Clinical trial NCT04626414
Conditions: Anemia, Iron Deficiency
Keywords: iron deficiency, anaemia
Sponsor: Shield Therapeutics
Start date: 2020-09-28; Completion date: 2020-11-13
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of the study is to compare the Pharmacokinetics (PK) of the new ferric maltol suspension, in adults, with the existing ferric maltol capsule.

Detailed description:
Open-label, Phase 1, four way crossover study to compare the PK of the new ferric maltol suspension, in healthy volunteers, with the existing ferric maltol capsules under fed and fasted conditions.

32 subjects will be randomised to 1:1:1:1 ratio to receive one of the treatment sequences.

Based on the randomised sequence, subjects will receive a single dose of 30mg ferric maltol capsule in a fed/ fasted condition and 30 mg (5ml) ferric maltol suspension in a fed/ fasted condition.

Subject participation in the study will consist of 3 periods:

1. Screening: up to 14 days
2. Randomised treatment: 8 days
3. Post-treatment follow up: 3-7 days following drug discontinuation

Arms: arm 1: Single dose of 30 mg ferric maltol capsule in a fed condition arm 2: Single dose of 30 mg ferric maltol capsule in a fasted condition arm 3: Single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition arm 4: Single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
Interventions: intervention 1: Ferric maltol capsule intervention 2: Ferric maltol suspension
Intervention descriptions: intervention 1: single dose of 30 mg capsule intervention 2: single dose of 30mg (5ml) oral suspension

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL
A randomized, open label, single dose, four way crossover, Phase I study to compare the
pharmacokinetics of ferric maltol capsules and oral suspension under fasted and fed conditions in
adult healthy volunteers
Protocol Number:
ST10 01 104
Test Drug:
Ferric Maltol (ST10)
EudraCT Number:
2018 000079 34
Study Name:
Phase 1 crossover study of the PK of ferric maltol capsules and
suspension
Sponsor:
Shield TX (UK) Limited, Northern Design Center, Baltic Business
Quarter, Gateshead Quays, NE8 3DF United Kingdom
Version/Date:
Version 2.0, 15 July 2020
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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2 TABLE OF CONTENTS
1
PROTOCOL APPROVALS ..................................................................................................................2
2
TABLE OF CONTENTS.......................................................................................................................3
3
ABBREVIATION INDEX.....................................................................................................................7
4
SYNOPSIS.........................................................................................................................................9
5
BACKGROUND INFORMATION...................................................................................................... 20
5.1
OVERVIEW OF DISEASE .........................................................................................................20
5.2
CURRENT TREATMENT OF DISEASE ......................................................................................21
5.3
OVERVIEW OF TEST PRODUCT..............................................................................................22
5.4
DOSE SELECTION AND RESULTS OF PREVIOUS CLINICAL STUDIES .......................................22
5.4.1
Phase 3 studies in adults...............................................................................................23
5.4.2
Phase I studies in adults................................................................................................24
5.4.3
Phase I study in children and adolescents ....................................................................24
5.5
RATIONALE FOR THE STUDY..................................................................................................26
5.5.1
Study Population........................................................................................................... 26
5.5.2
Study Treatment Duration ............................................................................................26
5.6
RISK BENEFIT EVALUATION...................................................................................................27
6
STUDY OBJECTIVES AND ENDPOINTS............................................................................................29
6.1
PRIMARY OBJECTIVE .............................................................................................................29
6.2
SECONDARY OBJECTIVES ...................................................................................................... 29
6.3
PRIMARY ENDPOINTS............................................................................................................29
6.4
SECONDARY ENDPOINTS.......................................................................................................29
6.5
EXPLORATORY ENDPOINTS...................................................................................................30
7
INVESTIGATIONAL PLAN ...............................................................................................................31
7.1
STUDY OVERVIEW .................................................................................................................31
7.2
INVESTIGATIONAL SITES........................................................................................................32
7.3
INCLUSION AND EXCLUSION CRITERIA .................................................................................32
7.3.1
Inclusion Criteria ...........................................................................................................32
7.3.2
Exclusion criteria...........................................................................................................33
7.4
CONCOMITANT MEDICATION...............................................................................................34
7.4.1
Not Permitted ............................................................................................................... 34
7.4.2
Permitted ......................................................................................................................35
7.4.3
Potential Medication Interactions ................................................................................35
7.5
INDIVIDUAL DISCONTINUATION CRITERIA............................................................................35


