Clinical trial NCT02968368
Conditions: Renal Insufficiency, Chronic Iron-Deficiency Anemia
Sponsor: Shield Therapeutics
Start date: 2016-12-01; Completion date: 2018-10-10
Enrollment: 167 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of oral ferric maltol compared with placebo in the treatment of IDA in subjects with CKD

Detailed description:

Arms: arm 1: 30mg capsules BID arm 2: Matching placebo capsules BID
Interventions: intervention 1: Ferric maltol intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
 
 
 
Page 1 of 44 
 
 
  
 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Placebo Controlled, Prospective, Multicenter Study with Oral Ferric Maltol 
for the Treatment of Iron Deficiency Anemia in Subjects with Chronic Kidney Disease. 
 
 
Protocol Number: 
ST10-01-303  
 
Test Drug:  
 
Ferric Maltol (ST10) 
 
IND Number:   
114832 
 
Study Name: 
 
AEGIS CKD 
 
Sponsor: 
Shield TX (UK) Limited 
Northern Design Centre, Studio 6, 3rd Floor, Baltic Business Quarter, 
Gateshead Quays, United Kingdom. NE8 3DF 
 
Version/Date:  
 12 September 2016 V2.1 
 
(Note: Only change from Version 2.0 is formatting of Section 9.2) 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is provided in confidence.  It is understood that this 
information will not be used, disclosed or published without written consent of Shield TX (UK) 
Limited


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1 
PROTOCOL APPROVALS  
 
 
 
 
 
 
Name:  
Mark Sampson, MBChB 
Company: 
Shield TX (UK) Limited 
Position:  
VP, Medical Affairs 
 
Signature: 
___________________________ 
 
Date: 
 
___________________________ 
 
 
 
 
 
 
Name:  
Ann Yellowlees PhD 
Company: 
Quantics Consulting Limited 
Position:  
Director of Biostatistics 
 
Signature: 
___________________________ 
 
Date: 
 
___________________________ 
 
 
 
 


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TABLE OF CONTENTS 
1 
PROTOCOL APPROVALS .................................................................................................................. 2 
2 
ABBREVIATION INDEX ..................................................................................................................... 6 
3 
SYNOPSIS ......................................................................................................................................... 8 
4 
BACKGROUND INFORMATION ...................................................................................................... 13 
4.1 
OVERVIEW OF DISEASE ......................................................................................................... 13 
4.2 
CURRENT TREATMENT OF DISEASE ...................................................................................... 13 
4.3 
OVERVIEW OF TEST PRODUCT .............................................................................................. 14 
4.4 
DOSE SELECTION AND RESULTS OF PREVIOUS CLINICAL STUDIES ....................................... 14 
4.5 
RATIONALE FOR THE STUDY ................................................................................................. 15 
4.5.1 
Study Population ........................................................................................................... 15 
4.5.2 
Study Treatment Duration ............................................................................................ 16 
4.6 
RISK-BENEFIT EVALUATION ................................................................................................... 16 
5 
STUDY OBJECTIVES AND ENDPOINTS............................................................................................ 18 
5.1 
PRIMARY OBJECTIVE ............................................................................................................. 18 
5.2 
SECONDARY OBJECTIVE ........................................................................................................ 18 
5.3 
PRIMARY ENDPOINT ............................................................................................................. 18 
5.4 
SECONDARY ENDPOINTS ....................................................................................................... 18 
5.5 
PHARMACOKINETIC ENDPOINTS .......................................................................................... 18 
5.6 
EXPLORATORY ENDPOINTS ................................................................................................... 18 
6 
INVESTIGATIONAL PLAN ............................................................................................................... 19 
6.1 
STUDY OVERVIEW ................................................................................................................. 19 
6.2 
INVESTIGATIONAL SITES ....................................................................................................... 19 
6.3 
INCLUSION AND EXCLUSION CRITERIA ................................................................................. 19 
6.3.1 
Inclusion Criteria ........................................................................................................... 19 
6.3.2 
Exclusion criteria ........................................................................................................... 20 
6.4 
CONCOMITANT MEDICATION ............................................................................................... 21 
6.4.1 
Not Permitted ............................................................................................................... 21 
6.4.2 
Permitted ...................................................................................................................... 21 
6.4.3 
Potential Medication Interactions ................................................................................ 21 
6.5 
INDIVIDUAL WITHDRAWAL CRITERIA ................................................................................... 22 
7 
TREATMENT OF SUBJECTS ............................................................................................................ 23 
7.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PRESENTATION ......................................... 23 
7.2 
PACKAGING ........................................................................................................................... 23 
7.3 
STORAGE ............................................................................................................................... 23 
7.4 
LABELLING ............................................................................................................................. 23 


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7.5 
DISPENSATION ...................................................................................................................... 23 
7.6 
ADMINISTRATION ................................................................................................................. 23 
7.7 
TREATMENT COMPLIANCE .................................................................................................... 24 
7.8 
CONTINUATION OF TREATMENT .......................................................................................... 24 
8 
ENROLMENT AND RANDOMIZATION PROCEDURES ..................................................................... 25 
8.1 
SCREENING ............................................................................................................................ 25 
8.2 
RANDOMIZATION .................................................................................................................. 25 
8.3 
BLINDING PROCEDURES ........................................................................................................ 25 
8.4 
EMERGENCY UNBLINDING .................................................................................................... 25 
9 
STUDY PROCEDURES ..................................................................................................................... 26 
9.1 
DESIGN SCHEMATIC .............................................................................................................. 26 
9.2 
SCHEDULE OF ASSESSMENTS ................................................................................................ 27 
9.3 
DEMOGRAPHICS AND MEDICAL HISTORY ............................................................................. 29 
9.4 
PHYSICAL EXAMINATION ...................................................................................................... 29 
9.5 
CONCOMITANT MEDICATIONS AND PROCEDURES .............................................................. 29 
9.6 
VITAL SIGNS ........................................................................................................................... 29 
9.7 
12-LEAD ECG ......................................................................................................................... 29 
9.8 
LABORATORY ASSESSMENTS ................................................................................................ 29 
9.8.1 
Hematology ................................................................................................................... 30 
9.8.2 
Chemistry ...................................................................................................................... 30 
9.8.3 
Iron Markers .................................................................................................................. 30 
9.8.4 
Estimated Glomerular Filtration Rate (eGFR) ............................................................... 30 
9.8.5 
Population Pharmacokinetics (PK) ................................................................................ 30 
9.8.6 
Retention Samples ........................................................................................................ 30 
9.8.7 
Urine Pregnancy Test .................................................................................................... 30 
10 
SAFETY ....................................................................................................................................... 31 
10.1 
DEFINITIONS .......................................................................................................................... 31 
10.1.1 
ADVERSE EVENT (AE) .................................................................................................... 31 
10.1.2 
SERIOUS ADVERSE EVENT (SAE) .................................................................................... 32 
10.2 
REPORTING AND DOCUMENTATION .................................................................................... 33 
10.2.1 
Immediate Reporting .................................................................................................... 33 
10.2.2 
Non-Immediate Reporting ............................................................................................ 34 
10.3 
EVALUATION ......................................................................................................................... 34 
10.3.1 
Intensity ........................................................................................................................ 34 
10.3.2 
Causality ........................................................................................................................ 35 
10.3.3 
Outcome ....................................................................................................................... 35 


