 1 to 10) subjects will visit the centre for two PK 
blood sampling sessions, Day 1 and Day 10.  On those days, sparse PK blood sampling will be 
performed at baseline (pre-morning dose) and then at two (2) additional post-dose times up 
to 6 hours after the morning dose of Ferric Maltol (see Section 10.7.2). 
The study will comprise of the following stages: 
 Screening: to determine subject eligibility for the study (within 14 days prior to the 
planned Ferric Maltol dosing period for each subject). 
 Randomised, Parallel Group, Open-Label Treatment Period: A treatment period of 10 
days with 2 visits on Day 1 and Day 10 for PK blood sampling. 
Eligible subjects will be randomly allocated to one of the three Ferric Maltol dose 
groups according to a centralised treatment allocation scheme, as follows: 
1. Group 1 – 12 subjects will receive 30 mg Ferric Maltol twice daily for 9 days 
(Days 1-9) plus a final 30mg dose on the morning of Day 10.  PK study Day 1 & 
Day 10. 
2. Group 2 – 12 subjects will receive 16.6 mg Ferric Maltol twice daily for 9 days 
(Days 1-9) plus a final 16.6mg dose on the morning of Day 10.  PK study Day 1 
& Day 10. 
3. Group 3 – 12 subjects will receive 7.8 mg Ferric Maltol twice daily for 9 days 
(Days 1-9) plus a final 7.8mg dose on the morning of Day 10.  PK study Day 1 & 
Day 10. 
 Post-treatment Safety Follow-up: 3-10 days following completion of the treatment 
period or premature discontinuation of study medication. 
Refer to Section 10.1 for a schematic of the study design and Section 10.2 for a detailed 
schedule of assessments. 
The randomisation scheme will be stratified by co-variates for age (10-14y, 15-17y) and sex 
(M/F).  This will ensure that a minimum of 25% of each gender and at least 3 children per age 
group (15-17 yrs and 10 to 14 yrs) are enrolled in each Ferric Maltol dose group. 
7.2 
INVESTIGATIONAL SITES 
Approximately 4-6 sites in the UK will participate in the study. 


 
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7.3 
INCLUSION AND EXCLUSION CRITERIA 
No deviations to the inclusion or exclusion criteria are permitted.   
7.3.1 Inclusion Criteria 
1. Ability to understand the information given in the Independent Ethics Committee (IEC) 
approved Information Sheet and Consent form. The parent or legal guardian of the study 
subject must sign and date the informed consent and authorisation to use protected 
health information (PHI) in accordance with national and local subject privacy regulations 
prior to any study mandated procedure.  The study participant will be asked to provide 
their assent to participate in the study using the IEC approved Assent form. 
2. 
Willing and able to comply with study requirements. 
3. 
Age ≥10 to ≤17 years at the time of informed consent and throughout duration of the 
study. 
4. 
A current diagnosis of iron deficiency (with or without anaemia); iron deficiency defined 
by ferritin <30 µg/L, or ferritin <50 µg/L with transferrin saturation (TSAT) <20%, as 
measured by the central laboratory at the Screening visit (subjects with or without 
anaemia may be enrolled providing Hb is 8.5 g/dL as measured at the Screening visit). 
5. Where appropriate, female subjects of childbearing potential must agree to use a reliable 
method of contraception until study completion and for at least 4 weeks following their 
final study visit.  Reliable 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), complete sexual 
abstinence, a vasectomized partner and oral contraceptive medications.   
 
7.3.2 Exclusion criteria 
A subject who meets any of the following criteria is not eligible for participation in the study. 
1. Has untreated or untreatable severe malabsorption syndrome e.g., untreated coeliac 
disease 
2. Has received within 28 days prior to Screening intramuscular or intravenous (IV) injection 
or administration of depot iron preparation. 
3. Has received oral iron supplementation within 7 days prior to Screening  
4. Has received blood transfusion within 12 weeks prior to Screening or is scheduled to have 
blood transfusion or donations during the study period.  
5. Has concomitant disease that would significantly compromise iron absorption or 
absorbed iron utilisation such as swallowing disorders and/or extensive small bowel 
resection. 


 
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6. Has chronic renal disease (eGFR <30mL/min), as assessed at Screening based on serum 
creatinine. 
7. Known hypersensitivity or allergy to either the active substance or excipients of Ferric 
Maltol capsules. 
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. 
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. 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. 
17. 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 other oral iron preparations (prescription and non-prescription) within 7 
days prior to Screening and throughout the study period. Over the Counter (OTC) 
multivitamins containing iron are permitted provided the dose remains stable throughout 
the study (from Screening to Post-Study visit). 
 Treatment with parenteral iron preparations within 28 days prior to Screening and 
throughout the study period. 
 Antibiotics, which are prohibited at screening and during the study. 
 Blood transfusions within 12 weeks before screening and during the study. 


 
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 Erythropoiesis stimulating agents within 28 days before screening and during the study. 
7.4.2 Permitted 
 Immunosuppressants taken at a stable dose for 12 weeks prior to randomisation and likely 
to stay stable throughout the study treatment period are permitted so long as there is no 
clinical evidence or suspicion of the immunosuppressant contributing to the subject’s 
anaemia (if relevant). 
 Vitamin B12 and folic acid supplements/replacement are allowed during the study 
 Over the Counter (OTC) oral supplements/multivitamin type preparations may be taken, 
however subjects are encouraged to keep the same dose during the course of the study. 
 Oral contraceptives are permitted, provided that the subject has been on a stable dose 
for at least 12 weeks prior to the Screening visit and dosage changes are not anticipated 
during the study. 
 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: quinolone or 
tetracycline antibiotics, bisphosphonates, angiotensin-converting enzyme inhibitors, folic 
acid, methyldopa, levodopa, carbidopa, levothyroxine, and mycophenolate.  
To minimise the potential for drug interactions, Ferric Maltol should be taken on an empty 
stomach at least 2 hours prior to other concomitant medications and/or supplements. 
 
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-
Study Visit within 3-10 days after the last dose of study drug (if the subject agrees in the case 
of withdrawn consent). 
Subjects may be discontinued prematurely during the study for the following reasons: 
 Withdrawal of informed consent. 
 Unwillingness or inability to comply with protocol requirements. 
 Pregnancy or not using a reliable method of birth control (female subject of 
childbearing potential, if applicable). 
 Use of prohibited concomitant medications. 
 Serious adverse events that are judged by the Investigator to be related to Ferric 


 
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Maltol. 
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-study visit, 
unless informed consent is withdrawn (and the subject and/or their parents or guardians do 
not agree to attend this visit follow-up visit).  
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 centres/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 will be supplied to study sites on behalf of Shield TX (UK) Ltd by Piramal 
Healthcare UK Limited, Whalton Close, Morpeth Northumberland, UK.  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. 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PRESENTATION 
Ferric Maltol is presented as a hard, gelatine, red capsule. For the purposes of this study 
capsules containing three different doses of iron and associated excipients will be provided: 
 30 mg capsule: Each capsule contains 30 mg iron and the following excipient(s) with 
known effect: lactose, Allura Red AC (E129) and Sunset Yellow FCF (E110).  
 16.6 mg capsule: Each capsule contains 16.6 mg iron and the following excipient(s) 
with known effect: lactose, Allura Red AC (E129) and Sunset Yellow FCF (E110). 
 7.8 mg capsule: Each capsule contains 7.8 mg iron and the following excipient(s) with 
known effect: lactose, Allura Red AC (E129) and Sunset Yellow FCF (E110). 
A full list of excipients can be found in the Investigator’s Brochure. 
8.2 
PACKAGING 
Ferric Maltol capsules will be supplied in white polypropylene securitainer with a tamper 
evident standard securitainer cap of white medium density polyethylene.  A single bottle 
containing 56 capsules will be provided to cover the entire 10-day treatment duration of the 
study for each subject.  Each bottle will be uniquely numbered to facilitate allocation to an 
individual subject at randomisation. 
8.3 
STORAGE 
IMP must be stored below 25 °C and must not be refrigerated or frozen.  In the event that the 
drug is exposed to temperatures greater than or equal to 25°C, the CRA/Sponsor should be 
contacted for review and further instruction. 
8.4 
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 Annex 13. 
Individual supplies packaging and labelling will be checked by the Investigator/designee 
before the subject takes their first dose of study medication at site on Day 1, after which 
subjects will take their medication home and continue dosing from Day 1 evening, then 


 
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morning and evening from Days 2 to 9.  The subject should withhold their morning dose on 
Day 10 until attending the site for PK assessments.  The final single dose will be taken under 
supervision at the study site on the morning of Day 10, after pre-dose PK blood samples have 
been collected. 
8.5 
DISPENSATION 
A specific strength bottle will be allocated to each subject according to the Ferric Maltol 
treatment randomly allocated for the 10-day dosing period using the eCRF system.  Sites will 
dispense the next available bottle ID number for the corresponding Ferric Maltol dose group 
to each individual subject.  Full details will be provided to sites in the Pharmacy File for the 
study. 
8.6 
ADMINISTRATION 
Eligible subjects will be randomly allocated to one of the three Ferric Maltol dose groups 
according to a centralised treatment allocation scheme in the eCRF, as follows: 
1. Group 1 – 12 subjects will receive 30 mg Ferric Maltol twice daily for 9 days 
(Days 1-9) plus a final 30mg dose on the morning of Day 10.  PK study Day 1 & 
Day 10. 
2. Group 2 – 12 subjects will receive 16.6 mg Ferric Maltol twice daily for 9 days 
(Days 1-9) plus a final 16.6mg dose on the morning of Day 10.  PK study Day 1 
& Day 10. 
3. Group 3 – 12 subjects will receive 7.8 mg Ferric Maltol twice daily for 9 days 
(Days 1-9) plus a final 7.8mg dose on the morning of Day 10.  PK study Day 1 & 
Day 10. 
Subjects should be instructed to take Ferric Maltol on an empty stomach (one hour before 
eating, or two hours after eating) with a glass of water, as the absorption of iron is reduced 
when taken with food. The capsules should be swallowed whole only. 
The first capsule of Ferric Maltol will be administered in the presence of the site staff on Day 1.  
For subsequent doses, depending upon the age of the subject, capsules may need to be 
administered under the supervision of the child’s parent or guardian.  Subjects will be 
instructed to withhold their final dose of Ferric Maltol on the morning of Day 10 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 capsule.  
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 will be given a Diary Card on Day 1 after first dosing 
with Ferric Maltol at the study site and will be instructed to complete this card daily from the 
evening of Day 1 until the evening of Day 9, in order to document the day and time that they 


 
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took their morning and evening doses of Ferric Maltol on those treatment days whilst at 
home.  Subjects will be instructed to return all unused supplies and all clinical study 
medication packaging on the morning of Day 10, having withheld their dose of Ferric Maltol 
that morning.  Compliance will be assessed from the Diary Card entries and unused capsule 
count. 
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 Visit 3, Day 10.  
 


 
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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 
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 randomisation, 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 14 days from 
the initial Screening visit date (if eligible based on retest results). 
9.2 
RANDOMISATION  
Subjects will be registered into the study at the Screening visit and assigned a unique 
subject identification number in the eCRF.  Subjects will be categorised during the 
screening process based upon their age (10 to 14 years of age and 15 to ≤ 17 years of age) 
and their gender. Age and gender will be incorporated into the randomisation as 
stratification factors.  This will ensure that a minimum of 25% of each gender and at least 
3 children per age group (15-17 yrs and 10 to 14 yrs) are enrolled and treated in each Ferric 
Maltol dose group. 
A final eligibility evaluation must be conducted by the Investigator/designee prior to 
randomisation in the eCRF system, once the results of all Screening assessments are 
available.  No subject may begin Ferric Maltol treatment prior to being randomised in the 
eCRF system. The randomisation procedure (created using a computer generated random 
permutation procedure) will assign the subject to one of the three study treatment groups 
(Ferric Maltol 30 mg, 16.6 mg or 7.8 mg BID).  The randomisation process will also specify 
which PK blood sampling schedule should be followed for an individual subject on Day 1 
and Day 10, in order to ensure that the minimum of three subjects per age group and Ferric 
Maltol dose group have PK samples collected at each of the required time point windows 
(see Section 10.7.2).  
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. 