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7.6
STUDY TERMINATION ........................................................................................................... 36
8
TREATMENT OF SUBJECTS ............................................................................................................37
8.1
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PRESENTATION .........................................37
8.2
COMPARATOR.......................................................................................................................38
8.3
TREATMENT ASSIGNMENT AND BLINDING ..........................................................................38
8.3.1
TREATMENT ASSIGNMENT AND ADMINISTRATION .....................................................38
8.3.2
WASHOUT PERIOD........................................................................................................ 40
8.3.3
FOLLOW UP................................................................................................................... 40
8.4
PACKAGING........................................................................................................................... 40
8.5
STORAGE ...............................................................................................................................40
8.6
LABELLING............................................................................................................................. 40
8.7
TREATMENT COMPLIANCE....................................................................................................40
8.8
CONTINUATION OF TREATMENT ..........................................................................................41
9
ENROLMENT AND RANDOMIZATION PROCEDURES.....................................................................42
9.1
SCREENING............................................................................................................................ 42
9.2
COVID 19 TESTING AND IMPLICATIONS ON THE TRIAL........................................................42
9.3
RANDOMIZATION..................................................................................................................42
9.4
REPLACEMENT POLICY..........................................................................................................43
9.5
BLINDING PROCEDURES........................................................................................................43
9.6
EMERGENCY UNBLINDING....................................................................................................43
10
STUDY PROCEDURES.....................................................................................................................44
10.1
DESIGN SCHEMATICS ............................................................................................................ 44
10.2
SCHEDULE OF ASSESSMENTS................................................................................................45
10.3
DEMOGRAPHICS AND MEDICAL HISTORY.............................................................................49
10.4
PHYSICAL EXAMINATION ......................................................................................................49
10.5
CONCOMITANT MEDICATIONS AND PROCEDURES ..............................................................49
10.6
VITAL SIGNS...........................................................................................................................49
10.7
LABORATORY ASSESSMENTS ................................................................................................50
10.7.1
Hematology and Clinical Chemistry ..............................................................................50
10.7.2
Pharmacokinetics.......................................................................................................... 50
10.7.3
Hepatitis B, C and HIV test ............................................................................................51
10.7.4
Urine Drug test.............................................................................................................. 51
10.7.5
Pregnancy Test.............................................................................................................. 51
10.7.6
Breath Alcohol Content Test.........................................................................................52


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10.7.7
COVID 19 Testing ..........................................................................................................52
10.7.8
ECG................................................................................................................................52
10.7.9
Overall blood volume....................................................................................................52
11
SAFETY...........................................................................................................................................53
11.1
DEFINITIONS..........................................................................................................................53
11.1.1
ADVERSE EVENT (AE) ....................................................................................................53
11.1.2
SERIOUS ADVERSE EVENT (SAE)....................................................................................54
11.2
REPORTING AND DOCUMENTATION ....................................................................................55
11.2.1
Immediate Reporting ....................................................................................................56
11.2.2
Non Immediate Reporting ............................................................................................57
11.3
EVALUATION .........................................................................................................................57
11.3.1
Intensity ........................................................................................................................57
11.3.2
Causality........................................................................................................................57
11.3.3
Outcome .......................................................................................................................58
11.4
RE EXPOSURE........................................................................................................................58
11.5
SAFETY ENDPOINTS...............................................................................................................58
12
STATISTICAL CONSIDERATIONS.....................................................................................................59
12.1
SAMPLE SIZE AND POWER CALCULATIONS...........................................................................59
12.2
STATISTICAL METHODS......................................................................................................... 59
12.2.1
Sensitivity Analyses....................................................................................................... 60
12.2.2
Imputation of Missing Data ..........................................................................................60
12.3
DEFINITION OF POPULATIONS..............................................................................................60
12.3.1
Randomized Population................................................................................................60
12.3.2
Safety Population.......................................................................................................... 60
12.3.3
Full Analysis Set.............................................................................................................60
13
ETHICAL CONSIDERATIONS ........................................................................................................... 61
13.1
DECLARATION OF HELSINKI...................................................................................................61
13.2
INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE...............................61
13.3
SUBJECT INFORMATION AND INFORMED CONSENT............................................................61
13.4
SUBJECT DATA PROTECTION.................................................................................................62
13.5
SUBJECT INSURANCE.............................................................................................................62
13.6
CONFLICT OF INTEREST.........................................................................................................62
13.7
REGISTRATION OF STUDY AND DISCLOSURE OF RESULTS....................................................62
14
STUDY MANAGEMENT..................................................................................................................63