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10.4 
RE-EXPOSURE ........................................................................................................................ 35 
10.5 
SAFETY ENDPOINTS ............................................................................................................... 35 
11 
STATISTICAL CONSIDERATIONS ................................................................................................. 36 
11.1 
SAMPLE SIZE AND POWER CALCULATIONS........................................................................... 36 
11.2 
STATISTICAL METHODS ......................................................................................................... 36 
11.2.1 
Primary Endpoint Analysis ............................................................................................ 36 
11.2.2 
Secondary and Exploratory Analyses ............................................................................ 36 
11.2.3 
Sensitivity Analyses ....................................................................................................... 36 
11.2.4 
Imputation of Missing Data........................................................................................... 37 
11.2.5 
Safety Analyses ............................................................................................................. 37 
11.3 
DEFINITION OF POPULATIONS .............................................................................................. 37 
11.3.1 
Randomized Population ................................................................................................ 37 
11.3.2 
Safety Population .......................................................................................................... 37 
11.3.3 
Intention- To-Treat (ITT) Population (Full Analysis Set) ................................................ 37 
11.3.4 
Per Protocol (PP) Population ......................................................................................... 37 
12 
ETHICAL CONSIDERATIONS ....................................................................................................... 38 
12.1 
DECLARATION OF HELSINKI .................................................................................................. 38 
12.2 
INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE ....................................................... 38 
12.3 
SUBJECT INFORMATION AND INFORMED CONSENT ............................................................ 38 
12.4 
SUBJECT DATA PROTECTION ................................................................................................. 39 
12.5 
SUBJECT INSURANCE ............................................................................................................. 39 
12.6 
CONFLICT OF INTEREST ......................................................................................................... 39 
12.7 
REGISTRATION OF STUDY AND DISCLOSURE OF RESULTS .................................................... 39 
13 
STUDY MANAGEMENT .............................................................................................................. 40 
13.1 
SOURCE DATA ....................................................................................................................... 40 
13.2 
QUALITY ASSURANCE ............................................................................................................ 40 
13.3 
MONITORING ........................................................................................................................ 40 
13.4 
STUDY FUNDING ................................................................................................................... 40 
13.5 
CONTRACT RESEARCH ORGANIZATION (CRO) ...................................................................... 40 
13.6 
AMENDMENTS TO THE STUDY PROTOCOL ........................................................................... 41 
13.7 
STUDY STOPPING RULES ....................................................................................................... 41 
13.8 
END OF STUDY....................................................................................................................... 41 
13.9 
RETENTION OF RECORDS ...................................................................................................... 41 
13.10 
SECURITY AND PUBLICATIONS .......................................................................................... 41 
14 
REFERENCES .............................................................................................................................. 43 


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2 
ABBREVIATION INDEX 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration Curve 
Bid 
Twice Daily  
C 
Celsius 
CHr 
Reticulocyte Hemoglobin Concentration 
CKD 
Chronic Kidney Disease 
CMAX 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
EC 
Ethics Committee  
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
ESA 
Erythropoiesis Stimulating Agent 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice  
GGT 
Gamma-Glutamyl Transpeptidase  
GI 
Gastrointestinal  
GMP 
Good Manufacturing Practice  
h  
Hour 
Hb 
Hemoglobin 
IBD 
Inflammatory Bowel Disease 
ICH 
International Conference on Harmonization  
ID 
Iron Deficiency 
IDA 
Iron Deficiency Anemia 
IMP  
Investigational Medical Product  
IRB 
Institutional Review Board  
ITT 
Intention-To-Treat  
IV 
Intravenous  
IXRS 
Interactive Tel/Web Response System 
KDGIO 
Kidney Disease Improving Global Outcomes Organization 
LOCF 
Last Observation Carried Forward 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MDRD 
Modified Diet in Renal Disease 
MMRM 
Mixed Model Repeat Measures 
NCS 
Non-Clinically Significant 


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ND-CKD 
Non Dialysis Dependent Chronic Kidney Disease 
OFP 
Oral Ferrous Product 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Electrocardiogram PR Interval 
QRS 
Electrocardiogram QRS Interval 
QT 
Electrocardiogram QT Interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SPC 
Summary of Product Characteristics  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
T1/2term 
Terminal Half-life 
TMAX 
Time to Maximum Plasma Concentration 
TSAT 
Transferrin Saturation 
UC 
Ulcerative Colitis  
WHO 
World Health Organization  
 


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3 
SYNOPSIS 
Title  
A phase 3, randomized, placebo controlled, prospective, multicenter study with 
oral ferric maltol for the treatment of iron deficiency anemia in subjects with 
chronic kidney disease. 
Protocol Number  ST10-01-303 
Study Name 
AEGIS CKD 
Test Drug 
Ferric maltol (ST10) 
Comparator 
Placebo 
Phase  
Phase 3 
Sites 
Approximately 35 sites  
Study Rationale 
The existing scientific and clinical experience with ferric maltol in the treatment 
of iron deficiency anemia (IDA) in patients with inflammatory bowel disorder 
(IBD) supports further investigation into the treatment of IDA with ferric maltol 
due to other causes. The need for improved management of IDA in patients with 
chronic kidney disease (CKD) is well established and ferric maltol could provide 
an effective and well-tolerated oral treatment for CKD patients as an alternative 
to oral ferrous products (which are often poorly tolerated and hence ineffective) 
and to intravenous (IV) iron administration (which may be inconvenient and is 
associated with risk of allergic reaction or iron overload). 
Objectives 
Primary Objective 
To evaluate the efficacy of oral ferric maltol compared with placebo in the 
treatment of IDA in subjects with CKD at 16 weeks. 
Secondary Objectives 
To evaluate the efficacy, safety, tolerability and pharmacokinetics of ferric maltol 
in subject with IDA and CKD over a treatment duration of up to 52 weeks. 
Endpoints  
Primary Endpoint 
Change in Hb concentration from baseline to Week 16.  
Secondary Endpoints 
• 
Proportion of subjects that achieve an increase in Hb concentration of ≥1 
g/dL at Week 16. 
• 
Proportion of subjects that achieve a Hb concentration of ≥11 g/dL at week 
16. 
• 
Change in Hb concentration from baseline to Week 8. 
• 
Proportion of subjects that achieve an increase in Hb concentration of ≥2 
g/dL at Week 16. 
• 
Change in Hb concentration from baseline to Week 4. 
• 
Changes in iron parameters (ferritin, TSAT, serum iron). 
• 
AEs/SAEs 


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Pharmacokinetic (PK) Endpoints 
Population based PK analysis of maltol, maltol glucuronide and serum iron. 
Exploratory Endpoints 
Proportion of subjects with a baseline Hb of <10 g/dL that achieve a Hb > 10g/dL. 
Design 
 
 
 
 
 
• 
Screening: Up to 14 days 
• 
Randomized, Double-Blind Treatment: 16 weeks treatment with oral ferric 
maltol, 30 mg capsule twice daily (bid) or oral matching placebo bid. 
Randomization will occur at a ratio of 2:1, ferric maltol to placebo. 
• 
Open-label Treatment: Up to 36 weeks treatment with ferric maltol. 
• 
End of Study: Week 52 or premature discontinuation. 
• 
Post-treatment safety follow-up: 14 days following discontinuation of study 
medication. 
Subjects that develop a ≥0.5g/dL decrease from baseline in Hb that falls below 
8.0g/dL on 2 consecutive weeks will be discontinued from study treatment. 
Subjects who discontinue from study treatment prior to Week 16 will be 
encouraged to continue with study visits and assessments up to and including 
assessments at week 16. 
Number of 
Subjects 
Approximately 168 subjects. 
Inclusion Criteria 
All of the following criteria must be met to randomize a subject in the study: 
1. 
Ability to understand the information given in the Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB) approved information 
sheet and consent form. Must sign and date the informed consent and 
authorization to use protected health information (PHI) in accordance with 
national and local subject privacy regulations prior to any study mandated 
procedure. 
2. 
Willing and able to comply with study requirements. 
3. 
Age ≥ 18 years at the time of informed consent. 
4. 
A current diagnosis of CKD with an estimated glomerular filtration rate 
(eGFR) of <60 mL/min/1.73m2 and ≥15 mL/min/1.73m2, as calculated using 
the abbreviated version of the Modified Diet in Renal Disease equation 
(MDRD) assessed via screening laboratory results. 
5. 
Iron deficiency anemia defined by the following criteria assessed via 
screening laboratory results: 
a. Hb <11.0g/dL and ≥8.0g/dL 
b. AND ferritin <250ng/mL with a Transferrin saturation (TSAT) <25% 
OR ferritin <500ng/mL with a TSAT of <15% 
6. 
Female subjects of childbearing potential (including perimenopausal 
females who have had a menstrual period within 1 year prior to screening) 
must agree to use a reliable method of contraception until study completion 


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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.  Female subjects who are surgically sterile (bilateral tubal 
ligation, bilateral oophorectomy or hysterectomy) or postmenopausal 
(defined as no menstrual period within 1 year of screening) are also allowed 
to participate. 
Exclusion Criteria 
 