 
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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 DESIGN SCHEMATIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Up to 14 
days 
Visit 1 
Post Study Visit 
3-10 days after last 
dose of Ferric 
Maltol 
Visit 4 
Randomisation 
(1) Dose of Ferric 
Maltol 
7.8, 16.6 or 30 mg 
(BID) 
(2) PK Sampling 
times on Day 1 
and Day 10 
PK Day 10 
 
Visit 3 
PK Day 1 
 
Visit 2 
10-day Ferric Maltol Treatment Period 
14-day Screening Period 
Post-Study follow-up 


 
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10.2 SCHEDULE OF ASSESSMENTS 
PERIOD 
SCREENING 
TREATMENT 
POST-STUDY FOLLOW-UP 
Visit Number 
1 
2 
3 
4 
Visit Name 
Screening 
Period1 
PK Day 1 
PK Day 2 
Post-Study Safety 
Follow-up4 
Visit Day/Duration 
Up to 14 days 
Day 1  
Day 10 
3-10 days after treatment 
discontinuation 
Informed Consent 
X 
 
 
 
Demographics7 
X 
 
 
 
Medical History 
X 
 
 
 
Concomitant Medications and 
Procedures 
X 
X 
X 
X 
Physical Examination 
X 
 
 
X 
Vital Signs2 
X 
X 
X 
X 
12-lead ECG2 
X 
 
X 
 
Urine Pregnancy Test3 
X 
X 
X 
X 
Haematology, Clinical 
Chemistry and screening Iron 
markers blood sampling3 
X 
 
X6 
 
Eligibility Confirmation and 
Randomisation 
X 
X3 
 
 
Dispense Study Drug 
 
X 
 
 
Supervised morning dosing 
with Ferric Maltol 
 
X 
X 
 
Sparse PK Blood Sampling for 
Iron markers, maltol/maltol 
glucuronide and NTBI5, 6 
 
X 
X 
 
Issue and Review of Subject 
Study Dosing Diary 
 
X 
X 
 
Subject to Return Study Drug 
for Accountability 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
1. 
A subject may be retested once for screening laboratory criteria that do not meet protocol in/exclusion criteria, so 
long as randomisation occurs no more than 14 days from the initial screening date (if eligible based on retest results). 
2. 
Vital Signs – supine systolic/diastolic blood pressure, pulse rate and body temperature at each visit; 12-lead ECG at 
Screening and Day 10 (between 1h and 4h post-dose) - machine reported routine ECG parameters (heart rate, PR interval, 
RR interval, QRS duration, QT interval) and overall clinical ECG interpretation will be recorded in the eCRF. 
3. 
Eligibility central laboratory sampling/assessments must be completed at Screening (Visit 1), before the subject is 
randomised and before the first dose of Ferric Maltol study treatment is taken.  Screening parameters to be tested will be:  


 
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Haematology:  red blood cell count, haemoglobin, haematocrit, mean cell volume (MCV), mean corpuscular haemoglobin 
(MCH), mean corpuscular haemoglobin (MCHC), white blood cell count (total and differential (% and absolute), absolute 
reticulocyte count and platelet count. 
Clinical Chemistry:  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. 
Urine pregnancy test for female subjects of childbearing potential. 
On Day 10 (Visit 3), haematology and clinical chemistry blood samples will be collected at one of the PK sampling times 
between 1h to 4h post dose).  Female subjects of childbearing potential will undergo urine pregnancy tests pre-dose on Day 
1 and Day 10 and at the Post-study visit. 
4. 
Subjects who discontinue from the study prematurely should have final assessments conducted per Visit 4/Post-
study Safety Follow Up, unless consent is withdrawn. 
5. 
On PK study Days 1 and 10, all subjects will have baseline PK blood samples collected immediately prior to Ferric 
Maltol dosing (0h).  Subjects will then have further PK blood samples collected at two (2) additional times between 0.5h and 
6h after dosing on Days 1 and 10; the post-dose PK sample time collection windows will be 0.5-1h, 1.0-2.0h, 2.0-3.0h, 3.0-
4.0h and 4.0-6.0h.  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.  For each individual subject, the post-dose 
PK blood sampling schedule will be the same on Day 1 and Day 10.  Post-dose blood samples should be collected within the 
time windows allocated only. N.B: For those subjects in PK Sample Schedule Group 1 (see summary table in Section 10.7.4), 
the PK blood samples for the 0.5-1h timepoint window should be taken at least 30 minutes before the PK blood samples for 
the 1-2h timepoint window on Day 1 and Day 10. Further details are provided in Section 10.7.2 and Section 10.7.4.  After the 
required post-dose PK blood sampling is completed on Day 1 and Day 10, an individual subject can be discharged from the 
site, providing the Investigator has no ongoing safety concerns. 
6. 
Iron markers to be tested from PK blood samples on Days 1 and 10 will be: serum iron, total and unsaturated iron 
binding capacity (TIBC, UIBC), transferrin, transferrin saturation (TSAT), ferritin and non-transferrin bound iron (NTBI). 
7. 
 A minimum of 25% of each gender and at least 3 subjects per age category (10 to 14y and 15-17yr) are to be 
enrolled in each Ferric Maltol dose group.  Height (m) and body weight (Kg) will be measured at Screening (Visit 1) only. 
 
 


 
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10.3 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 diagnosis regardless of onset, all clinically 
significant medical history from the past 5 years including all malignancies, sterilisations, 
hospitalisations and surgeries; the method of contraception for female subjects of 
childbearing potential, if applicable. Body weight (Kg), height (m) will be measured at the 
Screening visit only. 
10.4 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. 
10.5 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 with 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). 
10.6 VITAL SIGNS AND 12-LEAD ECG 
Body temperature (°C), blood pressure and pulse rate will be assessed at Screening, pre-dose 
on Days 1 and 10 and at Post-study; blood pressure and pulse rate should be measured after 
the subject has been supine for at least 5 minutes.  
A 12-lead ECG will be recorded at Screening and again on Day 10 (between 1h and 4h post-
dose).  Machine reported standard ECG parameters (heart rate, PR interval, RR interval, 
QRS duration, QT interval) and overall clinical ECG interpretation will be recorded in the eCRF. 
10.7 LABORATORY ASSESSMENTS 
10.7.1 Haematology and Clinical Chemistry 
Routine clinical laboratory safety bloods for haematology (1mL) and clinical chemistry/iron 
markers (5mL) evaluations will be collected at Screening to assess eligibility.  Haematology 
(1mL) and clinical chemistry (2.5mL) will be repeated on Day 10 (at one of the PK sampling 
times between 1h to 4h post dose).  Additional testing may be required if any abnormal value 
is reported and this must be followed until it is resolved (other than iron indices and low 


 
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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. 
10.7.1.1 Haematology test parameters 
Red blood cell count, haemoglobin, haematocrit, mean cell volume (MCV), mean corpuscular 
haemoglobin (MCH), mean corpuscular haemoglobin (MCHC), white blood cell count (total 
and differential (% and absolute), absolute reticulocyte count and platelet count. 
10.7.1.2 Clinical Chemistry and Screening Iron Markers test parameters 
Clinical Chemistry: 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. 
10.7.2 Pharmacokinetics 
Blood samples for maltol and maltol glucuronide on Day 1 and Day 2 (Visits 2 and 3) 
3mL venous blood samples will be collected in lithium-heparin tubes by indwelling cannula or 
venepuncture at the required times on the PK assessment days (Days 1 & 10), relative to the 
time of Ferric Maltol morning dosing:  pre-dose then two further times between 0.5-6 hours 
post-dose (see Section 10.7.4). 
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 
details of the required sample collection, processing and handling logistics will be specified in 


 
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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 and Non-Transferrin Bound Iron (NTBI) on Day 1 and Day 10 
(Visits 2 and 3) 
5mL venous blood samples will be collected in serum separator tubes (SST) by indwelling 
cannula or venepuncture at the following times on the PK assessment days (Days 1 & 10), 
relative to the time of Ferric Maltol dosing:  pre-dose then then two further times between 
0.5-6 hours post-dose (same times as blood samples for maltol/maltol glucuronide for each 
individual, see Section 10.7.4). 
Following collection and mixing, blood samples will be centrifuged and the resultant serum 
samples separated and split into 1 primary (ambient) and 2 frozen (-20°C) 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) and ferritin.  Frozen serum aliquots will be stored at site for later 
onward shipping on dry ice to the central laboratory.  One (1) aliquot of frozen serum from 
each sampling timepoint on Day 1 and Day 10 will be assayed for serum concentrations of 
NTBI using an appropriately validated method; the second serum aliquot per timepoint will 
stored as a backup sample at 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. 
10.7.3 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 with Ferric Maltol on Day 1; 
the result of this test must be negative for dosing with Ferric Maltol to commence on Day 1.  
Repeat urine pregnancy testing will also be conducted on Day 10 and at the Post-study visit. 
Full details of the required sample collection and processing procedures will be described in 
the study-specific Laboratory Manual. 
10.7.4 Summary table of sparse PK blood sampling schedule on Day 1 and Day 10 
On PK study Days 1 and 10, all subjects will have baseline (pre-dose) PK blood samples 
collected immediately prior to Ferric Maltol dosing (0h).  Subjects will then have further PK 
blood samples collected at two (2) additional times between 0.5h and 6h after dosing on 
Days 1 and 10; within each Ferric Maltol dose group (7.8mg 16.6mg or 30mg BID), the post-
dose PK sample time collection windows will be 0.5-1h, 1.0-2.0h, 2.0-3.0h, 3.0-4.0h and 4.0-
6.0h.  The twelve (12) subjects within each Ferric Maltol dose group will be assigned to the 
required post-dose PK blood sampling schedule in sequential order at the time of 


 
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randomisation, based on current subject enrolment across all study sites.  This is summarised 
in the following table: 
 
 
 
 
 
 
 
 
 
 
 
For each individual subject, the post-dose PK blood sampling schedule will be the same on 
Day 1 and Day 10.  Post-dose samples for each subject must be collected within the allocated 
time-windows (e.g. Between 0.5-1h or 1-2h); the exact time of sample collection will be 
recorded in the eCRF.  For those subjects in PK Sample Schedule Group 1 (see above table), 
the PK blood samples for the 0.5-1h timepoint window should be taken at 30 minutes before 
the PK blood samples for the 1-2h timepoint window on Day 1 and Day 10, to provide an 
adequate spread of actual sampling times for the population PK analysis.  
After the required post-dose PK blood sampling is completed on Day 1 and Day 10, an 
individual subject can be discharged from the site, providing the Investigator has no ongoing 
safety concerns for the subject. 
10.7.5 Overall blood volume  
The individual volume of blood collected throughout the study (Screening and PK assessment 
days) will be 57.5mL.
PK Sample 
Schedule  
Day 1 and 
Day 10 
PK Sample 
Schedule 
Group 1 
(N=3/12) 
PK Sample 
Schedule 
Group 2 
(N=3/12) 
PK Sample 
Schedule 
Group 3 
(N=3/12) 
PK Sample 
Schedule 
Group 4 
(N=3/12) 
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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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/symptoms 
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, ECG 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 an AE (e.g. appendicitis, abdominal pain).  
• 
Pre-existing disease or medical condition documented at baseline that does not 
worsen. 


 
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• 
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 subjects 
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. 
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 


 
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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) such as 
discontinuation of subject's previous treatment during a washout period, 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 is obtained through study completion or 
premature discontinuation must be reported on the AE form in the CRF and reported within 
24 hours to the Sponsor.  All AEs occurring from the time of the first dose of study treatment 
through study completion or premature discontinuation must be reported on the AE form in 
the CRF.  
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. 


 
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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 (also 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 1483431831 
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 and the updated AE form if 
appropriate.   
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.  


 
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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. 
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).  
However, 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 
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 


 
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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. 
11.5 SAFETY ENDPOINTS 
During the study, safety endpoints will be treatment-emergent AEs and SAEs, including 
clinically significant changes from baseline in vital signs, physical examination, routine clinical 
laboratory abnormalities (other than iron deficiency/anaemia indices) and ECG wave interval, 
waveform or rhythm. 