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14.1
SOURCE DATA .......................................................................................................................63
14.2
QUALITY ASSURANCE............................................................................................................63
14.3
MONITORING........................................................................................................................63
14.4
STUDY FUNDING ...................................................................................................................64
14.5
CONTRACT RESEARCH ORGANIZATION (CRO) ......................................................................64
14.6
AMENDMENTS TO THE STUDY PROTOCOL...........................................................................64
14.7
STUDY STOPPING RULES .......................................................................................................64
14.8
END OF STUDY.......................................................................................................................64
14.9
RETENTION OF RECORDS ...................................................................................................... 65
14.10 SECURITY AND PUBLICATIONS..............................................................................................65
15
REFERENCES..................................................................................................................................66


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3 ABBREVIATION INDEX
AE
Adverse Event
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AUC
Area Under the Plasma Concentration Curve
AUC(0 inf)
Area Under the Plasma Concentration Curve for 0 infinity
AUClast
Area Under the Plasma Concentration Curve from 0 up to the last
measurable concentration (non below) quantification limit after
dosing
BID
Twice Daily
BUN
Blood Urea Nitrogen
BP
Blood pressure
C
Celsius
CA
Competent Authority
CD
Crohn͛s Disease
CI
Confidence Interval
CKD
Chronic Kidney Disease
Cmax
Maximum Observed Concentration
COVID 19
Coronavirus Disease 2019
CRA
Clinical Research Associate
CRF/eCRF
Case Report Form/electronic Case Report Form
CRO
Contract Research Organization
CS
Clinically Significant
CSR
Clinical Study Report
CV
Coefficient Variation
ECG
Electrocardiogram
eGFR
Estimated Glomerular Filtration Rate
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma Glutamyl Transpeptidase
GI
Gastrointestinal
hr
Hour
Hb
Hemoglobin
HIV
Human Immunodeficiency Virus
IBD
Inflammatory Bowel Disease
ICH
International Conference on Harmonization
ID
Iron Deficiency
IDA
Iron Deficiency Anemia


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IEC
Independent Ethics Committee
IMP
Investigational Medical Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Contraceptive Devices
IV
Intravenous
MAA
Marketing Authorization Application
NCS
Non Clinically Significant
NTBI
Non Transferrin Bound Iron
OFP
Oral Ferrous Product
PHI
Protected Health Information
PIP
Pediatric Investigational Plan
PK
Pharmacokinetics
PSP
Pediatric Study Plan
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS CoV 2 RT
PCR
Severe Acute Respiratory Syndromeʹassociated Coronavirus Real
Time Reverse TranscriptaseʹPolymerase Chain Reaction
SD
Standard Deviation
TEAE
Treatment emergent Adverse event
TESAE
Treatment emergent Serious Adverse event
TIBC
Total Iron Binding Capacity
TLAG
The delay between the time of dosing and time of appearance of
concentration in the sampling compartment.
Tmax
Time to Maximum Plasma Concentration
TNF a
Tumor Necrosis Factor alpha
TSAT
Transferrin Saturation
T1/2
Apparent terminal elimination half life
UC
Ulcerative Colitis
UIBC
Unsaturated Iron Binding Capacity
WHO
World Health Organization
yrs
Years
z
Apparent terminal elimination rate constant, determined by linear
regression of the terminal points of the ln linear plasma
concentration time curve.