A subject who meets any of the following criteria is not eligible for participation 
in the study. 
1. Anemia due to any cause other than iron deficiency, including, but not 
limited to: 
a. Untreated or untreatable severe malabsorption syndrome. 
b. Myelosuppression use (permitted if taken at a stable dose and 
frequency for at least 12 weeks prior to randomization and are 
expected to stay stable throughout the double-blind treatment 
period so long as there is no clinical evidence of the 
myelosuppression contributing to the subject’s anemia). 
2. Administration with any of the following prior to randomization: 
a. IV iron injection within the previous 4 weeks or administration of 
intramuscular or depot iron preparation within the previous 12 
weeks. 
b. Single agent oral iron supplementation, taken specifically to treat 
anemia (e.g. ferrous sulfate, fumarate and gluconate) within the 
previous 2 weeks. Multivitamins are permitted.  
c. Use if ferric citrate and sucroferric oxyhydroxide within the previous 
1 week. 
d. ESAs within the previous 4 weeks  
e. Blood transfusion or donation within the previous 12 weeks. 
f. Dimercaprol or cloramphenicol within the previous 7 days. 
g. Current use of methyldopa. 
3. Currently receiving dialysis or initiation of dialysis is considered likely during 
the study. 
4. Renal transplant within 12 months prior to randomization or is considered 
likely during the study. 
5. Known hypersensitivity or allergy to the active substance or excipients of 
ferric maltol or placebo capsules. 
6. Contraindication 
for 
treatment 
with 
iron 
preparations, 
e.g. 
hemochromatosis, chronic hemolytic disease, sideroblastic anemia, 
thalassemia, or lead intoxication induced anemia. 
7. Impaired liver function as indicated by alanine aminotransferase (ALT) or 
aspartate transaminase (AST) > 3 times the upper limit of normal as assessed 


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via screening laboratory results. 
8. Clinically significant vitamin B12 or folic acid deficiency as determined by the 
screening laboratory results (retest following at least 2 weeks of starting 
treatment with vitamin B12 or folate replacement is permitted). 
9. Pregnant or breast feeding.  
10. Concomitant medical conditions with significant active bleeding likely to 
initiate or prolong anemia; for example coagulation disorders or recurrent GI 
bleeding. 
11. Scheduled or expected major surgery during the course of the study. (Minor 
surgeries not associated with significant blood loss, in the Investigator’s 
judgement, are permitted e.g. surgery related to fistulae or vascular access, 
minor dental extractions, incision and drainage of abscess or simple 
excisions). 
12. Participation in any other interventional clinical study within 30 days prior to 
screening. 
13. Cardiovascular, 
liver, 
renal, 
hematologic, 
psychiatric, 
neurologic, 
gastrointestinal, immunologic, endocrine, metabolic, or central nervous 
system disease that, in the opinion of the Investigator, may adversely affect 
the safety of the subject and/or efficacy of the study drug or severely limit 
the lifespan of the subject. 
14. Any other unspecified reason that, in the opinion of the Investigator or the 
Sponsor make the subject unsuitable for enrolment. 
Concomitant 
Medication 
Not Permitted 
• 
IV iron injections, intramuscular or depot iron administrations. 
• 
Single agent oral iron supplementation, taken specifically to treat anemia 
(e.g. ferrous sulfate, fumarate and gluconate).  
• 
Ferric citrate or sucroferric oxyhydroxide. 
• 
ESAs. 
• 
Blood transfusions or donations. 
• 
Dimercaprol, chloramphenicol or methyldopa 
Permitted 
• 
Myelosuppressants taken at a stable dose and frequency (so long as there is 
no clinical evidence of the myelosuppressant contributing to the subject’s 
anemia). 
• 
Multivitamins containing iron. 
Withdrawal 
Criteria 
• 
Withdrawal of informed consent. 
• 
Unwillingness or inability to comply with protocol requirements. 
• 
Pregnancy or not using a reliable method of birth control if female of 
childbearing potential. 
• 
A ≥0.5g/dL decrease from baseline in Hb that falls below 8.0g/dL on 2 


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consecutive weeks. 
• 
Ferritin >700ng/mL with a TSAT of >50% sustained for 2 consecutive weeks. 
• 
SAEs that are judged by the Investigator to be related to study drug. 
• 
Use of prohibited concomitant medications. 
• 
Initiation of dialysis. 
• 
Blood transfusions or donations for any cause. 
• 
Any dose or frequency changes to myelosuppressants during the double-
blind treatment period. 
• 
Requirement for major surgery. Minor surgeries not associated with 
significant blood loss, in the Investigator’s judgement, are permitted (e.g. 
surgery related to fistulae or vascular access, minor dental extractions, 
incision and drainage of abscess or simple excisions). 
Subjects who discontinue study treatment prior to Week 16 will be encouraged 
to continue with study visits and assessments up to and including assessments at 
week 16. 
Investigational 
Medicinal 
Product  
Ferric maltol, 30 mg capsules or matching placebo twice daily. To be taken orally 
first thing in the morning before breakfast and last thing at night before bed. 
Capsules must be taken on an empty stomach with water only. 
Statistical 
Methods 
Sample size calculation 
A sample size of 135 subjects (Randomized 2:1, ferric maltol:Placebo, 90 in the 
ferric maltol group and 45 placebo) will have 95% power to detect a statistically 
significant treatment difference of 1.0g/dL between ferric maltol and placebo on 
the primary endpoint, using a two-sided 0.05 significance level. This calculation 
assumes a common standard deviation of 1.5g/dl which is based on a pooled 
estimate of SDs obtained from published trials. Assuming a drop-out rate of 20%, 
approximately 168 subjects total will be recruited.  Subjects will be stratified 
based on baseline Hb value and eGFR. 
Statistical Methods 
An Analysis of Covariance (ANCOVA) will be used to analyse the primary 
endpoint: change in Hb concentration from baseline to Week 16.  Missing change 
from baseline hemoglobin concentration data for week 16 will be imputed using 
multiple imputation methodology.  This will generate 10 complete datasets 
containing imputed values for those missing in the original dataset. Hb 
concentrations at baseline, Week 4, Week 8 and gender will be considered as 
variables helpful in guiding this imputation. For each imputed dataset, the 
change from baseline to Week 16 complete datasets will be analysed using 
analysis of covariance (ANCOVA) with factors for treatment and disease and a 
covariate of baseline hemoglobin and eGFR. By combining the results from these 
analyses, the treatment estimates will be constructed using the parameter 
estimates and associated standard errors. Similarly the difference of the adjusted 
treatment means (ferric maltol – placebo) will be presented with the associated 
standard error and 2-sided 95 % confidence interval. The primary endpoint 
analysis will be performed using the intention-to-treat (ITT) population.   