 
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12 STATISTICAL CONSIDERATIONS 
12.1 SAMPLE SIZE AND POWER CALCULATIONS 
Pharmacokinetic data from the pivotal GCP PK studies conducted in both IBD patients and 
patients with IDA of any cause demonstrated that uptake of maltol and iron into the plasma 
after administration of Ferric Maltol display completely independent absorption profiles 
(studies ST10-01-101 and ST10-01-102).  In study ST10-01-101, the PK and iron uptake of 
Ferric Maltol was investigated in blood and urine after single and repeated twice daily oral 
doses of 30 mg, 60 mg and 90 mg for 8 days in subjects with iron deficiency (with or without 
anaemia) through measurement of serum iron, TSAT, ferritin, total iron binding capacity, and 
soluble transferrin receptor, as well as plasma and urine concentrations of maltol and maltol 
glucuronide.  In sub-study ST10-01-102, the PK and iron uptake of Ferric Maltol after a 30 mg 
single dose administered at steady-state were investigated in patients already being treated 
in the open label phase of studies ST10-01-301 or ST10-01-302 through measurement of 
serum iron, transferrin, TSAT, total iron binding capacity, ferritin, soluble transferrin receptor, 
plus plasma and urine concentrations of maltol and maltol glucuronide. 
In sub-study ST10-01-102, with 15 IBD patients participating in the open-label phase of 
studies ST10-01-301 and ST10-01-302, plasma concentrations of maltol above the limit of 
assay detection were transiently observed between 15min and 4h after dosing (mean Cmax 
67.3ng/mL; median Tmax 1.0h; mean AUC 136h*ng/mL; mean t½term 0.8h).  However, 
consistent with earlier studies of ST10, maltol glucuronide predominated in plasma (mean 
Cmax 4677ng/mL; median Tmax 1.0h; mean AUC 9651h*ng/mL and mean t½term 1.1h).  
Maximal change in serum iron and TSAT was observed 2h 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%). 
Therefore, as agreed with the EU CAs in the PIP, the inclusion of 36 subjects aged 10-17 years 
(12 per treatment group) in this study is considered to be adequate to characterise the iron 
uptake and PK parameters for the range of Ferric Maltol doses in an iron deficient adolescent 
population (with or without anaemia).     
12.2 STATISTICAL METHODS 
The following provides a summary of the statistical data analysis methods to be used.  Full 
details of the planned PK and statistical analysis will be specified in the Statistical Analysis Plan 
(SAP) for the study prior to database lock. 
12.2.1 Primary Endpoint Analysis 
The primary endpoints for the study are pharmacokinetic parameters  
1. Population PK analysis (PPK) of maltol and maltol glucuronide in plasma from PK 
samples collected on Day 1 (after first morning dose) and Day 10 (after last morning 
dose).  Parameters to be derived and reported for each Ferric Maltol dose will be:  


 
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Cmax, Cave(0-6h), AUC(0-6h), AUC(0-inf) on Day 1 and Day 10, and ratios of 
Day 10/Day 1 for these parameters. 
 
Tmax, half-life (t1/2). 
 
 Apparent systemic clearance (CL/F), apparent volume of distribution (V/F). 
Descriptive statistics for plasma concentrations of maltol and maltol glucuronide by 
time of collection on Day 1 and Day 10 will also be presented, including Ctrough. 
 
2. Descriptive and population PK analysis of serum iron and TSAT from PK samples 
collected on Day 1 and Day 10.  Parameters to be derived and reported for each Ferric 
Maltol dose will be: 
 
Change from pre-dose (Ctrough) to maximum post-dose (Cmax) value for serum 
iron and TSAT; Cave(0-6h). 
 
Pre-dose adjusted Incremental AUC(0-6h) on Day 1 and Day 10 from a 
population PK analysis approach, and percentage change from Day 1 to Day 
10.  
 
Apparent systemic clearance (CL/F), apparent volume of distribution (V/F). 
Descriptive statistics for serum iron and TSAT by time of collection on Day 1 and Day 10 
will also be presented. 
Population PK models will be built using a nonlinear mixed effects modelling technique with 
NONMEM® software. It is planned that the first order conditional estimation (FOCE) method 
will be used for model development. If this is not feasible (i.e. the model will fail to converge), 
the first order (FO) method will be used instead. Different models will be attempted to fit the 
PK concentration-time data. The models will include but not limited to one-compartment 
linear model, one-compartment linear model with first order absorption, two-compartment 
linear mammillary model, two-compartment linear mammillary model with first order 
absorption, three- compartment linear model, and three-compartment linear model with 
first order absorption. 
For each individual model, model stability will be assessed with the following: 
 Model parameter estimates not close to a boundary; 
 Shrinkage for interindividual variability terms (ETA) and residual unknown variability 
(EPS) < 30%; 
 Condition number (ratio of the largest to the smallest eigenvalues) <100; and 
 Correlation less than 0.95 between any two parameter estimates. 
For the final PPK model, diagnostic plots will be presented. 


 
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The plasma maltol and maltol glucuronide concentration-time profile at steady state will be 
predicted using the PPK parameters estimates in the final model.  
The pre-dose adjusted incremental AUC(0-6h) on Day 1 and Day 10 in serum iron and TSAT will 
be calculated with non-compartmental methods using a population approach. Ratio between 
Day 10 and Day 1 will be calculated. 
12.2.2 Secondary Endpoint Analyses 
Secondary endpoints are: 
1. Descriptive analysis of transferrin, TIBC, UIBC and ferritin concentrations from PK 
samples collected on Day 1 and Day 10. 
2. Descriptive analysis of non-transferrin bound iron (NTBI) concentrations from PK 
samples collected on Day 1 and Day 10. 
3. Descriptive analysis of haemoglobin concentration and absolute reticulocyte count 
from haematology samples collected at Screening and Day 10.  
4. Treatment-emergent Adverse Events (AEs) will be summarised. 
5. Treatment-emergent Serious Adverse Events (SAEs) will be summarised. 
6. Treatment-emergent Adverse Events leading to premature discontinuation of study 
drug/PK assessments will be summarised. 
7. Clinical laboratory safety blood results at Screening and Day 10 will be summarised. 
8. Changes in vital signs and 12-lead ECG will be summarised. 
9. Concomitant medications will be summarised. 
In general, data for these secondary endpoints will be listed and summarised by dose group, 
as described in the SAP.  
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. 
Vital signs, body weight and height will be evaluated and summarised with appropriate 
descriptive statistics. 
Abnormal findings on physical examination and 12-lead ECG clinical interpretation will be 
described by shift tables with description of shift from baseline categories of normal to 
abnormal.  12-lead ECG parameters will be listed and summarised descriptively. 
Screening clinical laboratory data will be listed and summarised with appropriate descriptive 
statistics and for Day 10 results, changes from Screening will be summarised. 
Concomitant medications will be listed and summarised by WHO preferred term. 
12.2.3 Sensitivity Analyses 
Any planned sensitivity analyses will be documented in the SAP prior to database lock. 


 
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12.2.4 Imputation of Missing Data 
All data will be used according to availability, with no imputation for missing data. 
12.3 DEFINITION OF POPULATIONS  
12.3.1 Randomised Population 
All subjects who are randomised. 
12.3.2 Safety Population 
All subjects who have had at least one dose of study drug and one subsequent contact with 
the Investigator will be analysed for safety.  
12.3.3 Intention- To-Treat (ITT) Population (Full Analysis Set) 
For PPK, all subjects who have had at least one dose of study drug and who have at least one 
evaluable post-dose PK sample will be included in the ITT analysis.  The ITT analysis will be 
used in the PPK analysis.  
 


 
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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 54 of 59 
 
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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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 55 of 59 
 
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 (e.g. EU Data 
Protection Directive 95/46/EC).  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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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 56 of 59 
 
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 ECGs 
and 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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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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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. 
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. 
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. 


 
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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 58 of 59 
 
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 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. 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 until 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 property until the final fulfilment of the contract and 
may only be passed on to registration authorities and license partners with the Sponsor / 
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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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 59 of 59 
 
15 REFERENCES 
Barrand MA, Callingham BA. Evidence for regulatory control of iron uptake from ferric maltol 
across the small intestine of the rat. Br J Pharmacol 1991a: 102: 408-14. 
Barrand MA, Callingham BA, Dobbin P, Hider RC. Dissociation of a ferric maltol complex and 
its subsequent metabolism during absorption across the small intestine of the rat. Br J 
Pharmacol 1991b; 102: 723-9. 
BNF for Children. At: http://www.bnf.org/bnf/org_450055.htm. Accessed August 2012. 
British Columbia Guidelines and Protocols. Iron deficiency - investigation and management. 
Effective date: 15 June 2010. 
Bokemeyer B, Krummenerl A, Maaser C, Howaldt S, Mroß M, Mallard N.  Randomized Open-
Label Phase 1 Study of the Pharmacokinetics of Ferric Maltol in Inflammatory Bowel Disease 
Patients with Iron Deficiency. Eur J Drug Metab Pharmacokinet. 2016; Apr 21. [Epub ahead of 
print] 
Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut 
2004; 53: 1190-7. 
Gasche C, Ahmad T, Tulassay Z, Baumgart DC, Bokemeyer B, Büning C, Howaldt S, Stallmach 
A; AEGIS Study Group.  Ferric maltol is effective in correcting iron deficiency anemia in 
patients with inflammatory bowel disease: results from a phase-3 clinical trial program. 
Inflamm Bowel Dis. 2015; 21(3): 579-88 
Latest version of the Investigator’s Brochure for Ferric Maltol (ST10-021, ST10). 
Mamula P, Piccoli DA, Peck SN, Markowitz JE, Baldassano RN. Total dose intravenous infusion 
of iron dextran for iron-deficiency anemia in children with inflammatory bowel disease. J 
Pediatr Gastroenterol Nutr 2002; 34: 286-90. 
Schmidt C, Ahmad T, Tulassay Z, Baumgart DC, Bokemeyer B, Howaldt S, Stallmach A, Büning 
C; AEGIS Study Group.. Ferric maltol therapy for iron deficiency anaemia in patients with 
inflammatory bowel disease: long-term extension data from a Phase 3 study. Aliment 
Pharmacol Ther. 2016; 44(3):259-70. 
Thayu M, Mamula P. Treatment of iron deficiency anemia in pediatric inflammatory bowel 
disease. Curr Treat Options Gastroenterol 2005; 8: 411-7 
Weiss G, Gasche C. Pathogenesis and treatment of anemia in inflammatory bowel disease. 
Haematologica 2010; 95: 175-8. 
World Health Organization (WHO): Toxicological evaluation of certain food additives. 
International Programme on Chemical Safety IPCS. WHO Food Additives Series 1980; No. 16: 
123-129. 
World Health Organization (WHO):  Evaluation of certain food additives. Sixty-fifth report of 
the Joint FAO / WHO Expert Committee on Food Additives. WHO Technical Report Series 
2006; No. 934: 36-41. 

SAP_001.pdf: 
 
  
STATISTICAL ANALYSIS PLAN 
 
CLINICAL STUDY PROTOCOL: A Phase 1, Open‐Label, Randomised, Repeat Dose, Parallel Group 
Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Ferric Maltol at Three Dosage 
Levels in Paediatric Subjects Aged 10‐17 Years of Age with Iron Deficiency (with or without 
Anaemia) 
Protocol Number: 
ST10‐01‐103   
Test Drug:  
 
Ferric Maltol  
EudraCT Number:  
2016‐002192‐10  
NCT Number:   
NCT03181451 
Study Name:    
AEGIS Kids PK 
Sponsor: 
Shield TX (UK) Limited, Northern Design Centre, Baltic Business Quarter, 
Gateshead Quays, NE8 3DF United Kingdom   
 
Version/Date: 
 Version 2.0, Final, 11 May 2018 
 
 
 
 
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. 


 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 1, Open-Label, Randomised, Repeat Dose, Parallel Group Study to 
Evaluate the Pharmacokinetics, Safety and Tolerability of Ferric Maltol at 
Three Dosage Levels in Paediatric Subjects Aged 10-17 Years of Age with 
Iron Deficiency (with or without Anaemia) 
 
 
Investigational Product:  Ferric Maltol 
Protocol Number: ST10-01-103 
 
 
 
Sponsor: 
Shield TX (UK) Limited 
Northern Design Centre 
Baltic Business Quarter 
Gateshead Quays 
NE8 3DF 
United Kingdom 
 
 
Protocol Version Number: Version 3.0, Final 
Protocol Date: 08 February 2017 
 
 
SAP Version Number: 2.0 
SAP Date: 11 May 2018 
 
 
 
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.






Shield TX (UK) Limited 
Statistical Analysis Plan 
ST10-01-103 
Version 2.0, 11 May 2018
 
 
Page 4 
 
VERSION HISTORY 
Version  
Date 
Description 
0.1 
21 June 2017 
Initial creation 
0.2 
28 October 2017 
 Removed Per Protocol Population from Section 5; 
 Update Section 6.1; 
 Updated Section 7.2; 
 Updated Section 8; 
 Changed Safety Population to FAS/ITT for 
summary in Section 9.1; 
 Updated Section 10; 
0.3 
27 November 2017 
 Updated signature page; 
 Added the time period for AE and SAE capture in 
Section 4.4.1; 
 Added descriptive statistics for vital sign in 
Section 4.4.3; 
 Added descriptive statistics for ECG in Section 
4.4.4; 
 Removed test of significance from Section 6.2; 
 Added categorical data in Section 6.2; 
 Updated protocol deviation category in Section 
7.2; 
 Added descriptive statistics in Section 8.3; 
 Added Section 8.4 for the statistics of observed 
maltol, maltol glucuronide, serum iron, and TSAT; 
 Removed the calculation of TSAT from Section 
8.5.4; 
 Added the time curve for iron makers to Section 
9.1; 
 Added baseline definition in Sections 9.2, 10.3, 
10.4. 
0.4 
08 January 2018 
 Replaced Randomised Population with Dosed 
Group. 
 Added PPD for TSAT in Sections 8.3.4 and 8.3.5. 
0.5 
22 January 2018 
 Added the language “The concentration plots 
described above will be prepared based on the 
actual data, if applicable.” to Sections 8.4 and 9.1. 
 Updated Section 8.3: report a concentration values 
less than the LLOQ as <LLOQ value. 