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4 SYNOPSIS
Title
A randomized, open label, single dose, four way crossover, Phase
I study to compare the pharmacokinetics of ferric maltol capsules
and oral suspension under fasted and fed conditions in adult
healthy volunteers
Protocol Number
ST10 01 104
Study Name
Phase 1 crossover study of the PK of ferric maltol capsules and
suspension
Test Drug
Ferric Maltol (ST10)
Comparator
Not Applicable
Phase
Phase I
Sites
Approximately 1 2 sites
Study Rationale
The existing scientific and clinical experience with ferric maltol in
the treatment of IDA in patients with inflammatory bowel disease
(IBD) and chronic kidney disease (CKD) supports its further
investigation in the treatment of iron deficiency/IDA in children
and adolescents, in line with the Pediatric Investigation Plan (PIP)
for Ferric Maltol that has been reviewed and approved by the
European Medicines Agency (PIP reference: EMEA 001195 PIP
01 11) and the Pediatric Study Plan (PSP) agreed with the US FDA
(IND 114832).
Ferric Maltol makes iron available in the gastrointestinal tract,
providing the iron in a biologically labile form for uptake across
duodenal mucosal cells and ultimately hematopoiesis and
storage on ferritin.
Randomized
Phase
III
studies
(ST10 01 301/302)
have
demonstrated that Ferric Maltol over a 12 week period
effectively increases Hb by over 2 g/dL compared to baseline in
iron deficiency anemia patients with inflammatory bowel disease
(IBD). Ferric Maltol was also demonstrated to be well tolerated
(87% of subjects completing 12 weeks of study treatment) and
with a side effect profile comparable to the placebo group. These
data formed the basis of a Marketing Authorization Application
(MAA) submission and subsequent EU centralized marketing


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authorization. Ferric Maltol 30 mg capsules (Feraccru®) are
approved for the treatment of Iron Deficiency in adults taken BID.
A randomized Phase III study (ST10 01 303) in 167 patients with
IDA in Chronic Kidney Disease (CKD) over 16 week double blind
phase and an open label 36 week treatment in 125 subjects
demonstrated positive safety, efficacy and tolerability. Changes
in TSAT, ferritin, and serum iron concentrations indicated an
improvement in all iron parameters in the ferric maltol group
compared to the placebo group and through the open label 36
week treatment period to Week 52. Overall, Ferric Maltol
resulted in clinically and statistically significant increase in Hb
compared to placebo.
As part of the pediatric clinical development, a Phase I PK study
was performed to understand the kinetics of the absorption of
iron and absorption and the elimination of maltol in a pediatric
subject group in order to establish a safe and effective dose in
children and adolescents, aged 10 17 years. All 3 doses of Ferric
maltol were well tolerated and had a favorable safety profile over
a 10 day period.
A new oral suspension formulation of ferric maltol has been
developed to provide an age appropriate formulation for
pediatric subjects. This study is designed to compare the PK of
the new suspension, in adults, with the existing ferric maltol
capsule.
Objectives
Primary objective:
To evaluate the pharmacokinetics (PK) of iron absorption after a
single 30 mg dose of ferric maltol administered as capsule or oral
suspension in fasted and fed conditions, via primary parameters
Cmax and AUClast.
Secondary objectives:
To evaluate the pharmacokinetics (PK) after a single 30 mg dose
of ferric maltol administered as a capsule or oral suspension
(fasted and fed conditions); through measurements of transferrin
saturation (TSAT), baseline corrected serum iron, transferrin,
total and unsaturated iron binding capacity (TIBC and UIBC), and
plasma of maltol and maltol glucuronide.