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4 
BACKGROUND INFORMATION 
4.1 
OVERVIEW OF DISEASE 
IDA is commonly associated with chronic kidney disease (CKD) and it is one of the leading causes of 
morbidity and mortality (Regidor 2006; Hsu 2002). It is appropriate to administer regular iron 
replacement therapy as part of standard medical care Post 2006; KDOQI 2006). IDA can be due to 
multiple factors, most significantly lack of production of erythropoietin, blood loss through 
gastrointestinal (GI) bleeding, medical procedures and/or impaired dietary iron absorption (Lopez 
2015).  In some patients there may be an inflammatory component to their CKD, and chronic 
inflammation can make absorption and utilization of iron less efficient compared to the normal state 
(Zaritsky 2009).  Anemia can be found in CKD patients receiving dialysis and also in non-dialysis 
dependent CKD (ND-CKD) patients (Gotloib 2006; Post 2006).  IDA is defined by lower than normal 
hemoglobin (Hb), ferritin and transferrin-saturation (TSAT) levels (KDOQI 2006). 
The incidence of anemia varies with the severity or stage of CKD; the percentage of patients with 
haemoglobin ≤ 12 g/dL increases from 26.7% to 75.5% when glomerular filtration rate decreases 
from ≥ 60 mL/min/1.73 m2 to < 15 mL/min/1.73 m2. Prevalence of haemoglobin ≤ 10 g/dL increases 
substantially from 5.2% to 27.2% when glomerular filtration rate diminishes from ≥ 
60 mL/min/1.73 m2 to < 15 mL/min/1.73 m2 (Hsu 2002; McClellan 2004; Stauffer 2014). The use of 
erythropoiesis stimulating agents (ESAs) has made significant improvements to managing anemia in 
CKD.  However excessive use is associated with cardiovascular events and increased mortality 
(KDOQI 2006) such that the US Food and Drug Administration (FDA) has issued revised guidance on 
their use (FDA 2011).  The importance of ESA use in combination with correction of ID is well-
recognized, enabling anemia correction with lower doses of ESAs (Fishbane 1997; KDOQI 2006). 
Replacement of iron stores with oral ferrous iron can be affected by non-adherence to the 
prescribed course of medication due to the incidence and severity of GI side effects in patients with 
CKD (Charytan 2005; Macdougall 1999; Horl 2007). Moreover, in CKD, there may be reduced 
absorption of ferrous iron associated with inflammation (Ganz 2003). IV iron or oral iron is 
recommended for non-dialysis CKD patients (KDOQI 2006) but IV iron administration when 
treatment with oral ferrous products is ineffective or not tolerated (KIDGO 2012; Lopez 2015). 
However IV iron administration is not subject to normal gut physiological control mechanisms of iron 
absorption and depletion, and therefore iron overload is a potential risk (Vecchio 2016; Horl 2007).  
Infused or IV push iron products are associated with a small but significant risk of infusion reactions, 
and administration requires appropriate resuscitation equipment and staff to be on hand (KDOQI 
2006).  While this may not be an issue in hemodialysis clinics for those patients on home dialysis, 
peritoneal or hemodialysis, IV iron requires a hospital or clinic visit which may be inconvenient to 
patients/carers and is costly (Bhandari 2011).  
In consideration of the above, an effective and tolerable oral iron replacement therapy would be a 
significant improvement to the care of ND-CKD and home dialyzed patients as an alternative to IV 
irons or poorly tolerated OFPs. 
4.2 
CURRENT TREATMENT OF DISEASE 
CKD management guidelines, Kidney Disease Outcomes Quality Initiative (KDOQI 2006) specify iron 
replacement therapy is indicated to target a Hb level of 11 g/dL or greater, a serum ferritin of 
greater than 100 ng/mL and a TSAT of greater than 20% and that the route can be either IV 
administration or oral. The Kidney Disease Improving Global Outcomes (KIDGO 2012) guidelines 


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recommend, for ND-CKD patients, an initial 1-3 month trial of oral iron therapy or, alternatively, IV 
iron based on severity of iron deficiency, availability of venous access, response to prior oral iron 
therapy, side effects with prior oral or IV iron therapy, patient compliance and cost. 
Oral iron, ferrous sulfate, is available in multiple formulations and dosages, but is typically taken as 
200 mg tablets (65 mg elemental iron) 2 to 3 times daily (ferrous sulfate patient information leaflet 
2015). However, as the duodenum can maximally absorb only 10-20 mg of iron a day, greater than 
90% of ingested iron is not absorbed, leading to symptomatic adverse events (AEs) including 
potential mucosal erosions and enteric siderosis (Zhu, 2010).  Common adverse effects of oral iron 
supplements include nausea, epigastric discomfort, and constipation, all of which appear dose-
related. Adverse effects can occur in up to 20% of subjects, significantly impairing compliance and 
rendering the treatment ineffective (Zhu, 2010).  
4.3 
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 authorization was granted 
for ferric maltol in February 2016. 
Unlike OFPs, which are often given with food in order to reduce side effects, ferric maltol can, and 
should, be given on an empty stomach to maximise bioavailability.  Oral ferric iron chelated 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 2006; Barrand 1991). 
4.4 
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 1991). Therefore, a model was developed to determine 
the optimal dose.  Data from 6 previous studies of ferric maltol in subject with IBD and IDA were 
used to estimate absorption rates in the study population.  Using these data, the model suggested 
that in a compliant study population, 30 mg ferric maltol bid would result in correction of baseline 
anemia in the majority of subjects. 
An open-label, randomized Phase 1 study evaluated the pharmacokinetics of ferric maltol and its 
effect on iron indices in IBD patients with iron deficiency (with or without anemia). 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, with 
linear increases in exposure, no accumulation over 7 days, and improvements in iron uptake across 
the dose range 30–90 mg bid. 
The dose chosen for Phase 3 studies is 30 mg bid ferric maltol, or 60 mg elemental iron total daily 
dose.   


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A Phase 3 study has been completed in subjects with IDA and Inflammatory Bowel Disease (IBD), 
who are intolerant of oral iron products or are unsuitable for treatment with them (ST10-01-301 and 
ST10-01-302; Gasche 2014). 128 subjects were randomized 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.  
Refer to the Investigator Brochure for further information. 
4.5 
RATIONALE FOR THE STUDY 
Clinical studies conducted to date provide evidence for the therapeutic potential of ferric maltol in 
patients with IDA in inflammatory bowel disease 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 2014) 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 inflammatory bowel disorder (IBD) supports its further investigation in the treatment of IDA 
due to other causes. The need for improved management of IDA in patients with chronic kidney 
disease (CKD) is well established and ferric maltol could provide an effective and well-tolerated oral 
treatment for CKD patients as an alternative to oral ferrous products (which are often poorly 
tolerated and hence ineffective) and to intravenous (IV) iron administration (which may be 
inconvenient and is associated with risk of allergic reaction or iron overload). 
4.5.1 
Study Population 
Adult subjects will be enrolled who have a diagnosis of CKD with an eGFR of <60 and at least 
15mL/min/1.73m2. It is anticipated that this population will in general have less significant renal 
disease and comorbidities and be better able to tolerate the placebo phase of the study. Subjects 
will also have IDA as defined by Hb, ferritin and TSAT levels. Subjects should not be severely anemic 
and so will have Hb ≥8.0 g/dL.  Subjects who have recently received IV iron, a blood transfusion or 
renal transplant will not be permitted to enter the study.   
All subjects entering this study will be anemic (Hb <11.0 g/dL) which falls below the lower limit of 
normal Hb (13.5g /dL for males, 12.0 g /dL for females per KDOQI 2006) for investigational purposes 
since the benefits to subjects being treated with ferric maltol with a Hb between 11 g/dL and the 
lower limit of normal could be marginal. Additionally, the cut-off of 11.0 g/dL is in line with KDOQI 
2006 who specify a target Hb level of 11g/dL or greater.  
The inclusion criteria of <250 ng/mL ferritin with a <25% TSAT and or a <500ng/mL ferritin with a 
<15% TSAT is indicative of iron deficiency and representative of the population likely to benefit from 
iron treatment.   
Subjects who develop Hb concentration decreases of ≥0.5g/dL from baseline that falls below 8.0g/dL 


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on 2 consecutive weeks will be withdrawn from the study and corrective measures implemented 
outside of the study. Withdrawal from the study would also be possible based on any AE, including 
anemia related symptoms, which the Investigator deemed significant.  There is little data available 
on long or medium term Hb changes in CKD placebo treated subjects, so it is not possible to 
accurately predict how many subjects may have to withdraw during the 16 week placebo controlled 
period.  However a study looking at ESA treatment in over 2000 anemic, CKD diabetic patients 
followed for 2.3 years showed that  55% of patients on placebo and without ESA treatment 
maintained a Hb >9.0 g/dL and that on average, Hb levels were either stable or increased in both the 
active and placebo groups (Skali 2013).  The Hb decline in this study is not reported separately for 
hemodialysis and non-dialysis subjects, nor by iron replete or deficient subjects, however over a 2 
year period the Hb decline did appear slow for most patients.   
 