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Statistical Analysis Plan 
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Version 2.0, 11 May 2018
 
 
Page 5 
 
Version  
Date 
Description 
1.0 
23 January 2018 
 Version 1.0. 
1.1 
07 March 2018 
 Removed individual concentration plots for maltol, 
maltol glucuronide, serum iron and TSAT in 
Section 8.4; 
 Removed individual concentration plots for 
transferrin, TIBC, UIBC, ferritin and NTBI in 
Section 9.4. 
 Added CSR and Non-CSR reportable deviations in 
Section 7.2 
1.2 
11 May 2018 
 Update the baseline definition in Sections 4.3.2, 
4.4.2.1, 4.4.2.2, 4.4.4, 7.3, and 10.2. 
 
 
 


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Page 6 
 
TABLE OF CONTENTS 
1 
Introduction ........................................................................................................................... 10 
2 
Overview ............................................................................................................................... 10 
2.1  Objectives ....................................................................................................................... 10 
2.2  Trial Design .................................................................................................................... 10 
3 
STUDY ENDPOINTS ........................................................................................................... 13 
3.1  Primary Endpoints .......................................................................................................... 13 
3.2  Secondary Endpoints ...................................................................................................... 14 
3.3  Safety Endpoints ............................................................................................................ 14 
4 
STUDY ASSESSMENTS ..................................................................................................... 14 
4.1  Screening Visit and Baseline .......................................................................................... 14 
4.2  Primary Pharmacokinetic Measurements and Variables ................................................ 15 
4.2.1  PK blood sampling ............................................................................................... 15 
4.2.2  PK Parameters ...................................................................................................... 15 
4.3  Secondary Endpoint Measurements and Variables ........................................................ 16 
4.3.1  Iron Markers and Non-Transferrin Bound Iron (NTBI) ....................................... 16 
4.3.2  Haemoglobin Concentration and Absolute Reticulocyte Count .......................... 16 
4.4  Safety Measurements and Variables .............................................................................. 17 
4.4.1  Adverse Events ..................................................................................................... 17 
4.4.2  Safety Clinical Laboratory Measurements ........................................................... 18 
4.4.3  Vital Signs ............................................................................................................ 20 
4.4.4  12-Lead ECG ........................................................................................................ 20 
4.4.5  Physical Examination ........................................................................................... 21 
4.4.6  Prior and Concomitant Medications and Procedures ........................................... 21 
4.4.7  Study Drug Exposure and Compliance ................................................................ 21 
5 
Analysis Populations ............................................................................................................. 22 
5.1.1  Screened Population ............................................................................................. 22 
5.1.2  Dosed Group ......................................................................................................... 22 
5.1.3  Safety Population ................................................................................................. 22 
5.1.4  Full Analysis Set (FAS)/Intent-to-Treat (ITT) Population ................................... 22 
6 
General Considerations for Data Analysis ............................................................................ 23 
6.1  Date Format .................................................................................................................... 23 
6.2  Other Data Handling Approaches .................................................................................. 23 
7 
Analysis of Disposition and Subject Characteristics ............................................................. 23 
7.1  Disposition and Analysis Populations ............................................................................ 23 
7.2  Protocol Deviations and Violations ................................................................................ 24 
7.3  Demographics and Baseline Characteristics .................................................................. 27 
7.4  Medical History .............................................................................................................. 27 


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8 
Pharmacokinetic Analysis ..................................................................................................... 27 
8.1  Analysis Populations ...................................................................................................... 27 
8.2  Missing Dosing Information .......................................................................................... 27 
8.3  Missing concentrations ................................................................................................... 27 
8.4  Observed Maltol, Maltol Glucuronide, Serum Iron, and TSAT .................................... 28 
8.5  Population Pharmacokinetic Modelling ......................................................................... 28 
8.5.1  Basic Model Construction .................................................................................... 28 
8.5.2  Final Model Construction ..................................................................................... 29 
8.5.3  Covariate Model Construction ............................................................................. 29 
8.5.4  Concentration Prediction and Parameter Derivation ............................................ 29 
9 
Secondary endpoint analysis ................................................................................................. 35 
9.1  Transferrin, TIBC, UIBC, ferritin and Non-Transferrin Bound Iron (NTBI) ................ 35 
9.2  Haemoglobin Concentration and Absolute Reticulocyte Count .................................... 35 
10  SAFETY analysis .................................................................................................................. 36 
10.1 Adverse Events ............................................................................................................... 36 
10.2 Safety Laboratory Parameters ........................................................................................ 37 
10.3 Vital Signs ...................................................................................................................... 37 
10.4 12-Lead ECG Parameters ............................................................................................... 37 
10.5 Physical Examination ..................................................................................................... 37 
10.6 Prior and Concomitant Medications and Procedures ..................................................... 38 
10.7 Study Medication Exposure and Compliance ................................................................ 38 
11  Data Safety Monitoring Board .............................................................................................. 38 
12  Interim Analysis .................................................................................................................... 38 
13  Sample Size and Power Considerations ................................................................................ 38 
14  Changes from Protocol-Specified Statistical Analyses ......................................................... 38 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Plasma Concentration Curve 
AUC(0-6h) 
Area Under the Plasma Concentration Curve for 0-6h 
AUC(0-inf) 
Area Under the Plasma Concentration Curve for 0-infinity 
BID 
Twice Daily 
BMI 
Body Mass Index 
BQL 
Below the Quantifiable Limit 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
Cave(0-6h) 
Average Steady State Plasma Concentration from 0-6h 
CL/F 
Apparent Systemic Clearance 
Cmax 
Maximum Plasma Concentration 
CSR 
Clinical Study Report 
Ctrough 
Minimum Plasma Concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EU 
European Union 
FAS 
Full Analysis Set 
FO 
First Order 
FOCE 
First Order Conditional Estimation 
FOCEI 
First Order Conditional Estimation with Interaction 
GGT 
Gamma-Glutamyl Transpeptidase 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean Corpuscular Haemoglobin 


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MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Cell volume 
MRL 
Medpace Reference Laboratory 
NCA 
Non-Compartmental Analysis 
NTBI 
Non-Transferrin Bound Iron 
PIP 
Paediatric Investigation Plan 
PK 
Pharmacokinetics 
PPK 
Population Pharmacokinetics 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SI 
Système International d’Unités 
t1/2 
Half-life 
TEAE 
Treatment Emergent Adverse Event 
TIBC 
Total Iron Binding Capacity 
Tmax 
Time to Maximum Plasma Concentration 
TSAT 
Transferrin Saturation 
UIBC 
Unsaturated Iron Binding Capacity 
V/F 
Apparent Volume of Distribution 
WHO 
World Health Organisation 
 
 


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1 
INTRODUCTION 
The purpose of this document is to provide a description of the statistical methods and procedures 
to be implemented for the analysis of data from Shield Protocol ST10-01-103.  This document is 
based on protocol version 3.0, dated 08 February 2017.  If circumstances arise during the study 
such that more appropriate analytic procedures become available, the statistical analysis plan 
(SAP) may be revised.  Any revisions to the SAP (both alternative and additional methods) will 
be made prior to database lock and reasons for such revisions will be described in the final Clinical 
Study Report (CSR). 
2 
OVERVIEW 
2.1 
Objectives 
The primary objective of the study is to assess the pharmacokinetics (PK) and iron uptake of Ferric 
Maltol (ST10) in children and adolescents (aged 10-17 years) after twice daily [BID] oral doses of 
7.8 mg, 16.6 mg or 30 mg for 9 days (Days 1-9) and a single morning dose on Day 10 through 
measurement of serum iron, transferrin saturation (TSAT) and plasma concentrations of maltol 
and maltol glucuronide. 
The secondary objectives are the following: 
 To assess the effect of 7.8 mg, 16.6 mg or 30 mg Ferric Maltol in children and adolescents 
(aged 10-17 years) after twice daily oral doses for 9 days (Days 1 to 9) and a single morning 
dose on Day 10, on serum transferrin, total and unsaturated iron binding capacity (TIBC, 
UIBC), ferritin, non-transferrin bound iron (NTBI); routine haematology indices, including 
reticulocyte count, in blood. 
 To assess the safety and tolerability of 7.8 mg, 16.6 mg or 30 mg Ferric Maltol in children 
and adolescents (aged 10-17 years) after twice daily oral doses for 9 days (Days 1 to 9) and 
a single morning dose on Day 10, based upon vital signs, adverse events, concomitant 
medication, 12-lead Electrocardiogram (ECG) and clinical laboratory safety blood tests. 
2.2 
Trial Design 
This is a Phase 1, open label, randomised, repeat dose, parallel group study.   
 
Approximately 36 eligible subjects aged 10-17 years were to be randomised at a ratio of 1:1:1 to 
one of three doses of Ferric Maltol (7.8 mg, 16.6 mg or 30 mg BID) for nine days (Days 1 to 9); a 
final single dose was then be administered on the morning of Day 10.  Randomisation was to be 
stratified by age (10-14 years, 15-17 years) and gender (male, female) to ensure a minimum of 
25% of each gender and at least three children per age group are enrolled in each Ferric Maltol 
dose group. 
 
 
 


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The planned study consisted for three study periods: 
1. Screening Period; 
2. Open-Label Treatment Period; and  
3. Follow-Up Period. 
 
Table 1 contains details of the study periods, study visits and timing of the visits.  A short visit 
name has been generated to be included in tables and listings with limited space. 
 
Table 1 Study Visits 
Study  
Visit 
 
Period 
Study  
Day 
Visit Name 
Long 
Short 
1 
Screening 
-14 to -1 
Screening 
Screening 
2 
Open-Label Treatment 
1 
PK Day 1 
Day 1 
3 
Open-Label Treatment 
10 
PK Day 10 
Day 10 
4 
Follow-up 
3 -10 
Post-Study Safety Follow-up 
Follow-up 
 
The Screening Period consisted of one visit: Study Visit 1 (Screening) scheduled to take place 
within 14 days prior to the planned Open-Label Treatment Period for each subject.  The purpose 
of this visit was to determine subject eligibility for the study. 
The Treatment Period was to include two visits: Study Visit 2 (Day 1; PK Day 1) and Study Visit 
3 (Day 10; PK Day 10). 
The Follow-up Period included the last study visit: Study Visit 4 (Post-Study Safety Follow-up). 
This visit was to occur 3-10 days following completion of the Open-Label Treatment Period or 
premature discontinuation of study drug. 
The schedule of procedures can be found in Table 2. 
 