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To assess the safety and tolerability of ferric maltol after a single
dose of 30 mg administered as a capsule or oral suspension
(fasted and fed conditions); based on vital signs, adverse events,
concomitant medications and routine clinical laboratory safety
blood tests.
Endpoints
Primary endpoints:
1. PK analysis of total serum iron concentration; Cmax, AUClast in
fasted and fed conditions
Secondary endpoints:
1. PK analysis of total serum iron concentration; AUCinf in fasted
and fed conditions
2. PK analysis of baseline corrected serum iron concentration;
Cmax, AUClast,AUCinf in fasted and fed conditions
3. PK analysis of maltol and maltol glucuronide in plasma; Cmax,
AUClast in fasted and fed conditions
4. PK analysis of TSAT, TIBC, UIBC, transferrin; Cmax, AUClast in
fasted and fed conditions
5. Treatment emergent Adverse Events (AEs)
6. Serious Adverse Events (SAEs)
7. Treatment emergent Adverse Events leading to premature
discontinuation of study drug/PK assessments
8. Clinical laboratory safety blood results
9. Changes in vital signs
10. Concomitant medications
Design
The study will comprise of the following stages:
- 
Screening: to determine subject eligibility for the study
(within 14 days prior to the planned first ferric maltol dosing
period Day 1 for each subject)
- 
Randomized, Crossover phase: A treatment period of 4 days
with at least 48 hrs washout period between each dose
administration.


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During the crossover PK phase, subjects will be randomized in
a 1:1:1:1 ratio to receive one of the following treatment
sequences. 8 subjects will be randomized to each sequence:
Sequence A:
o Period 1; single dose of 30 mg ferric maltol capsule in
a fed condition
o Period 2; single dose of 30 mg (5 ml) ferric maltol
suspension in a fed condition
o Period 3; single dose of 30 mg ferric maltol capsule in
a fasted condition
o Period 4; single dose of 30 mg (5 ml) ferric maltol
suspension in a fasted condition
Sequence B:
o Period 1; single dose of 30 mg (5 ml) ferric maltol
suspension in a fasted condition
o Period 2; single dose of 30 mg ferric maltol capsule in
a fed condition
o Period 3; single dose of 30 mg (5 ml) ferric maltol
suspension in a fed condition
o Period 4; single dose of 30 mg ferric maltol capsule in
a fasted condition
Sequence C:
o Period 1; single dose of 30 mg ferric maltol capsule in
a fasted condition
o Period 2; single dose of 30 mg (5 ml) ferric maltol
suspension in a fasted condition
o Period 3; single dose of 30 mg ferric maltol capsule in
a fed condition
o Period 4; single dose of 30 mg (5 ml) ferric maltol
suspension in a fed condition
Sequence D:
o Period 1; single dose of 30 mg (5 ml) ferric maltol
suspension in a fed condition
o Period 2; single dose of 30 mg ferric maltol capsule in
a fasted condition


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o Period 3; single dose of 30 mg (5 ml) ferric maltol
suspension in a fasted condition
o Period 4; single dose of 30 mg ferric maltol capsule in
a fed condition
Prior to the first treatment period, subjects will arrive at the
Clinical Unit on Day 1 at least 13 hrs before dosing. After at
least 10 hours overnight fasting at the Clinical Unit subjects
will be randomized to one of the 4 treatment sequences. PK
samples will be collected pre dose and up to 24 hrs post dose
during each period (12 times including pre dose) for the
measurements of serum iron, TSAT, TIBC, UIBC, transferrin,
plasma maltol and maltol glucuronide.
There will be at least 48 hrs washout period between dose
administrations. Subjects will fast at least 10 hrs prior to each
treatment period dosing.
Subjects will stay at the Clinical Unit during the 4 treatment
and 3 washout periods and will be discharged on Day 8
following the last PK sampling timepoint.
- 
Post treatment safety follow up: Post study telephone
follow up will be conducted 3 7 days following Period 4
treatment. During early discontinuation a safety follow up at
the Clinical Unit will be performed 3 7 days after the last
study medication.
Number of Subjects
The target recruitment number is 32 and up to an additional 4
may be recruited to replace early withdrawing subjects.
Inclusion Criteria
1. Must voluntarily sign and date each Institutional Review
Board (IRB) approved informed consent form (ICF) prior
to the initiation of any screening or study specific
procedures.
2. Willing and able to comply with study requirements.
3. Healthy adult subjects 18 to 55 years of age, inclusive at
the time of informed consent.
4. Body Mass Index (BMI) of 18 32 kg/m2 inclusive
5. Female subjects of childbearing potential must not be
planning a pregnancy or be pregnant or lactating. All