4.5.2 
Study Treatment Duration 
Maximum treatment duration in this study is 52 weeks. Primary efficacy and safety of ferric maltol 
will be evaluated after the first 16 week double-blind phase after which time all ongoing subjects will 
receive open-label ferric maltol for up to an additional 36 weeks. Long-term safety and efficacy of 
ferric maltol will be examined during the open-label portion of the study.  As there is a 
physiologically-determined limit on the amount of iron that can be absorbed from oral iron 
medication, the study has a 16 week placebo controlled period.  This has been selected as the 
maximum duration likely to be clinically acceptable to achieve a meaningful Hb rise in IDA CKD 
patients. 
This study treatment duration will continue until the last randomized subject completes the study at 
Week 52 or prematurely withdraws from the study.  
4.6 
RISK-BENEFIT EVALUATION 
KIDGO recommends initiating treatment for IDA with oral ferrous products which are associated 
with GI side effects. If unsuccessful IV iron administration should be considered (see section 5.2). 
This is in accordance with the labelled warnings of marketed oral iron products. The Summary of 
Product Characteristics (SPCs) for the various OFPs which warn that oral iron salts may have a 
corrosive effect that may exacerbate the symptoms associated with certain GI disease states such as 
peptic ulcer disease or IBD (e.g., UC). But despite this warning there are limited comparative data 
from prospective clinical trials investigating the AE profile of marketed oral iron products as 
compared to placebo or active comparators or comparing IBD to different patient populations.  
The dose chosen for the Phase 3 development program, 30 mg bid, has been shown to be effective 
and well-tolerated in IDA patients with IBD for up to 64 weeks of treatment.  In contrast to other 
marketed iron products, in particular ferrous drugs, the sugar derivative maltol strongly chelates 
iron, stabilizes iron in the less toxic ferric (Fe3+) form and renders it readily available for absorption 
in the intestinal tract. Consequently, the frequency of typical adverse effects is hypothesized to be 
reduced with administration of ferric maltol. This hypothesis is confirmed by ferric maltol being well-
tolerated in patients who are intolerant to oral ferrous products in clinical studies ST10-01-301 and 
ST10-01-302; furthermore, unlike oral ferrous products, ferric maltol did not increase flare of 
underlying disease in these patients compared to placebo treatment.    
The current study design does not pose additional risk for the subjects as no additional 
interventional procedures are planned during the study period, except for blood sampling similar to 
clinical routine.  The patients randomized to placebo will be monitored and withdrawn should the 


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Hb fall ≥0.5g/dL from baseline that falls below 8.0g/dL on 2 consecutive weeks. 
The intervals of Hb measurement within the schedule of study visits fall within KDOQI guidelines on 
monitoring Hb in patients receiving iron replacement.  All patients who complete the randomized 
phase and remain on-treatment will enter an extended open-label phase of ferric maltol treatment 
and potentially benefit from iron replacement.  The safety profile of ferric maltol as established from 
completed studies is considered acceptable and therefore the overall benefit/risk to subjects 
entering this study is also acceptable. 
Refer to the Investigator’s Brochure for further details on risk/benefit assessment. 
 


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5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
PRIMARY OBJECTIVE 
To evaluate the efficacy of oral ferric maltol compared with placebo in the treatment of IDA in 
subjects with CKD at 16 weeks. 
5.2 
SECONDARY OBJECTIVE 
To evaluate the efficacy, safety, tolerability and pharmacokinetics of ferric maltol in subject with IDA 
and CKD over a treatment duration of up to 52 weeks. 
5.3 
PRIMARY ENDPOINT 
Change in Hb concentration from baseline to Week 16.  
5.4 
SECONDARY ENDPOINTS 
• Proportion of subjects that achieve an increase in Hb concentration of ≥1 g/dL at Week 16. 
• 
Proportion of subjects that achieve a Hb concentration of ≥11 g/dL at week 16. 
• 
Change in Hb concentration from baseline to Week 8. 
• Proportion of subjects that achieve an increase in Hb concentration of ≥2 g/dL at Week 16. 
• 
Change in Hb concentration from baseline to Week 4. 
• 
Changes in iron parameters (ferritin, TSAT, serum iron). 
• 
AEs/SAEs 
Additional long-term endpoints up to Week 52/End of Study visit similar to the efficacy and safety 
endpoints described above. 
5.5 
PHARMACOKINETIC ENDPOINTS 
Population based PK analysis of maltol, maltol glucuronide and serum iron. 
5.6 
EXPLORATORY ENDPOINTS 
Proportion of subjects with a baseline Hb of <10 g/dL that achieve a Hb > 10g/dL


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6 
INVESTIGATIONAL PLAN 
6.1 
STUDY OVERVIEW 
This is a phase 3, randomized, double-blind, placebo-controlled, prospective, multicenter study. 
Approximately 168 eligible subjects will be randomized at a ratio of 2:1, ferric maltol to placebo.  
The study will comprise of the following: 
• 
Screening: Up to 14 days 
• 
Randomized, Double-Blind Treatment: 16 weeks treatment with oral ferric maltol, 30 mg 
capsule twice daily (bid) or oral matching placebo bid.  
• 
Open-label Treatment: Up to 36 weeks treatment with ferric maltol. 
• 
End of Study: Week 52 or premature discontinuation. 
• 
Post-treatment safety follow-up: 14 days following discontinuation of study medication. 
 
Refer to Section 10 for a schematic of the study design and for details of visits and assessments.  
6.2 
INVESTIGATIONAL SITES 
Approximately 35 sites will participate. 
6.3 
INCLUSION AND EXCLUSION CRITERIA 
No deviations to the inclusion or exclusion criteria are permitted.   
6.3.1 
Inclusion Criteria 
All of the following criteria must be met to randomize a subject in the study: 
1. 
Ability to understand the information given in the Independent Ethics Committee (IEC) or 
Institutional Review Board (IRB) approved information sheet and consent form. Must sign and 
date the informed consent and authorization to use protected health information (PHI) in 
accordance with national and local subject privacy regulations prior to any study mandated 
procedure. 
2. 
Willing and able to comply with study requirements. 
3. 
Age ≥ 18 years at the time of informed consent. 
4. 
A current diagnosis of CKD with an estimated glomerular filtration rate (eGFR) of <60 
mL/min/1.73m2 and ≥15 mL/min/1.73m2, as calculated using the abbreviated version of the 
Modified Diet in Renal Disease equation (MDRD) assessed via screening laboratory results. 
5. 
Iron deficiency anemia defined by the following criteria assessed via screening laboratory 
results: 
a. Hb <11.0g/dL and ≥8.0g/dL 
b. AND ferritin <250ng/mL with a Transferrin saturation (TSAT) <25% OR ferritin 
<500ng/mL with a TSAT of <15% 
6. 
Female subjects of childbearing potential (including perimenopausal females who have had a 
menstrual period within 1 year prior to screening) 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 


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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.  Female subjects who are surgically sterile (bilateral tubal 
ligation, bilateral oophorectomy or hysterectomy) or postmenopausal (defined as no menstrual 
period within 1 year of screening) are also allowed to participate. 
 
6.3.2 
Exclusion criteria 
A subject who meets any of the following criteria is not eligible for participation in the study. 
1. Anemia due to any cause other than iron deficiency, including, but not limited to: 
a. Untreated or untreatable severe malabsorption syndrome. 
b. Myelosuppression use (permitted if taken at a stable dose and frequency for at least 
12 weeks prior to randomization and are expected to stay stable throughout the 
double-blind treatment period so long as there is no clinical evidence of the 
myelosuppression contributing to the subject’s anemia). 
2. Administration with any of the following prior to randomization: 
a. IV iron injection within the previous 4 weeks or administration of intramuscular or 
depot iron preparation within the previous 12 weeks. 
b. Single agent oral iron supplementation, taken specifically to treat anemia (e.g. 
ferrous sulfate, fumarate and gluconate) within the previous 2 weeks. Multivitamins 
are permitted.  
c. Use if ferric citrate and sucroferric oxyhydroxide within the previous 1 week. 
d. ESAs within the previous 4 weeks  
e. Blood transfusion or donation within the previous 12 weeks. 
f. Dimercaprol or cloramphenicol within the previous 7 days. 
g. Current use of methyldopa. 
3. Currently receiving dialysis or initiation of dialysis is considered likely during the study. 
4. Renal transplant within 12 months prior to randomization or is considered likely during the 
study. 
5. Known hypersensitivity or allergy to the active substance or excipients of ferric maltol or placebo 
capsules. 
6. Contraindication for treatment with iron preparations, e.g. hemochromatosis, chronic hemolytic 
disease, sideroblastic anemia, thalassemia, or lead intoxication induced anemia. 
7. Impaired liver function as indicated by alanine aminotransferase (ALT) or aspartate transaminase 
(AST) > 3 times the upper limit of normal as assessed via screening laboratory results. 
8. Clinically significant vitamin B12 or folic acid deficiency as determined by the screening 
laboratory results (retest following at least 2 weeks of starting treatment with vitamin B12 or 
folate replacement is permitted). 