 


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Table 2 Schedule of Procedures 
Period 
Screening
Open-Label Treatment 
Follow-up 
Study Visit 
1 
2 
3 
4 
Short Name 
Screening
Day 1 
Day 10 
Follow-up4 
Day 
 
1 
10 
 
Informed Consent 
X 
 
 
 
Demographics7 
X 
 
 
 
Medical History 
X 
 
 
 
Concomitant Medications and 
Procedures 
X 
X 
X 
X 
Physical Examination 
X 
 
 
X 
Vital Signs1 
X 
X 
X 
X 
12-lead ECG2 
X 
 
X 
 
Urine Pregnancy Test3 
X 
X 
X 
X 
Haematology, Clinical Chemistry and 
screening Iron markers blood sampling3 
X 
 
X6 
 
Eligibility confirmation and 
Randomisation 
X 
X3 
 
 
Dispense Study Drug 
 
X 
 
 
Supervised morning dosing with Ferric 
Maltol 
 
X 
X 
 
Sparse PK Blood Sampling for Iron 
markers, maltol/maltol glucuronide and 
NTBI5, 6 
 
X 
X 
 
Issue and Review of Subject Study 
Dosing Diary 
 
X 
X 
 
Subject to Return Study Drug for 
Accountability 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
1 Vital Signs – supine systolic/diastolic blood pressure, pulse rate and body temperature at each visit. 
2 12-lead ECG at Screening and Day 10 (between 1h and 4h post-dose) – machine reported routine ECG parameters  
  (heart rate, PR interval, RR interval, QTS duration, QT interval) and overall clinical ECG interpretation. 
3 Eligibility central laboratory sampling/assessments must be completed at Screening (Study Visit 1), before the  
  subject is randomised and before the first dose of Ferric Maltol study drug is taken.  Screening parameters to  
  be tested: 
  Haematology: red blood cell count, haemoglobin, haematocrit, mean cell volume (MCV), mean corpuscular   
  haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), white blood cell count (total and    
  differential (% and absolute), absolute reticulocyte count and platelet count.  
  Clinical Chemistry: 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.  
  Urine pregnancy test for female subjects of childbearing potential. 
  On Day 10, haematology and clinical chemistry blood samples will be collected at one of the PK  
  sampling times between 1h to 4h post dose).  Female subjects of childbearing potential will undergo urine  
  pregnancy tests pre-dose on Day 1 and Day 1- and at the Post-study visit. 
4 Subjects who discontinue from the study prematurely should have final assessments conducted per Study Visit 4,  


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  unless consent is withdrawn. 
5 On PK study Days1 and 10, all subjects will have baseline PK blood samples collected immediately prior to 
   Ferric Maltol dosing (0h).  Subjects will then have further PK blood samples collected at two additional times  
  between 0.5h and 6h after dosing on Days 1 and 10; the post-dose PK sample time collection windows will be 0.5- 
  1h, 1.0-2.0h, 2.0-3.0h, 3.0-4.0h and 4.0-6.0h.  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.  For each individual subject, the post-dose PK blood sampling schedule will be the same on Day 1 and  
  Day 10.   
6 Iron markers to be tested from PK blood samples on Days 1 and 10 will be: serum iron, total and unsaturated iron  
  binding capacity (TIBC, UICB), transferrin, transferrin saturation (TSAT), ferritin and non-transferrin bound iron  
  (NTBI). 
7 Demographics include age, gender, ethnicity and race and are recorded at the Screening Visit; Height (m) and  
  body weight (kg) will be measured at the Screening Visit only. 
3 
STUDY ENDPOINTS 
3.1 
Primary Endpoints 
The primary endpoints for the study are pharmacokinetic parameters. 
 
1. Population PK analysis of maltol and maltol glucuronide in plasma from PK samples collected 
on Day 1 (after first morning dose) and Day 10 (after last morning dose).  Parameters to be 
derived and reported for each Ferric Maltol dose are: 
 Cmax, Cave(0-6h), AUC(0-6h), and AUC(0-Inf) on Day 1 and Day 10 and ratios of Day 10/Day 
1 for these parameters; 
 Tmax; 
 Half-life (t1/2);  
 Apparent systemic clearance (CL/F); and 
 Apparent volume of distribution (V/F). 
 
Plasma concentrations, including Ctrough of maltol and maltol glucuronide by time of collection 
on Day 1 and Day 10 will also be presented. 
 
2. Descriptive and population PK analysis of serum iron and TSAT from PK samples collected 
on Day 1 and Day 10.  Parameters to be derived and reported for each Ferric Maltol dose are: 
 Change from pre-dose (Ctrough) to maximum post-dose (Cmax) value for serum iron and 
TSAT; Cave(0-6h); 
 Pre-dose adjusted Incremental AUC(0-6h) on Day 1 and Day 10 from a population PK 
analysis approach, and percent change from Day 1 to Day 10; and 
 Apparent systemic clearance (CL/F), apparent volume of distribution (V/F). 
Serum iron and TSAT by time of collection on Day 1 and Day 10 will also be presented. 
 
 


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3.2 
Secondary Endpoints 
The secondary endpoints for the study are: 
1. Transferrin, TIBC, UIBC and ferritin concentrations from PK samples collected on Day 1 
and Day 10; 
2. Non-transferrin bound iron (NTBI) concentrations from PK samples collected on Day 1 
and Day 10; and 
3. Haemoglobin concentration and absolute reticulocyte count from haematology samples 
collected at Screening and Day 10. 
 
3.3 
Safety Endpoints 
The safety endpoints for the study are: 
1. Adverse Events (AEs) - Treatment Emergent Adverse Events (TEAEs), Treatment 
Emergent Serious Adverse Events (SAEs) and TEAEs leading to premature 
discontinuation of study drug/PK assessments; 
2. Clinical laboratory safety blood results at Screening and Day 10; 
3. Changes in vital signs and 12-lead ECG; and  
4. Concomitant medications. 
4 
STUDY ASSESSMENTS 
4.1 
Screening Visit and Baseline 
Written informed consent was to be obtained from each subject/legal guardian on the Screening 
Visit before any study assessment or test was conducted. 
 
Demographic information, including date of birth, race, ethnicity and gender, was to be recorded 
at the Screening Visit. 
 
All current medical conditions, all medical history relevant to iron deficiency diagnosis regardless 
of onset and all clinically significant medical history from the past five years including all 
malignancies, sterilisations, hospitalisations and surgeries were to be collected at the Screening 
Visit.  For female subjects of childbearing potential, the method of contraception was also 
collected at this visit. 
 
Body weight and height were to be measured at the Screening Visit only.  Body Mass Index (BMI) 
will be derived using height and weight as measured at the Screening Visit as: 
 
ܤܯܫൌ ܹ݄݁݅݃ݐ ሺ݇݃ሻ
ሾܪ݄݁݅݃ݐ ሺ݉ሻሿଶ 
 


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4.2 
Primary Pharmacokinetic Measurements and Variables 
4.2.1 PK blood sampling 
On study days 1 and 10, all subjects were to have baseline (pre-dose) PK blood samples collected 
immediately prior to Ferric Maltol dosing (0h).  Subjects were then to have further PK blood 
samples collected at two additional times between 0.5h and 6h after dosing on Days 1 and 10; 
within each Ferric Maltol dose group (7.8 mg, 16.6 mg or 30 mg BID), the post-dose PK sample 
time collection windows were 0.5-1h, 1.0-2.0h, 2.0-3.0h, 3.0-4.0h and 4.0-6.0h.  The 12 subjects 
within each Ferric Maltol dose group were 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.  Table 3 details the sparse PK blood sample schedule. 
 
Table 3 Sparse PK Blood Sampling Schedule 
 
PK Sample Schedule 
Group 1 
(N = 3/12) 
Group 2 
(N = 3/12) 
Group 3 
(N = 3/12) 
Group 4 
(N = 3/12) 
Pre-dose (0h) 
X 
X 
X 
X 
0.5 – 1h 
X 
X 
 
 
1.0 – 2.0h 
X 
 
X 
 
2.0 – 3.0h 
 
X 
 
X 
3.0 – 4.0h 
 
 
X 
 
4.0 – 6.0h 
 
 
 
X 
 
For each individual subject, the post-dose PK blood sampling schedule was to be the same on Day 
1 and Day 10.  Post-dose samples for each subject were to be collected within the allocated time-
windows (e.g. between 0.5-1h or 1-2h); the exact time of the sample collection was to be recorded 
in the eCRF.  For those subjects in PK Sample Schedule Group 1 (see Table 3), the PK blood 
samples for the 0.5-1h timepoint window were to be taken at 30 minutes prior to the PK blood 
samples for the 1-2h timepoint window on Day 1 and Day 10, to provide an adequate spread of 
actual sampling times for the population PK analysis. 
 
4.2.2 PK Parameters 
PK samples were to be collected on Day 1 and Day 10, pre-dose and post-dose according to the 
PK Sample Schedule Group that the subject was assigned to. 
 
Maltol (ng/dL) and Maltol Glucuronide (µg/mL) results will be available from the data export 
from the bioanalytical laboratory, ABS Laboratories Ltd. 
 
Serum iron (µmol/L) and TSAT (%) will be available from the standard export from Medpace 
Reference Laboratory (MRL).  The data transport files from MRL will contain serum iron and 


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TSAT in the standard reporting units of the reporting laboratory and in Système International 
d’Unités (SI) units.  
 
Cmax, Cave(0-6h), AUC(0-6h), AUC(0-inf), Tmax, half-life (t1/2), apparent systemic clearance (CL/F), 
apparent volume of distribution (V/F) and Ctrough will be derived for maltol, maltol glucuronide, 
serum iron and TSAT at Day 1 and Day 10. 
 
4.3 
Secondary Endpoint Measurements and Variables 
4.3.1 Iron Markers and Non-Transferrin Bound Iron (NTBI) 
Iron markers include transferrin, total and unsaturated iron binding capacity (TIBC and UIBC) and 
ferritin.  Iron markers and NTBI were to be collected on Day 1 and Day 10, pre-dose and post-
dose according to the PK Sample Schedule Group that the subject was assigned to. 
 
The following list of iron markers and NTBI will be available from the standard export from MRL: 
 Transferrin (units) g/l 
 TIBC (units) μmol/L 
 UIBC (units) μmol/L 
 Ferritin (µg/L) μg/L 
 NTBI (units) <0.2 eLPI unit =negative, ≥0.2 eLPI unit=positive 
 
The data transport files from MRL will contain iron markers in the standard reporting units of the 
reporting laboratory and in SI units.  All iron markers will be converted to and reported using units 
indicated in parenthesis above. 
 
Baseline for iron markers and NTBI is defined as the pre-dose value observed at the Day 1 Visit.  
Change from baseline to each post-baseline visit/timepoint will be derived for each parameter as 
visit/timepoint value minus baseline. 
 
NTBI results will be available from the data export from Afferix Ltd. 
 
4.3.2 Haemoglobin Concentration and Absolute Reticulocyte Count 
Haemoglobin concentration and absolute reticulocyte counts were to be collected at the Screening 
Visit and on Day 10.   
 
Haemoglobin concentration (g/dL) and absolute reticulocyte counts (10^6 Cells/μL) will be 
available from the standard export from MRL.  The data transport files from MRL will contain 
haemoglobin concentration and absolute reticulocyte counts in the standard reporting units of the 


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reporting laboratory and in SI units; values will be converted to and reported using units indicated 
in parenthesis above. 
 
Baseline for haemoglobin concentration and absolute reticulocyte count is defined as the value 
observed at the Screening Visit. If the Screening retest is performed, the values of Screening retest 
will be used as baseline. Change from baseline to Day 10 will be derived for each parameter as 
visit value minus baseline. 
 
4.4 
Safety Measurements and Variables 
4.4.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical product and does not necessarily have a causal relationship with this treatment.  
 
Any serious adverse event (SAE) that occurred from informed consent being obtained at the 
Screening Visit until two week after the last dose was to be recorded in the eCRF.  Any AE that 
occurred from the time of dosing until the end of the study was to be recorded in the eCRF. The 
following details were to be recorded for each adverse event: 
 Adverse event reported term; 
 Start date and time and stop date; 
 Outcome (fatal, ongoing/not resolved, recovered, recovered with sequelae, unknown); 
 Severity (mild, moderate, severe); 
 Relationship to study drug (related, not related); 
 Action taken with study drug (dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, other, unknown); 
 Other action taken, not related to study drug (none, concomitant medication required, non-
drug therapy required); 
 Cause study discontinuation (yes, no); 
 Serious (yes, no); and 
 If serious: 
o Death (yes, no); 
o Life-threatening (yes, no); 
o Inpatient hospitalisation (yes, no); 
o Prolongation of hospitalisation (yes, no); 
o Congenital anomaly or birth defect (yes, no); 
o Persistent or significant disability/incapacity (yes, no); and 
o Judged as medically significant (yes, no). 
 
Adverse events will be coded using MedDRA version 19.0. 


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Adverse events defined as treatment emergent adverse events (TEAE) if they occur after the first 
dose intake of study drug.  Treatment emergent adverse events will be identified by comparing the 
recorded start date and time of the event with the date and time of the first dose intake of study 
drug. Identification of the treatment emergent status of adverse events with a partial start date will 
be determined using the available incomplete date information.  For example, if the adverse event 
has a missing day field but the non-missing month and year fields place the start of the event after 
the start of study drug, then the event will be assigned to the treatment emergent class.  For adverse 
events where the available partial date information is inconclusive (for example, missing day but 
available month and year are equal to the month and year of start of study drug) then the event will 
be classified as treatment emergent.  In particular, adverse events with a completely missing start 
date will be assumed to be treatment emergent (unless the stop date places the event prior to 
starting study drug). 
 
4.4.2 Safety Clinical Laboratory Measurements 
Routine clinical laboratory safety bloods for haematology and clinical chemistry evaluations were 
to be obtained at the Screening Visit and at Day 10. 
 