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female subjects must have a negative result for the
pregnancy tests performed at screening and each
treatment period.
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 1% per year
when used consistently and correctly, such as hormonal
contraception (oral, implant, injection, ring, or patch) and
intrauterine contraceptive devices (IUDs) at least 3
months prior to Screening or a vasectomized partner.
Note: Complete abstinence from sexual intercourse is an
acceptable form of contraceptive practice.
7. Female subjects of non childbearing potential must be
either surgically sterile (hysterectomy, bilateral tubal
ligation,
bilateral
salpingectomy
and/or
bilateral
oophorectomy at least 26 weeks before the Screening
Visit) or post menopausal, defined as spontaneous
amenorrhea for at least 2 years.
8. Male subjects with partners of childbearing potential
must have had surgical sterilization (vasectomy) at least
26 weeks prior to Screening or use a male barrier
method of contraception (i.e. male condom with
spermicide) during any sexual intercourse, from Study
Day 1 (beginning of confinement) until 3 months after
the Follow up Visit.
Note: Complete abstinence from sexual intercourse is an
acceptable form of contraceptive practice.
9. Male subjects must agree to abstain from sperm
donation from initial study drug administration through 3
months after administration of the last dose of study
drug.
Exclusion Criteria
A subject who meets any of the following criteria is not eligible
for participation in the study.


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1. Known hypersensitivity or allergy to the active substance or
excipients of Ferric maltol oral suspension or capsules;
2. Presence
or
history
of
any
significant
cardiovascular,
gastrointestinal, hepatic, renal, pulmonary, hematologic,
endocrine, immunologic, dermatologic, neurological, or
psychiatric disease, as determined by the Investigator;
3. Presence or history of any other condition (including surgery)
known to interfere
with the
absorption,
distribution,
metabolism, or excretion of medicines;
4. Recent (within 6 months of screening) history of drug or
alcohol abuse;
5. Positive screen results for drugs of abuse or alcohol at
screening or Study Day 1;
6. Consumption of alcohol within 72 hrs prior to study drug
administration;
7. Positive test result for hepatitis B surface antigen (HBSaAg),
hepatitis
C
virus
antibody
(HCV
Ab),
or
human
immunodeficiency virus antibody (HIV Ab) at screening;
8. Donation or loss of 550 mL or more blood volume (including
plasmapheresis) or receipt of a transfusions of any blood
product within 8 weeks prior to study drug administration
and 14 days for plasma donation unless medically inadvisable;
9. Use of any prescription medications or over the counter
medications, including herbal products from screening until
study
completion,
other
than
medication
used
for
contraception or for treatment of any emergent AE at the
discretion of the Investigator;
10. Has received within 28 days prior to Screening intramuscular
or intravenous (IV) injection or administration of depot iron
preparation;
11. Has received oral iron supplementation within 7 days prior to
Screening;
12. Has concomitant disease that would significantly compromise
iron
absorption
or
absorbed
iron
utilization
such
as
swallowing
disorders;
gastric
pH
disturbances
and/or
extensive small bowel resection;


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13. Scheduled or expected hospitalization and/or surgery during
the course of the study;
14. Diagnosed to be COVID 19 positive by polymerase chain
reaction testing (SARS CoV 2 RT PCR positive) of a respiratory
specimen (preferably a nasopharyngeal swab) on Day 2;
15. Participation in any other interventional clinical study within
28 days prior to Screening;
16. Any other unspecified reason that, in the opinion of the
Investigator or the Sponsor makes the subject unsuitable for
enrolment.
Concomitant Medication
Not Permitted:
 Treatment with other oral iron preparations (prescription and
non prescription) within 7 days prior to screening and
throughout the study period;
 Treatment with parenteral iron preparations within 28 days
prior to screening and throughout the study period;
 Oral antibiotics, which are prohibited at screening and during
the study;
 Blood transfusions within 12 weeks before screening and
during the study;
 Erythropoiesis stimulating agents within 28 days before
screening and during the study;
 Multivitamins
within
7
days
prior
to
screening
and
throughout the study period;
 Other prescription or over the counter medications, including
herbal products from screening until study completion.
Permitted:
 Oral contraceptives are allowed during the study, but the
subjects must have been on a stable dose for 3 months before
randomisation;
 If necessary, medication used for treatment of any emergent
AE at the discretion of the Investigator may be given.