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9. Pregnant or breast feeding.  
10. Concomitant medical conditions with significant active bleeding likely to initiate or prolong 
anemia; for example coagulation disorders or recurrent GI bleeding. 
11. Scheduled or expected major surgery during the course of the study. (Minor surgeries not 
associated with significant blood loss, in the Investigator’s judgement, are permitted e.g. surgery 
related to fistulae or vascular access, minor dental extractions, incision and drainage of abscess 
or simple excisions). 
12. Participation in any other interventional clinical study within 30 days prior to screening. 
13. Cardiovascular, liver, renal, hematologic, psychiatric, neurologic, gastrointestinal, immunologic, 
endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, 
may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit 
the lifespan of the subject. 
14. Any other unspecified reason that, in the opinion of the Investigator or the Sponsor make the 
subject unsuitable for enrolment. 
6.4 
CONCOMITANT MEDICATION 
6.4.1 
Not Permitted 
• IV iron injections, intramuscular or depot iron administrations. 
• Single agent oral iron supplementation, taken specifically to treat anemia (e.g. ferrous 
sulfate, fumarate and gluconate).  
• Ferric citrate or sucroferric oxyhydroxide. 
• ESAs. 
• Blood transfusions or donations. 
• Dimercaprol, chloramphenicol or methyldopa 
6.4.2 
Permitted 
• Myelosuppressants taken at a stable dose and frequency (so long as there is no clinical 
evidence of the myelosuppressant contributing to the subject’s anemia). 
• Multivitamins containing iron. 
6.4.3 
Potential Medication Interactions 
As some iron based medications are known to bind to other oral medications and affect absorption, 
ferric maltol must be administered at least 2 hours before any of these concomitant medications are 
taken: penicillamine, bisphosphonates, ciprofloxacin, entacapone, levodopa, levofloxacin, 
levothyroxine (thyroxine), moxifloxacin, mycophenolate, norfloxacin and ofloxacin.  
Absorption of both iron and antibiotic may be reduced if oral iron is given with tetracycline. 
Administration of iron preparations and tetracyclines should be separated by 2 to 3 hours.  


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Absorption of oral iron may be reduced by calcium and magnesium salts (such as magnesium 
trisilicate). Administration of iron preparations with such compounds should be separated by at least 
2 hours. 
6.5 
INDIVIDUAL WITHDRAWAL CRITERIA 
Subjects 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 an End of Study Visit and a follow-up call 14 days after the 
last dose of study drug (if the subject agrees in the case of withdrawn consent). 
Subjects who discontinue study treatment prior to Week 16 will be encouraged to continue with 
study visits and assessments up to and including assessments at week 16. 
 
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 if female of childbearing potential. 
• 
A ≥0.5g/dL decrease from baseline in Hb that falls below 8.0g/dL on 2 consecutive weeks. 
• 
Ferritin >700ng/mL with a TSAT of >50% sustained for 2 consecutive weeks. 
• 
SAEs that are judged by the Investigator to be related to study drug. 
• 
Use of prohibited concomitant medications. 
• Initiation of dialysis. 
• Blood transfusions or donations for any cause. 
• Any dose or frequency changes to myelosuppressants and/or ESAs (greater than 20% over 
an 8 week period) during the double-blind treatment period. 
• Requirement for major surgery. Minor surgeries not associated with significant blood loss, in 
the Investigator’s judgement, are permitted (e.g. surgery related to fistulae or vascular 
access, minor dental extractions, incision and drainage of abscess or simple excisions). 
The reason for study drug discontinuation and the date of last dose should be recorded in the CRF.  


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7 
TREATMENT OF SUBJECTS 
Shield TX (UK) Limited will provide ferric maltol and matching placebo to all study sites. Sites must 
arrange storage of Investigational Medicinal Product (IMP) in a temperature monitored, secure 
location which is accessible to authorized individuals only. 
7.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PRESENTATION 
Ferric maltol is presented as a hard, gelatin, red capsule, 19 mm long x 7 mm diameter (size 1). Each 
capsule contains 30 mg iron and the following excipient(s) with known effect: 91.5 mg of lactose, 0.5 
mg of Allura Red AC (E129) and 0.3 mg Sunset Yellow FCF (E110). A full list of excipients can be found 
in the Investigator’s Brochure. 
Placebo will be provided identical in appearance to ferric maltol hard, gelatin, red capsules and the 
same excipients with the active substance replaced with the primary excipient lactose. 
7.2 
PACKAGING 
The product will be supplied in a white polypropylene securitainer with a tamper evident standard 
securitainer cap of white medium density polyethylene.  An appropriate number of bottles 
containing 56 capsules will be provided to cover intervals between study visits. 
7.3 
STORAGE 
IMP must be stored below 25 °C (77 °F) 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 Sponsor should be contacted for 
review and further instruction. 
7.4 
LABELLING  
All kits and bottles will be identified by a unique kit number for the double-blind treatment period. 
Kits and bottles for the open-label treatment period will be clearly labelled as ferric maltol. 
Labels of the IMP will contain information according to 21CFR Section 312.6. 
7.5 
DISPENSATION 
Specific containers will be allocated to specific subjects via the central IXRS/randomization system 
for dispensation according to the treatment randomly allocated during the 16 week double-blind 
treatment period. 
7.6 
ADMINISTRATION 
Eligible subjects will be randomized to receive one of the following treatments for the first 16 weeks 
of the study: 
• 
Oral ferric maltol, 30 mg capsule bid. 
• 
Oral matching placebo capsule bid. 
Following 16 weeks of randomized treatment, all subjects will receive open-label treatment with 
ferric maltol for up to an additional 36 weeks. 
Subjects should be instructed to take one capsule of ferric maltol (or placebo) twice daily, morning 
and evening, on an empty stomach (with half a glass of water), as the absorption of iron is reduced 
when taken with food. 


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If a subject forgets to take a dose he/she should take the next dose as normal.  Do not take a double 
dose to make up for a forgotten capsule. 
7.7 
TREATMENT COMPLIANCE 
Subjects will be instructed to take the study drug as described in detail on the drug labels and by the 
study site.  Subjects will be instructed to return all unused supplies and all clinical study medication 
packaging at each visit.  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.  The 
Investigator will use the IMP only within the framework of this clinical study and in accordance with 
the existing study protocol.   
If a subject is found to be persistently non-compliant with the study medication (defined as less than 
80% or more than 120% compliant with the dosage schedule as measured at two separate visits), a 
decision will be made by the Investigator and Sponsor as to whether the subject should be 
withdrawn from the study treatment. 
7.8 
CONTINUATION OF TREATMENT 
No further provisions are made for access to the study treatment under this protocol following the 
Week 52 / End of Study visit.


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8 
ENROLMENT AND RANDOMIZATION PROCEDURES 
Full details of procedures will be provided in the Investigator Site File. 
8.1 
SCREENING 
Subjects will be evaluated according to the inclusion and exclusion criteria (sections 6.3.1 and 6.3.2). 
Subjects will be deemed eligible for randomization 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 randomization, the reasons for exclusion will be documented in the 
subject’s medical notes and on the study screening log. 
A subject may be retested once for laboratory criteria that do not meet protocol criteria so long as 
randomization occurs no more than 14 days from the initial test result (if eligible).  
8.2 
RANDOMIZATION  
A final eligibility evaluation must be conducted immediately prior to randomization. If a subject is 
deemed eligible a centralized IXRS/randomization system will be used to assign the subject to ferric 
maltol or placebo.   
Subjects will be randomized in a 2:1 ratio (ferric maltol:placebo) and will be stratified according to 
the subjects baseline Hb (<9.5 or ≥9.5g/dL) and eGFR (≤30 or >30mL/min/1.73m2).  
8.3 
BLINDING PROCEDURES 
The Investigator and site staff, subjects, monitors, Sponsor and CRO staff will remain blinded to the 
treatment assignment during the conduct of the randomized phase of the study. The randomization 
codes will be released to the Sponsor for the purpose of the primary analysis only when the clinical 
database for the randomized phase of the study has been locked and a final Statistical Analysis Plan 
(SAP) is in place.   
The randomization list is kept strictly confidential.  It is accessible only to authorized persons who 
are not involved in the conduct and analysis of the study until time of un-blinding. The IXRS system 
will allow un-blinding by the vendor used by the Sponsor for reporting of suspected unexpected 
serious adverse reactions (SUSAR) as required by the regulatory agencies.  The evaluation and 
decision as to whether a Serious Adverse Event (SAE) qualifies as an SUSAR is the responsibility of 
the Sponsor.  
8.4 
EMERGENCY UNBLINDING 
Under normal circumstances, the blind should not be broken. The blind should be broken only if 
specific emergency treatment would be dictated by knowing the treatment status of the subject. It is 
highly unlikely that this situation will occur during this study.  In such cases the Investigator can 
break the blind via the IXRS/randomization system. The system will encourage the Investigator to 
discuss the situation with Sponsor prior to breaking the code. Un-blinding will result in 
discontinuation of the subject from the study treatment and withdrawal from the study.