4.4.2.1 Haematology 
The following haematology parameters will be available from the standard export from MRL: 
 Red blood cell count (10^12/L); 
 Haematocrit (%); 
 Mean cell volume (MCV) (fL) ; 
 Mean corpuscular haemoglobin (MCH) (pg); 
 Mean corpuscular haemoglobin concentration (MCHC) (g/L); 
 White blood cell count (total and differential (% and absolute)) (10^9/L); and 
 Platelet count (10^9/L). 
 
The data transport files from MRL will contain haematology parameters in the standard reporting 
units of the reporting laboratory and in SI units; values will be converted to and reported using 
units indicated in parenthesis above. 
 
Baseline for all haematology parameters is defined as the value observed at the Screening Visit.  
If the Screening retest is performed, the values of Screening retest will be used as baseline.  Change 
from baseline to Day 10 will be derived for each parameter as visit value minus baseline. 
 
4.4.2.2 Clinical Chemistry 
The following clinical chemistry parameters will be available from the standard export from MRL: 


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 ALT (U/L); 
 AST (U/L); 
 Alkaline phosphatase (U/L); 
 Gamma-glutamyl transpeptidase  (GGT) (U/L); 
 Total bilirubin (μmol/L); 
 Creatinine (μmol/L); 
 Amylase (U/L); 
 Blood urea nitrogen (BUN) (mg/dL); 
 Phosphorous (mg/dL); 
 Sodium (mmol/L); 
 Potassium (mmol/L); 
 Chloride (mmol/L); 
 Calcium (mmol/L); 
 Total cholesterol (mmol/L); 
 Uric acid (μmol/L); 
 Glucose (mmol/L); 
 Total protein (g/L); and 
 Albumin (g/L). 
 
The data transport files from MRL will contain clinical chemistry parameters in the standard 
reporting units of the reporting laboratory and in SI units; values will be converted to and reported 
using units indicated in parenthesis above. 
 
Baseline for all clinical chemistry parameters is defined as the value observed at the Screening 
Visit. If the Screening retest is performed, the values of Screening retest will be used as baseline. 
Change from baseline to Day 10 will be derived for each parameter as visit value minus baseline. 
 
4.4.2.3 Urine Pregnancy Test 
For females of childbearing potential, a urine pregnancy test will be conducted at the Screening 
Visit, prior to first dose of study drug on Day 1, prior to study drug dosing on Day 10 and at the 
Follow-Up Visit. 
 
For all Safety Clinical Laboratory measurements, values outside the reference range will be 
categorized as above (RH: Reference High) or below (RL: Reference Low) the reference range 
based on the Central Laboratory’s normal reference range.  Notable Low (NL), Notable High 
(NH), Critical Low (CL) and Critical High (CH) values will also be flagged. 
 


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4.4.3 Vital Signs 
Body temperature (ºC), diastolic and systolic blood pressure (mmHg) and pulse rate (beats/min) 
were to be assessed at the Screening Visit, pre-dose on Days 1 and 10 and at the Follow-up Visit. 
 
For all vital signs parameters, baseline is defined as the pre-dose value on Day 1.  If a pre-dose 
value at Day 1 is not available, the value from the Screening Visit will be used as the baseline 
value.  Change from baseline to each post-baseline visit (Day 10 and Follow-up) will be derived 
as visit value minus baseline. Observed values and change from baseline will be summarized by 
dose group and visit/timepoint descriptively. Data will also be listed by dose group and 
visit/timepoint. 
 
4.4.4 12-Lead ECG 
A 12-lead ECG was to be recorded at the Screening Visit and at Day 10 (between 1h and 4h post-
dose).  Machine reported standard ECG parameters were to be recorded in the eCRF and include: 
 Heart Rate (beats/min); 
 PR Interval (msec); 
 RR Interval (msec); 
 QRS Duration (msec);  
 QT Interval (msec); and 
 Overall clinical interpretation (Normal, Abnormal, Indeterminate, Not Evaluable, 
Unknown). 
 
The following additional parameters will be derived from the standard ECG parameters: 
 QTcB Interval (msec), defined as: 
ܳܶܿܤൌ ܳܶ ܫ݊ݐ݁ݎݒ݈ܽ
√ܴܴ ܫ݊ݐ݁ݎݒ݈ܽ
 
 
 QTcF Interval (msec), defined as: 
ܳܶܿܨൌ ܳܶ ܫ݊ݐ݁ݎݒ݈ܽ
√ܴܴ ܫ݊ݐ݁ݎݒ݈ܽ
య
 
 
For all ECG parameters, baseline is defined as the value observed at the Screening Visit. If the 
Screening retest is performed, the values of Screening retest will be used as baseline. Change from 
baseline (to Day 10) will be derived as visit value minus baseline. Observed values and change 
from baseline will be summarized descriptively by dose group and visit/timepoint. Data will also 
be listed by dose group and visit/timepoint. 
 


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4.4.5 Physical Examination 
A brief physical examination was to be conducted at the Screening and Follow-up Visits.  The 
examination was to include an assessment of general appearance, skin, head, eyes, ears, nose and 
throat, cardiovascular, respiratory, abdominal, gastrointestinal and musculoskeletal systems. 
 
4.4.6 Prior and Concomitant Medications and Procedures 
Medications taken blood transfusion at the time of the Screening Visit and those stopped within 
three months of the Screening Visit were to be documented on the Prior & Concomitant 
Medications eCRF.  Medications initiated, stopped or with dose and/or frequency changes 
throughout the study were also to be documented on the Prior & Concomitant Medications eCRF.  
The medication name, dose (and unit), start and stop dates of medication, indication, frequency 
and route were to be recorded.  All medications will be coded using the WHO Drug, Dictionary, 
September 2016. 
 
Any medical procedure performed within three months prior to the Screening Visit or performed 
throughout the study were to be documented on the Concomitant Procedures eCRF.  Medical 
procedures include any therapeutic intervention such as surgery/biopsy, physical therapy of 
diagnostic assessment.  Details of the procedure with start and stop dates were to be recorded.   
All medical procedures will be coded using MedDRA version 19.0. 
 
Medications and procedures will be identified as either prior or concomitant according to the start 
and/or stop dates recorded on the eCRF.  Medications/procedures with a stop date prior to the 
Screening Visit will be considered as prior medications/procedures.  Medications/procedures that 
start before the Screening Visit and are continued into the study are considered as concomitant 
medications/procedures as are medications/procedures that have a reported start date on or after 
the date of the Screening Visit.  The prior/concomitant status for medications/procedures with a 
partial start and/or stop date will be determined using the available incomplete date information 
using a similar method as that described previously for adverse events with partial start dates. 
 
4.4.7 Study Drug Exposure and Compliance 
Study drug was to be dispensed at the Day 1 Visit and returned at the Day 10 Visit or Early 
Termination Visit.  The first dose intake of Ferric Maltol was to be taken on site during the Day 1 
Visit and the last intake was to be taken on site on the morning of the Day 10 Visit after the pre-
dose PK blood samples had been taken.  All unused medication was to be returned at the Day 10 
or Early Termination Visit.  A record of the number of capsules dispensed and returned for each 
subjects was to be documented in the eCRF. 
 


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Compliance will be evaluated by comparing the expected number of capsules of study drug 
administered with the actual number of capsules of study drug administered during the open-label 
treatment period.   
 
Assuming that the subject takes the first dose on the morning of Day 1 and the last dose on the 
morning of Day 10, the expected number of capsules taken is assumed to be 19 capsules (i.e. 2 
capsules per day on Days 1 to 9 plus 1 capsule on the morning of Day 10).  If the subject does not 
complete the open-label treatment period as planned then the expected number of capsules will be 
calculated taking into account the timing of the first and last doses. 
 
The actual number of capsules taken will derived as the difference in the number of capsules 
dispensed and returned as recorded in the eCRF. 
 
Compliance will therefore be derived as: 
 
ܥ݋݉݌݈݅ܽ݊ܿ݁ൌ 
ܣܿݐݑ݈ܽ ݊ݑܾ݉݁ݎ ݋݂ ܿܽ݌ݏݑ݈݁ݏ ݐܽ݇݁݊
ܧݔ݌݁ܿݐ݁݀ ݊ݑܾ݉݁ݎ ݋݂ ܿܽ݌ݏݑ݈݁ݏ ݐܽ݇݁݊  ൈ100% 
 
5 
ANALYSIS POPULATIONS 
The analysis populations, defined below, will be used to perform the data analyses.  In the Dosed 
Group subjects will be presented according to the dose group they were allocated to.  In the Safety, 
Full Analysis Set/Intent-to Treat Populations, any subjects who received a different dose than they 
were allocated will be presented according to the dose they actually received. 
5.1.1 Screened Population 
The Screened Population will include all subjects screened for inclusion into the study. 
5.1.2 Dosed Group 
The Dosed Group will include all subjects who take at least one dose of study drug. 
5.1.3 Safety Population 
The Safety Population will include all subjects who take at least one dose of study drug and have 
one subsequent contact with the Investigator.  This population will be used to summarize all safety 
data. 
5.1.4 Full Analysis Set (FAS)/Intent-to-Treat (ITT) Population 
The Full Analysis Set (FAS)/Intent-to-Treat (ITT) Population will include all subjects who take at 
least one dose of study drug and have at least one evaluable post-dose PK sample.  This population 
will be used in the PPK analysis.  


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6 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
Statistical analyses will be performed using SAS® (Version 9.3 or later).  All available data will 
be presented in subject data listings, which will be sorted by dose group, subject identifier and 
where appropriate, visit number and visit/assessment date. 
Listings will contain data for all attended visits whether scheduled or unscheduled and visits will 
be listed in the order in which they were attended.  Tables will only summarise data for the 
scheduled visits. 
Dose groups will be displayed in all output using the following labels: 
 Ferric Maltol 7.8 mg bid 
 Ferric Maltol 16.6 mg bid 
 Ferric Maltol 30 mg bid 
6.1 
Date Format 
 Only the actual age will be used in this study. The YYYY-01-01 will be used for the Date of Birth. 
Partial days will be allowed for the duration of disease. 
6.2 
Other Data Handling Approaches 
Descriptive statistics (n, mean, standard deviation (SD), median, maximum and minimum) will be 
used to summarise the continuous data.  Discrete measures will be summarized using counts and 
percentages (derived from the number of non-missing observations); the number of non-missing 
(n) observations will also be presented.   
Unless otherwise stated, descriptive statistics showing the mean or median will be displayed to 
one more decimal place than the original data; the standard deviation will be displayed to two 
decimal places more than the original data and minimum and maximum values will be displayed 
to the same number of decimal places as the original data.   
All fractional numeric values will be printed with a zero to the left of the decimal point (e.g., 0.12, 
0.3 etc.). Percentage values will be printed with one digit to the right of the decimal point (e.g., 
52.3%, 8.9% etc.). 
Categorical data will be summarized descriptively using frequency counts and corresponding 
percentages.  
7 
ANALYSIS OF DISPOSITION AND SUBJECT CHARACTERISTICS 
7.1 
Disposition and Analysis Populations 
Subject disposition will be presented for all subjects in the Screened Population.  The number and 
percentage of subjects who meet each of the following categories will be summarised by dose 
group and overall, as appropriate: 


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 Screened; 
 Screen success; 
 Screen failure and reasons for screen failure; 
 Dosed; 
 Complete the open-label treatment period; and 
 Prematurely discontinue during the open-label treatment period and reasons for study 
discontinuation.  
 
Subjects who screen fail will be listed detailing date of screen failure and primary reason for screen 
failure.   
 
The number of subjects in the Screened Population, Dosed Group, Safety Population, and FAS/ITT 
Population will be tabulated by dose group and overall.  A listing of analysis population inclusion 
will also be provided. 
 
Inclusion/Exclusion criteria deviations will be listed and summarized for the Dosed Group and 
those excluded from the Screened Population. 
 
All available visit dates will be listed for the Screened Population. 
 
A listing of informed consent will be provided for the Screened Population.  This listing will 
contain the date of informed consent (for the subject and/or parent/guardian) and the protocol 
version to which informed consent was provided; details of reconsent, as appropriate, will also be 
included. 
 
Treatment details will be listed for the FAS/ITT Population and will contain, for each subject, 
details of the stratification variables (gender and age group), date of randomization, randomization 
number, the dose group the subject was randomised/assigned to (‘Planned’) and the dose the 
subject actually received (‘Actual’), the date of first dose of study drug and the PK Sampling Group 
the subject was allocated to. 
 