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Discontinuation Criteria
Subjects may be discontinued prematurely during the study for
the following reasons:
 Withdrawal of informed consent;
 Unwillingness
or
inability
to
comply
with
protocol
requirements;
 Pregnancy or not using a reliable method of birth control
(female subject of childbearing potential);
 Use of prohibited concomitant medications;
 Serious adverse events that are judged by the Investigator to
be related to study treatment;
 Blood transfusions for any cause during the study treatment
period;
The reason for study drug discontinuation and the date of last
dose should be recorded in the eCRF. Subjects who discontinue
treatment prematurely must return for safety follow up at the
Clinical Unit 3 7 days after last medication, unless informed
consent is withdrawn (and the subject does not agree to attend
this follow up visit).
Investigational Medicinal
Product
Comparator
Packaging
Administration
Ferric maltol oral suspension: oral suspension containing 30 mg
elemental iron, in the form of 231.5 mg ferric maltol, in 5 ml
suspension.
Ferric maltol capsules: gelatin capsules with 30 mg elemental
iron, in the form of 231.5 mg ferric maltol.
Ferric maltol bottles for capsules and oral suspension will be
labelled for clinical trials use.
Ferric maltol capsule and suspension fasted conditions: following
an overnight fast of at least 10 hours, the Investigator or his/her
staff will administer to each subject a single dose of ferric maltol
according to randomization sequence in a sitting position.
Capsules should be taken with 240 ml potable tap water.
Suspension can be taken with 240 ml potable tap water if needed.


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Water is allowed during the 10 hrs fasting butnot allowed for one
hour before and two hours after drug administration (except for
drug administration). No food will be allowed for at least 4 hours
post dose.
Ferric maltol capsule and suspension fed conditions: following an
overnight fast of at least 10 hours subjects will receive a test meal
30 minutes prior to administration of the drug product. Subjects
should finish their meal in 30 minutes or less; however, the
capsule or suspension will be administered by the Investigator or
his staff 30 minutes after start of the meal. Capsules should be
taken with 240 ml potable tap water. Suspension can be taken
with 240 ml potable tap water if needed. No food will be allowed
for at least 4 hours post dose. Water is allowed during the 10 hrs
fasting but not allowed for one hour before and two hours after
drug administration (except for drug administration).
Statistical Methods
Sample size calculation
The sample size is based on the comparisons of each of the
primary PK parameters Cmax and AUClast for total serum iron
between the formulations for each of the two conditions: fed and
fasted. Each comparison will be made via the ratio of the two
values of the parameter between the formulations. The 90%
confidence interval (CI) for this ratio will be reported.
Thus, there are 4 primary endpoints:
In fed condition
Cmax (suspension) / Cmax (capsule)
AUClast (suspension) /AUClast (capsule)
In fasted condition
Cmax (suspension) / Cmax (capsule)
AUClast (suspension) /AUClast (capsule)
Data from a previous study (ST10 01 101) were used to provide
estimates of the standard deviations (SDs) of the logs of the
within subject ratios of the parameters Cmaxand AUClast(between
formulations). Assuming the SD is no greater than 0.38, and that
the true ratio is 1, 20 subjects would provide a probability of at
least 80% of each individual confidence interval lying within (80%,
125%). Further assuming that all the 4 ratios to be reported are