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9 
STUDY PROCEDURES 
9.1 
DESIGN SCHEMATIC 
 
 


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9.2 
SCHEDULE OF ASSESSMENTS 
PERIODS 
SCREENING 
RANDOMIZED TREATMENT 
OPEN-LABEL TREATMENT 
FOLLOW-UP 
Visit Duration 
1-14 days 
16 weeks 
36 weeks 
14 days after last 
dose3 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Visit Name 
Screening 
Period1 
Randomization 
Week 4 
Week 8 
Week 12 
(Telephone) 
Week 16 
End of 
Randomized 
Treatment 
Period 
Week 20 
(Telephone) 
Week 24 
Week 32 
Week 42 
Week 52  
End of Study2 
Telephone Follow-
up 
Visit Window 
 
14 days from 
Screening1 
±3 days of Randomization 
±7 days of Randomization 
14-21 days after last 
dose of study drug 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications and 
Procedures 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Vital Signs 
 
X4 
 
 
 
X 
 
 
 
 
X 
 
12-Lead ECG 
 
X4 
 
 
 
 
 
 
 
 
X 
 
Urine Pregnancy Test 
X 
X4 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Hematology, 
Chemistry and Iron 
markers 
X 
X4 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Population PK 
Sampling5 
 
X4 
X 
 
 
X 
 
 
 
 
X5 
 
eGFR 
X 
 
 
 
 
X 
 
 
 
 
X5 
 
Retention Samples5 
 
X4 
 
 
 
X 
 
 
 
 
X 
 
Eligibility 
Confirmation and 
Randomization 
 
X4 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Return Study Drug 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Note: unscheduled visits may be required (e.g. repeat laboratory sampling or safety assessments). 
1. A subject may be retested once for laboratory criteria that do not meet protocol criteria so long as randomization occurs no more than 14 days from the initial test 
result (if eligible). 
Subjects who withdraw from the study before Week 16 should have assessments conducted per Week 16/ End of Randomized Treatment Period or per Week 52/End of 
Study  if withdrawn after Week 16. Subjects who discontinue from study treatment prior to Week 16 will be encouraged to continue with study visits and assessments 
up to and including assessments at week 16. 
2. Follow-up call not required if the subject prematurely discontinued treatment and the End of Study Visit occurred 14 days after the last dose taken. 
3. Laboratory sampling and assessments must be completed prior to the first dose of study treatment. 
4. Population PK samples are only required at Week 52 / End of Study visit if the subject has discontinued treatment prior to Week 16. Retention samples only 
applicable for sites with access to a -70/80OC freezer for storage. 


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9.3 
DEMOGRAPHICS AND MEDICAL HISTORY 
The following will be documented at screening and updated (if required) prior to randomization: 
year of birth, race and ethnicity, gender, all current medical conditions, all medical history relevant 
to IDA and or CKD regardless of onset and all known iron replacement therapies. Additionally, 
clinically significant medical history from the past 5 years will be documented including malignancies 
sterilisations, hospitalizations, surgeries, ESA treatment history and the method of contraception for 
female subjects of childbearing potential. 
9.4 
PHYSICAL EXAMINATION 
A brief physical exam will be conducted and will include body weight, height (screening only) and an 
assessment of general appearance, skin, head, eyes, ears, nose and throat, cardiovascular, 
respiratory, abdominal, gastrointestinal and musculoskeletal. The Investigator will record any 
clinically significant finding as an AE. 
9.5 
CONCOMITANT MEDICATIONS AND PROCEDURES 
The following will be documented at screening and updated (if required) prior to randomization: all 
current medications at the time of screening or stopped within 12 weeks of screening and any 
medical procedure performed within 4 weeks 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 will include any therapeutic intervention such as 
surgery/biopsy, physical therapy or diagnostic assessment (e.g. blood gas measurement). 
9.6 
VITAL SIGNS 
Blood pressure and heart rate will be measured after the subject has been supine for 5 minutes.  
9.7 
12-LEAD ECG 
A 12-lead ECG will be conducted after the subject has been supine for 5 minutes. 
9.8 
LABORATORY ASSESSMENTS 
All analyses will be conducted via the central laboratory unless specified. Planned assessments are 
for both efficacy and safety purposes. The primary endpoint of the study, hemoglobin, will be 
analysed via the hematology panel and will be reported in g/dL. 
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).    
The signed paper copy of the laboratory report is retained at the investigational site.  The electronic 
file transferred from the central laboratory to the Sponsor will be considered source data for 
laboratory analysis.  
Full details of the required sample collection and processing procedures will be described in the 
Central Laboratory Manual for the study. 


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9.8.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, red blood cell Hb, mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin (MCHC), white blood cell count (total and differential), 
absolute reticulocyte count, mean reticulocyte hemoglobin content (CHr), mean cell volume (MCV) 
and platelet count.  
9.8.2 
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. The following will be analysed during screening 
only: vitamin B12, C-reactive protein (CRP) and folate.  
9.8.3 
Iron Markers 
Serum iron, ferritin, transferrin, total iron-binding capacity and TSAT. Soluble transferrin receptor 
will be analysed at baseline, week 4, week 16 and week 52 only. 
9.8.4 
Estimated Glomerular Filtration Rate (eGFR) 
Analysed at screening, week 16 and week 52/End of Study only via the central laboratory using the 
Modified Diet in Renal Disease equation (MDRD). 
9.8.5 
Population Pharmacokinetics (PK) 
Population based PK analysis of maltol and key metabolites (maltol glucuronide) will be conducted. 
Serum iron will also be analysed using the results collected via iron marker samples (Section 10.8.3). 
Single point sampling at specified visits will be conducted in accordance with FDA Guidance on 
Population Pharmacokinetics (February 1999). Subjects will be instructed to hold the morning dose 
of study drug until after the study visit. The date and time (hour and minute) of the last dose of 
study drug, prior to sampling, is to be recorded by the subject.  
9.8.6 
Retention Samples 
Serum and plasma samples will be collected for future analysis by sites with access to a -70/80oC 
freezer only. No genetic testing will be completed on any samples obtained during the study. 
Samples will be stored for a maximum of 5 years following the last study sample taken. Analyses will 
be restricted to safety related analyses and exploratory efficacy related analyses of ferric maltol 
related to the treatment of IDA. 
9.8.7 
Urine Pregnancy Test 
Females of childbearing potential only. A urine pregnancy test should be conducted using kits 
provided by the central laboratory. 


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10 SAFETY  
10.1 DEFINITIONS 
10.1.1 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. 
• 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. 


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• Overdose of either study drug or concomitant medication without any signs or symptoms.  
10.1.2 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 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 jeopardize 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. 


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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 catheterization), or car accident on the way to the hospital for a study 
visit, etc. 
10.2 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 documented on the AE form in the CRF and reported to the Sponsor via an 
SAE form within 24 hours of awareness.   All AEs occurring from the time of the first dose of study 
treatment through study completion or premature discontinuation must be documented 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. 
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 stabilization or until the event is otherwise 
explained. 
10.2.1 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. 


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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 hours 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.  
As soon as the Sponsor is informed about an SAE, an evaluation and potential reporting to central 
IRBs/ECs, competent authorities and other concerned parties will occur as required. The Investigator 
will be responsible for reporting to any local IRB/EC as required. 
10.2.2 Non-Immediate Reporting 
AEs that do not qualify for immediate reporting will be documented in the CRF and reported in the 
Clinical Study Report (CSR). 
10.3 EVALUATION 
AEs and the corresponding entries in the CRF will be reviewed by the Investigator or qualified 
member of the study staff. 
10.3.1 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. 


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10.3.2 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 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.  
10.3.3 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). 
10.4 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. 
10.5 SAFETY ENDPOINTS 
During the study, safety endpoints will include treatment-emergent AEs and SAEs including clinically 
significant changes from baseline in vital signs, body weight, laboratory or ECG abnormalities. 