7.2 
Protocol Deviations and Violations 
CSR reportable protocol deviation include the following categories: 
 Inclusion: Subject enrolled did not meet all inclusion criteria (CRA to specify inclusion 
criteria not met in eMVR); 
 Exclusion: Subject enrolled met exclusion criteria (CRA to specify exclusion criteria met 
in eMVR); 
 Withdrawal Criteria: Patient met one or more withdrawal criteria and continued in the 
study: 


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 Subject withdrew informed consent; 
 Subject unwilling or unable to comply with protocol requirements;  
 Subject became pregnant or was not using a reliable method of birth control, if 
female and of childbearing potential; 
 Subject experienced SAEs judged by the investigator to be related to study drug 
(Ferric Maltol); or 
 Subject used prohibited concomitant medication(s). 
 Investigational Product:  
 Subject received incorrect dose of study medication (specify dose and timepoint); 
 Subject was dispensed incorrect dose; 
 Study drug compliance <80% per Patient Dosing Card on V3 Day 10 or IP 
accountability; 
 Study drug compliance >120% per Patient Dosing Card on V3 Day 10 or IP 
accountability; or 
 Incorrect data provided for stratification at  randomisation (specify data). 
 Restricted Concomitant Procedure/Medication Change:  
 Subject initiated drug therapy not permitted per protocol (specify medication and 
timepoint); 
 Immunosuppressant (specify) not take at a stable dose 12 week prior to 
randomisation 
 Study Procedures: 
 Hematology, chemistry, and iron markers not obtained at appropriate visit(s) 
(specify visit and marker); 
 PK sample not collected (specify visit, PK schedule group and timepoint(s)); or 
 PK sample collected, but not within assigned timepoints ((specify visit, PK 
schedule group, timepoint(s) assigned and timepoint(s) collected)   
 Day 10 visit was not performed on day 10 past Day 1 visit exactly. 
 Breaches in GCP: 
 Subjects (or legal representative) did not sign Informed Consent and Assent prior 
to study procedures; 
 Patient (or legal representative) did not sign amendment to Informed Consent and 
Assent which included new study procedures prior to those procedures being 
performed. 
 
CSR non-reportable protocol deviations include the following categories: 
 SAE reporting: Investigator site did not complete the required SAE information including 
relevant CRF pages or SAE reporting Form and/or notify/submit report to Medpace 
within 24 hours; 
 Informed consent:  


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 An error in the Informed Consent and Assent administration occurred (specify); 
 The Subjects (or legal representative) did not properly sign or did not date the ICF 
(specify versions); 
 The ICF signed by the subject or legally authorized representative is not in the 
subject's primary language; 
 Incorrect Informed Consent and Assent version signed by the subject (specify 
ICF/assent version); 
 Updated Informed Consent and Assent not signed at the first opportunity 
following approval (specify updated Informed Consent and Assent version); 
 A study procedure or medication administration occurred prior to signing the 
Informed Consent and Assent; 
 A subject received IP or has further visits or data collected AFTER withdrawing 
consent for participation in the study; or 
 Subject was not given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study. 
 Subjects (or legal representative) did not sign Informed Consent and Assent prior 
to second screening 
 Study procedures:  
 Physical exam not completed at visit (specify visit); 
 Physical exam not completed at visit (specify visit); 
 Subject was not at rest for 5 minutes prior to Vital signs (BP and HR) being 
obtained (specify visit); 
 Urine pregnancy test not completed (specify visit); or 
 Vital signs not completed at visit (specify vital sign and visit). 
 Investigational product (other than wrong treatment): 
 Study IP stored outside specified ranges in the protocol; 
 IP storage temperature excursion not reported (specify range and dates); 
 Subject dosed with study medication before all inclusion/exclusion were 
confirmed (specify criteria not confirmed prior to first dose); or 
 IP dose administration instructions not followed (please specify). 
 Day 9 evening dose missed 
 Visit windows: Subject was outside of the visit window (specify # of days) for Screening, 
Day 1 Treatment and Post-Study Follow-Up visits (specify visit). 
 
Protocol deviations will be summarized with frequency distributions (counts and percentages) by 
dose group and category for the FAS/ITT population.  The denominators for calculating 
percentages will be based on the number of subjects in the FAS/ITT population for each dose 
group and overall.  
 


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Protocol deviations will be provided within a data listing by subject for each dose group. 
7.3 
Demographics and Baseline Characteristics 
Demographic characteristics (year of birth, age, ethnicity, race and gender) and baseline 
characteristics (height, weight and BMI) as recorded at the Screening Visit will be summarised by 
dose group and overall using descriptive statistics for the Safety and ITT/FAS Populations.  A 
demographics and baseline characteristics listings will also be produced for the Screened 
Population. If the Screening retest is performed, the values of Screening retest will be used as 
baseline. 
 
A listing of reproductive status will be provided for the female subjects only and will contain 
details of whether the female is of child bearing potential and the method(s) of contraception. 
 
7.4 
Medical History 
Medical history (event/diagnosis, start and stop dates and status at end of study) will be presented 
for the Screened Population.  Medical history will be summarised by dose group and overall by 
System Organ Class and Preferred Term for the Safety Population. 
8 
PHARMACOKINETIC ANALYSIS 
8.1 
Analysis Populations 
The FAS/ITT Population will be used for the primary endpoint analysis. 
 
8.2 
Missing Dosing Information 
If dosing information is missing, a patient’s pre-dose time will be used to impute dosing time to 
calculate relative time for post-dosing timepoints. 
 
8.3 
Missing concentrations 
Missing concentrations related to serum iron, TSAT, transferrin, TIBC, UIBC, and NTBI will not 
be not imputed or used in the analysis.  If the dosing history information for a patient is missing, 
the sampling for that patient relative to the missing dose will not be included in the analysis.  
 
For maltol and maltol glucuronide assessment, all drug concentration below the quantifiable limit 
(BQL) are treated as zero. When more than half (>50%) of the values at a single timepoint are 
BQL, mean and median values are reported as BQL. Standard deviation and %CV are not reported; 
maximum and minimum values are reported as observed (including BQL). If, as the result of the 
calculation (eg. dose normalization, descriptive statistics) a concentration value is less than the 
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8.4 
 Observed Maltol, Maltol Glucuronide, Serum Iron, and TSAT 
The observed values for maltol, maltol glucuronide, serum iron, and TSAT will be summarized by 
dose group and by visit/timepoint for FAS/ITT Population using the flowing descriptive statistics: 
n (the number of subjects), arithmetic mean, minimum and maximum.  
 
The change from baseline values of serum iron and TSAT will be summarized by dose group for 
each post-baseline visit/timepoint for FAS/ITT Population using the flowing descriptive statistics: 
n (the number of subjects), arithmetic mean, median, minimum and maximum.  
 
The observed data for maltol, maltol glucuronide, serum iron, and TSAT will also be listed by 
dose group for each individual subject for FAS/ITT Population. 
 
For maltol and maltol glucuronide, the mean observed plasma concentrations will be plotted on a 
linear and semi-logarithmic scale against nominal time range by dose group and visit. Geometric 
mean observed plasma concentrations will be plotted on a linear scale against nominal time range 
by dose group and visit. Combined observed plasma concentrations will be plotted on a linear and 
semi-logarithmic scale against actual timepoint for each dose group and visit. 
 
For serum iron, the mean observed serum concentrations will be plotted on a linear and semi-
logarithmic scale against nominal time range by dose group and visit. Combined observed serum 
concentrations will be plotted on a linear and semi-logarithmic scale against actual timepoint for 
each dose group and visit. The change of baseline will be plotted similarly.  
Mean observed TSAT will be plotted on a linear scale against nominal time range by dose group 
and visit. Combined observed TSAT will be plotted on a linear scale against actual timepoint for 
each dose group and visit. The change of baseline will be plotted similarly. 
 
The concentration plots described above will be prepared based on the actual data, if applicable. 
 
8.5 
Population Pharmacokinetic Modelling 
The FAS/ITT Population will be used for the PPK analysis. 
8.5.1 Basic Model Construction 
The maltol and maltol glucuronide concentrations will be analysed simultaneously by means of 
fitting the compartment models to observed concentration data using a population PK (PPK) 
approach.  
 
Likewise, the serum iron and TSAT concentrations will be analysed. If the PPK modelling for 
TSAT is not feasible, population PD (PPD) approach may be performed.  
 


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Population PK models will be built using a nonlinear mixed effects modelling technique with 
NONMEM® software.  It is planned that the first order conditional estimation with interaction 
(FOCEI) method will be used for model development.  If this is not feasible (i.e. the model will 
fail to converge), the first order conditional estimation (FOCE) and the first order (FO) method 
will be used instead.  
 
Different models will be attempted to fit the PK concentration-time data.  The models will include, 
but are not limited to, one-compartment linear model, one-compartment linear model with first 
order absorption, two-compartment linear mammillary model, two-compartment linear 
mammillary model with first order absorption, three-compartment linear model, and three-
compartment linear model with first order absorption, linear compartment model with zero order 
absorption or saturable absorption.  Furthermore, a nonlinear compartment model may also be 
tested, if possible.  
For each individual model, model stability will be assessed with the following: 
 Model parameter estimates not close to a boundary; 
 Shrinkage for interindividual variability terms (ETA) and residual unknown variability 
(EPS) < 30%; 
 Condition number (ratio of the largest to the smallest eigenvalues) <1000; and 
 Correlation less than 0.90 between any two parameter estimates. 
 
For the final PPK model, diagnostic plots will be presented and assessed. 
 
8.5.2 Final Model Construction 
Based on the results of the above assessments, the final base model will be judged and finalized. 
 
8.5.3 Covariate Model Construction 
If applicable, the following covariates will be evaluated for their potential significant impact on 
the PK.  Age, race and ethnicity, gender, all current medical conditions, all medical history relevant 
to iron deficiency diagnosis regardless of onset, all clinically significant medical history from the 
past five years including all malignancies, sterilisations, hospitalisations and surgeries, the method 
of contraception for female subjects of childbearing potential and body weight. 
  
8.5.4 Concentration Prediction and Parameter Derivation 
The serum iron, plasma maltol, plasma maltol glucuronide concentration, and TSAT versus time 
profile on Days 1 and 10 will be predicted for each subject using the individual PK parameters 
estimates from the final model.  
 


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Standard non-compartmental methods (NCA) will be used for the PK parameter calculations based 
on the predicted concentrations.  The Linear Up Log Down method (equivalent to the Linear 
Up/Log Down option in WinNonlin® Professional) will be used in the computation of AUC.   
 
Maltol and maltol glucuronide: 
The following parameters for Day 1 will be derived for each Ferric Maltol dose based on the 
predicted maltol and maltol glucuronide concentrations, if applicable: 
 
Table 4 Parameters for Maltol and Maltol Glucuronide on Day 1 
Parameters 
Description 
Cmax 
Maximum plasma concentration directly from data 
Tmax 
Time to reach maximum concentration directly from data 
λz 
Apparent first-order terminal elimination rate constant  
t½ 
Terminal elimination half-life, calculated as ln(2)/ λz 
AUC0-6h 
Area under the plasma concentration versus time curve from time zero to 6hr. 
AUC0-inf 
Area under the plasma concentration versus time curve from time zero 
extrapolated to infinity time 
CL/F 
Apparent clearance calculated as Dose/AUC0-inf 
Vz/F 
Apparent volume of distribution (as Dose/ [λz *AUC0-∞]) 
 
 
 


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The following parameters for Day 10 will be derived for each subject based on the predicted maltol 
and maltol glucuronide concentrations, if applicable: 
 
Table 5 Parameters for Maltol and Maltol Glucuronide on Day 10 
Parameters 
Description 
Tau 
The dosing interval for steady-state data tau=12 
Cmax 
Maximum concentration between dose time and dose time + Tau. If not unique, then 
the first maximum is used. 
Ctrough 
Minimum concentration between dose time and dose time + Tau 
Tmax 
Time to reach Cmax during a dosing interval 
AUC0-6h 
Area under the plasma concentration versus time curve from time zero to 6hr. 
AUC0-tau 
Area under the plasma concentration versus time curve from time zero to Tau 
Cave(0-6h) 
Average Steady State Plasma Concentration from 0-6h, calculated as AUC0-6h 
divided by 6 
CLss/F 
Apparent clearance calculated as Dose/AUC0-tau  
RCmax 
Accumulation ratio based on maximum concentrations after first dose and last 
dose, calculated as CmaxDay10/CmaxDay1 
RAUC0-6h 
Accumulation ratio based on AUC0-6 after first dose and last dose, calculated as 
AUC0-6(Day10)/AUC0-6(Day1) 
 
Pharmacokinetic parameters of maltol and maltol glucuronide will be listed by dose group for each 
individual subject and summarized by dose group using the following descriptive statistics: n (the 
number of subjects), arithmetic mean, SD (standard deviation), geometric mean, geometric CV 
(coefficient of variation), median, minimum and maximum.  
Plasma concentration-time courses of maltol/maltol glucuronide on Day 1 and Day 10, including 
Ctrough, will be tabulated and graphically displayed per subject and summary statistics will be 
provided for each dose group for a specific timepoint/day. Plots of mean and geometric mean and 
plots with combined individual time courses will be provided by dose group. 
Actual and/or dose-normalized pharmacokinetic parameters of Cmax and AUCs will be graphically 
displayed for maltol and maltol-glucuronide as function of the dose, to explore dose-
proportionality. 
 