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11 STATISTICAL CONSIDERATIONS 
11.1 SAMPLE SIZE AND POWER CALCULATIONS 
A sample size of 135 subjects (Randomized 2:1, ferric maltol:Placebo, 90 in ferric maltol group and 
45 placebo) will have 95% power to detect a statistically significant treatment difference of 1.0g/dL 
between ferric maltol and placebo on the primary endpoint, using a two-sided 0.05 significance 
level. This calculation assumes a common standard deviation of 1.5g/dl which is based on a pooled 
estimate of SDs obtained from published trials (Feraheme prescribing information 2010; Quinibi 
2011; Macdougall 2014 Schwenk 2010; Singh 2006; Wyck 2005). Assuming a drop-out rate of 20%, 
approximately 168 subjects total will be recruited.  Subjects randomization will be stratified based 
on baseline Hb value and eGFR. 
11.2 STATISTICAL METHODS 
11.2.1 Primary Endpoint Analysis 
Effectiveness will be analysed by determining whether the Test group shows a statistically significant 
superiority as compared to the Control group.  
An Analysis of Covariance (ANCOVA) will be used to analyse the primary endpoint: change in Hb 
concentration from baseline to Week 16.  Missing change from baseline hemoglobin concentration 
data for week 16 will be imputed using multiple imputation methodology.  This will generate 10 
complete datasets containing imputed values for those missing in the original dataset. Hb 
concentrations at baseline, Week 4, Week 8 and gender will be considered as variables helpful in 
guiding this imputation. For each imputed dataset, the change from baseline to Week 16 complete 
datasets will be analysed using ANCOVA with factors for treatment and disease and a covariate of 
baseline hemoglobin and eGFR. By combining the results from these analyses, the treatment 
estimates will be constructed using the parameter estimates and associated standard errors. 
Similarly the difference of the adjusted treatment means (ferric maltol – placebo) will be presented 
with the associated standard error and 2-sided 95 % confidence interval.  
The primary endpoint analysis will be performed using the intention-to-treat (ITT) population.   
11.2.2 Secondary and Exploratory Analyses 
Details regarding methods for analysis of secondary endpoints will be provided in the Statistical 
Analysis Plan (SAP). The SAP will also detail the analysis of exploratory and long-term endpoints.  
No formal multiple comparisons procedure will be used to control the type I error rate for the 
analysis of secondary or other exploratory endpoints, including those defined for the long-term 
open-label phase of the study.  For these analyses, confidence intervals and/or p-values will be 
displayed for descriptive purposes only. 
11.2.3 Sensitivity Analyses 
For the primary endpoint, the following sensitivity analyses will be performed: 
• 
The primary analysis defined in Section 12.2.1 (with multiple imputation) will be repeated 
using the per protocol (PP) population.   
• 
The ANCOVA will be repeated for the ITT population but based on observed data only 
(complete case analysis without imputation). 


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• 
The ANCOVA will be repeated for the ITT population but  using last observation carried 
forward (LOCF without imputation)  
• 
A mixed model for repeated measures (MMRM) ANCOVA will be conducted using observed 
data only. 
Other sensitivity analyses will be documented in the SAP. 
11.2.4 Imputation of Missing Data 
Missing values for efficacy variables will be replaced for the secondary endpoint analyses as 
follows: 
• For the endpoint ‘Increase in Hb concentration of ≥1 g/dL at Week 16’, subjects not 
returning to a follow-up visit will be assumed not to have reached the desired concentration.  
• For the endpoint ‘Hb concentration ≥11 g/dL at week 16’, subjects not returning to a follow-
up visit will be assumed not to have reached the desired concentration.   
• For the endpoint ‘Increase in Hb concentration of ≥2 g/dL at Week 16’, subjects not 
returning to a follow-up visit will be assumed to have not reached the desired concentration.  
Safety data will be used according to availability, with no imputation for missing data. 
Imputation of missing values for long-term and exploratory efficacy analyses will be defined in the 
SAP. 
11.2.5 Safety Analyses 
11.2.5.1 Adverse Events (AEs) 
AEs will be categorized 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. 
11.3 DEFINITION OF POPULATIONS  
11.3.1 Randomized Population 
All subjects who are randomized.  
11.3.2 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.  
11.3.3 Intention- To-Treat (ITT) Population (Full Analysis Set) 
For efficacy, all subjects who have been randomized will be included in the ITT analysis.   
11.3.4 Per Protocol (PP) Population 
The PP population includes all subjects eligible for ITT evaluation and, in addition, who do not have 
major protocol deviations. Protocol deviations occurring during the first 16 weeks of the study will 
be classified as major or minor prior to study un-blinding. 


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12 ETHICAL CONSIDERATIONS 
The Sponsor and Investigator must comply with this protocol, all applicable national and local 
regulations including International Conference on Harmonization (ICH) and Good Clinical Practice 
(GCP). 
12.1 DECLARATION OF HELSINKI 
The Sponsor and the Investigator must comply with the principles set forth by the Declaration of 
Helsinki. 
12.2 INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE 
The Investigator must ensure that the IRB/EC has approved the protocol, the Information Sheet and 
Consent Form and any other required study documents prior to starting the study. The Sponsor must 
approve any changes to the information sheet and consent form before submission to the IRB/EC.  
Prior to activation of a site and provision of IMP, the Sponsor must receive documentation to 
demonstrate IRB/EC 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/EC at least annually and more frequently if required 
by the IRB/EC. 
On completion or termination of the study the Investigator or Sponsor must submit a closeout letter 
to the IRB/EC (as required). A copy of the CSR synopsis will also be sent in accordance with local 
laws. 
12.3 SUBJECT INFORMATION AND INFORMED CONSENT 
IRB/EC approval of the written information sheet and consent form must be obtained prior to use. 
The Information Sheet will provide the subject 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 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 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 form.  
Each consent form must also contain an authorization for the Sponsor and Investigators to use and 
disclose Protected Health Information (PHI) in compliance with local law.  
No study assessments or procedures should be conducted until written informed consent has been 
provided. 
A copy of the information sheet and consent form signed and dated by the subject must be given to 
the subject. The signed consent form(s) will be retained with the study records. A description of the 
consent process must be documented in the subject’s medical record. 


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12.4 SUBJECT DATA PROTECTION 
Prior to any study test being conducted, including screening tests, subjects must provide 
authorization required by local law e.g. PHI authorization in North America). Subjects will not be 
identified by name (or initials) in the CRF 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. 
The subject will not be identified by name in the CRF or any study reports and all data will be used 
for research purposes only. 
12.5 SUBJECT INSURANCE 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow applicable 
local compensation laws. 
12.6 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. 
12.7 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 a publically accessible websites in accordance with the 
applicable laws and regulations. 


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13 STUDY MANAGEMENT 
13.1 SOURCE DATA 
The Investigator must ensure that all source documents (i.e., medical records) and CRF 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 CRF. 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 CRFs will be verified against source documents.  The CRF will not 
act as source except in the instance of laboratory data which will be transferred directly to the 
Sponsor.   
13.2 QUALITY ASSURANCE 
During and/or after study completion, Sponsor quality assurance officers, IRB/EC 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. 
13.3 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, CRFs, 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/EC/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.  
13.4 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. 
13.5 CONTRACT RESEARCH ORGANIZATION (CRO) 
A CRO will be contracted to be responsible for administrative aspects of the study including, but not 
limited to, study set-up, site initiation, monitoring, electronic CRF provision, data management 


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including electronic CRF provisioning, statistics and programming and reporting. Other vendors will 
be contracted to cover supportive services such as a central laboratory and IXR system. 
13.6 AMENDMENTS TO THE STUDY PROTOCOL 
Any significant changes to the protocol shall be submitted to the IRB/EC 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/EC and 
Regulatory Authorities will occur as required by local law. 
Amendments to the Information Sheet and Consent Form will be made if impacted by an 
amendment to the study protocol which will also be submitted and approved to the IRB/EC as 
required by local law.  
13.7 STUDY STOPPING RULES 
The Sponsor may terminate this study at any time after informing Investigators. 
13.8 END OF STUDY 
The end of study is the date of the last subject, last visit for final collection of data. 
13.9 RETENTION OF RECORDS 
The Investigator must retain the informed consent documentation, disposition of the IMP, CRFs, 
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 authorization 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. 
13.10  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.   


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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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