 


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Serum iron and TSAT: 
The following parameters for serum iron and TSAT on Day 1 will be derived for each subject 
based on the uncorrected and baseline-corrected predicted serum iron concentrations and TSAT, 
if applicable: 
 
Table 6 Parameters for Serum Iron and TSAT on Day 1 
Parameters 
Description 
Cmax 
Maximum plasma concentration directly from data 
Ctrough 
Pre-dose plasma concentration 
Change from 
Ctrough to Cmax 
Cmax - Ctrough 
Tmax 
Time to reach Cmax 
λz 
Apparent first-order terminal elimination rate constant  
AUC0-6h 
Area under the plasma concentration versus time curve from time zero to 6 h using 
the pre-dose adjusted concentration data 
AUC0-inf 
Area under the plasma concentration versus time curve from time zero extrapolated 
to infinity time using the pre-dose adjusted concentration data 
CL/F 
Apparent clearance calculated as Dose/AUC0-inf 
Vz/F 
Apparent volume of distribution (as Dose/ [λz *AUC0-∞]) 
 
 
 


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The following parameter for serum iron and TSAT on Day 10 will be derived for each subject 
based on the uncorrected and baseline-corrected predicted serum iron concentrations and TSAT, 
if applicable: 
 
Table 7 Parameters for Serum Iron and TSAT on Day 10 
Parameters 
Description 
Tau 
The dosing interval for steady-state data tau=12 
Cmax 
Maximum concentration between dose time and dose time + Tau. If not unique, then 
the first maximum is used. 
Ctrough 
Minimum concentration between dose time and dose time + Tau 
Change from 
Ctrough to Cmax 
Cmax - Ctrough 
AUC0-6h 
Area under the plasma concentration versus time curve from time zero to 6 h using 
pre-dose adjusted concentration data 
AUC0-tau 
Area under the plasma concentration versus time curve from time zero to Tau 
Cave(0-6h) 
Average Steady State Plasma Concentration from 0-6h, calculated as AUC0-6h 
divided by 6 
CL/F 
Apparent clearance calculated as Dose/AUC0-tau  
RCmax 
Accumulation ratio based on maximum concentrations after first dose and 
last dose, calculated as CmaxDay10/CmaxDay1 
RAUC0-6h 
Accumulation ratio based on AUC0-6 after first dose and last dose, 
calculated as AUC0-6(Day10)/AUC0-6(Day1) 
 
Pharmacokinetic parameters of serum iron and TSAT will be listed by dose group for each 
individual subject and summarized by dose group using the following descriptive statistics: n (the 
number of subjects), arithmetic mean, SD (standard deviation), geometric mean, geometric CV 
(coefficient of variation), median, minimum and maximum.   
Concentration-time courses of serum iron and TSAT on Day 1 and 10, including Ctrough on Day 1 
and 10 will be tabulated and graphically displayed per subject and summary statistics will be 
provided for each dose group and visit/timepoint. Plots of mean and geometric mean and plots 
with combined individual time courses will be provided by dose group. 
Actual and/or dose-normalized pharmacokinetic parameters of Cmax and AUCs will be graphically 
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If the PPK model is not feasible for TSAT and PPD model is used for TSAT, the following 
parameters for TSAT on Days 1 and 10 will be derived for each subject based on the predicted 
TSAT, if applicable: 
Table 8 Parameters for TSAT on Days 1 and 10 
Parameters 
Description 
Baseline 
Baseline response value before dosing 
Rmax 
Maximum response value 
Rmin 
Minimum response value 
Tmax 
Time to reach Rmax 
Tmin 
Time to reach Rmin 
AUC0-6h 
Area under the effect versus time curve from time zero to 6 h  
AUC0-24h 
Area under the effect versus time curve from time zero to 24 h 
AUC_Above_B 
Area under the response curve that is above the baseline 
AUC_Below_B 
Area that is below the baseline and above the response curve 
AUC_Net_B 
= AUC_Above_B - AUC_Below_B 
Time_Above_B 
Total time that response >= Baseline 
Time_ Below_B Total time that response < Baseline 
 


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9 
SECONDARY ENDPOINT ANALYSIS 
9.1 
Transferrin, TIBC, UIBC, ferritin and Non-Transferrin Bound Iron (NTBI) 
Transferrin, TIBC, UIBC and ferritin will be summarised by dose group and overall by 
visit/timepoint (Day 1 and Day 10/Pre-dose, 0.5-1h, 1-2h. 2-3h, 3-4h, 4-6h) for the FAS/ITT 
Population.  An additional summary table will present the change from baseline values at each 
post-baseline visit/timepoint and will include the baseline, visit/timepoint value and change from 
baseline values for subjects with both baseline and the specified post-baseline values.  
Baseline is defined as the last value observed before the first dose. 
  
NTBI will be listed by dose and timepoint for each individual subject; the number of samples 
considered negative (<0.2ePLI) and positive (=>0.2ePLI) will be summarised by dose group.  
Individual positive NTBI results (=>0.2ePLI units) will also be listed separately along with the 
corresponding serum iron, and TSAT results from those timepoints; plus the plasma Cmax, AUC0-6h  
for maltol and maltol glucuronide on the corresponding study day (Day 1 or Day 10). 
 
A listing of the iron markers and NTBI at each visit/timepoint will be provided for the FAS/ITT 
Population. 
 
Mean observed values of transferrin. TIBC, UIBC, and ferritin will be plotted on a linear scale 
against nominal time range by dose group and visit. Combined observed values will be plotted on 
a linear scale against actual timepoint for each dose group and visit. The change of baseline will 
be plotted similarly.  
 
Mean observed NTBI will be plotted on a linear scale against nominal time range by dose group 
and visit. Combined observed NTBI will be plotted on a linear scale against actual timepoint for 
each dose group and visit. 
 
The concentration plots described above will be prepared based on the actual data, if applicable. 
 
9.2 
Haemoglobin Concentration and Absolute Reticulocyte Count 
Haemoglobin concentration and absolute reticulocyte count will be summarised by dose group and 
overall by visit (Screening and Day 10) for the FAS/ITT Population.  An additional summary table 
will present the change from baseline values at Day 10 and will include the baseline, Day 10 and 
change from baseline values for subjects with both baseline and Day 10 values. Baseline is defined 
as the last value observed before the first dose. 
 
A listing of haemoglobin concentration and absolute reticulocyte count will be provided for the 
FAS/ITT Population. 


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10 SAFETY ANALYSIS 
10.1 Adverse Events 
All adverse events reported during the study will be listed for the Safety Population; the listing 
will contain an indicator for whether the event was considered as treatment emergent.  An 
additional listing will be provided for all serious adverse events. 
 
A summary overview of all adverse events by dose group and overall will be provided, which will 
present the number and percentage of subjects from the Safety Population satisfying each of the 
following categories: 
 Any adverse event (AE); 
 Any treatment emergent adverse event (TEAE); 
 Maximum severity of TEAEs –  mild, moderate, severe; 
 Relationship of TEAE to study drug – not related, related; 
 Action taken with study drug in relation to TEAE – dose not changed, dose 
reduced/increased, drug interrupted, drug withdrawn; 
 Any TEAE leading to study discontinuation; 
 Any serious adverse event (SAE); 
 Maximum severity of SAE – mild, moderate, severe; 
 Relationship of SAE to study drug – not related, related; 
 Action taken with study drug in relation to SAE – dose not changed, dose 
reduced/increased, drug interrupted, drug withdrawn; 
 Any SAE leading to study discontinuation; 
 Any SAEs leading to death. 
 
For the treatment emergent adverse events, the number, severity, relationship to study drug and 
action taken will be described by incidence tables.  Subjects with multiple episodes of the same 
TEAE (i.e. same Preferred Term) will be counted once in these tables.  Similarly, subjects with 
multiple severities for the same TEAE will be categorized by the maximum severity experienced; 
subjects with instances of the same TEAE recorded as both related an unrelated to study drug will 
be categorized as related and subjects with multiple actions taken within the same TEAE will be 
categorized according to the worst case.  Actions taken include drug withdrawn, drug interrupted, 
dose reduced/increase and dose not changed (listed from worst case to best case). 
 
Similar incidence tables will be presented for the serious adverse events. Separate incidence tables 
will also be presented for those TEAEs leading to withdrawal of study drug and to study 
discontinuation. 
 


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10.2 Safety Laboratory Parameters 
The safety laboratory parameters (Haematology and Clinical Chemistry) will be summarised by 
dose group and overall by visit (Screening and Day 10) for the Safety Population.  An additional 
summary table will present the change from baseline values at Day 10 and will include the 
baseline, Day 10 and change from baseline values for subjects with both baseline and Day 10 
values.  Shift tables (from Screening to Day 10) will also be presented the safety laboratory data. 
If the Screening retest is performed, the values of Screening retest will be used as baseline.  
 
All safety laboratory data, including normal ranges and abnormal laboratory flags, will be provided 
in data listings for the Screened Population. 
 
Pregnancy test results will be also be listed for the Screened Population. 
 
10.3 Vital Signs 
Vital signs data will be summarised by dose group and overall by visit (Screening, Days 1 and 10 
and Follow-up) for the Safety Population.  Change from baseline at each post-baseline visit (Day 
10 and Follow-up) will be presented in a separate summary table and will include baseline, post-
baseline values and change from baseline values for subjects with both baseline and specific post-
baseline values. Baseline is defined as the last value observed before the first dose. 
 
All vital signs data will be listed for the Screened Population and FAS/ITT Population. 
 
10.4 12-Lead ECG Parameters 
Continuous ECG parameters (Heart Rate, PR Interval, RR Interval, QRS Duration, QT Interval, 
QTcB Interval and QTcF Interval) will be summarised by dose group and overall by visit 
(Screening and Day 10) for the Safety Population.  Change from baseline at Day 10 will be 
presented in a separate summary table and will include baseline, post-baseline values and change 
from baseline values for subjects with both baseline and Day 10 values.  Baseline is defined as the 
last value observed before the first dose. 
 
Overall interpretation will also be summarised by dose group and overall by visit.  Shift tables 
(from baseline to Day 10) will also be generated for the overall interpretation results. 
 
All ECG data will be listed for the Screened Population and FAS/ITT Population. 
 
10.5 Physical Examination 
Findings from the physical examinations will be listed for the Screened Population. 
 


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Shift tables (from Screening to Day 10) will generated for the overall interpretation of the physical 
examination. 
10.6 Prior and Concomitant Medications and Procedures 
Prior and concomitant medications will be considered separately and will be summarised by dose 
group and overall by Anatomical Therapeutic Chemical (ATC) Classification System and 
Preferred Term for the Safety Population.  All medications will be listed for the Screened 
Population with an indicator for whether the medication is regarded as prior or concomitant.   
 
Similar summary tables and listings will be provided for the prior and concomitant procedures for 
FAS/ITT Population. 
 
10.7 Study Medication Exposure and Compliance 
The duration of exposure (days) to study drug and compliance will be summarised by dose group 
and overall for the Safety Population and FAS/ITT Population. 
 
Details of drug accountability (dispensing and return) will be listed for the Safety Population.  An 
additional listing will be provided for the Safety Population detailing exposure and compliance for 
each subject. 
11 DATA SAFETY MONITORING BOARD 
There are no provisions for a Data Safety Monitoring Board for this study. 
12 INTERIM ANALYSIS 
No interim analysis is planned for this study. 
13 SAMPLE SIZE AND POWER CONSIDERATIONS 
No formal sample size calculation has been carried out for this study.  The sample size is based on 
observations from previous studies (see protocol for more details) and has been agreed with the 
EU CAs in the PIP.  The inclusion of 36 subjects aged 10-17 years (12 per treatment group) is 
considered to be adequate to characterize the iron update and PK parameters for the range of Ferric 
Maltol doses in an iron deficient adolescent population (with or without anaemia). 
14 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
There are no planned changes to the current version of the protocol (Version 3.0, dated 08 February 
2017).