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independent, 31 subjects would provide probability of at least
80% of all 4 confidence intervals lying within (80%, 125%). As the
SD is uncertain, 32 subjects will be recruited in the study.
Statistical Methods
For each of total serum iron, baseline corrected serum iron,
maltol, maltol glucuronide, TSAT, TIBC, UBIC and transferrin,
concentration data will be listed for each individual subject, by
formulation and condition (fed / fasted).
The data will be
summarized, for each of the four formulations/conditions, at
each time point by using the following descriptive statistics: n
(the number of subjects), arithmetic mean, standard deviation
(SD), geometric mean, coefficient of variation (CV), median,
minimum and maximum, and a 90% confidence interval (CI) for
the mean.
Concentration time courses of each analyte will be graphically
displayed per subject. For each feeding condition, plots of the
geometric mean concentration and its 90% CI, versus time, by
formulation, will be provided, overlaid.
For serum iron, baseline corrected serum iron, maltol, maltol
glucuronide, TSAT, TIBC, UIBC and transferrin, the PK parameters
(Cmax, Tmax, AUClast, AUCinf,
z, t½) will be listed and summarized,
for each of the four formulations/conditions, using the following
descriptive statistics: n, arithmetic mean, SD, geometric mean,
CV, median, minimum and maximum.
For total serum iron and baseline corrected serum iron, the
within subject ratios between the two formulations, in each of
the conditions (fed and fasted) of the parameters Cmax,AUClastand
AUCinf will be calculated per subject. These ratios will be
summarized by n, geometric mean and a 90% confidence interval
for the mean.
Safety
data
will
be
listed
and
summarized
for
each
formulation/condition.


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5 BACKGROUND INFORMATION
5.1 
OVERVIEW OF DISEASE
The gold standard for diagnosing IDA is an iron stain of the bone marrow aspirate. Because
bone marrow aspiration is too invasive to be used on a regular basis, the accepted and reliable
method of diagnosis is based on a combination of parameters, including hematological and
iron metabolism indices. Typically, decreased serum concentrations of hemoglobin (Hb) and
iron, mean corpuscular volume, ferritin concentration and transferrin saturation are
accompanied by increased total iron binding capacity, transferrin concentration, red blood
cell distribution width and erythrocyte protoporphyrin in comparison to age appropriate
reference ranges. Additionally, hypochromasia (meant by an excess of 10% of hypochromic
cells) is noted on the peripheral blood smear (Thayu & Mamula, 2005; Mamula et al, 2002).
However, diagnosing IDA in the setting of inflammatory disease (e.g. Inflammatory Bowel
Disease, IBD) may be complicated due to inflammation. In these circumstances, many of the
laboratory measures of iron status may be unreliable, as inflammation influences parameters
of iron metabolism (Thayu & Mamula, 2005). For instance, the elevation in transferrin levels
typical of iron deficiency may not be found, as patients with low albumin tend also to have
low transferrin concentrations. Similarly, serum iron, transferrin saturation (TSAT), total iron
binding capacity (TIBC) and zinc protoporphyrin levels are often difficult to interpret in the
presence of inflammation. Finally, circulating concentrations of the iron storage protein
ferritin, the most accessible and well known measure of stored iron and the most powerful
test for iron deficiency, can be normal or even increased in response to inflammation, as it is
an acute phase reactant, even in the presence of severe iron deficiency. Therefore, this
parameter may not provide adequate information about the storage compartment in the
setting of inflammatory conditions such as IBD, making it a less reliable marker because it
adds confusion to the clinical picture.
Accordingly, it has been suggested that specific diagnostic criteria for IDA need to be adapted
to the level of inflammation. Thus, in patients without biochemical (C reactive protein, etc.)
or clinical (diarrhea, endoscopic findings, etc.) evidence of inflammation, the cut off point for
defining a low level of serum ferritin is <30
g/L; however, in the presence of inflammation,
the lower limit of this parameter consistent with normal iron stores should be increased up
to 100 g/L.
The soluble transferrin receptor, a cell surface glycoprotein, is a truncated fragment of the
membrane receptor whose levels are increased when the availability of bone marrow iron
stores for erythropoiesis are low, as in IDA. As the circulating concentration is not affected by
anemia of chronic disease, increased concentration of soluble transferrin receptor and the
ratio of soluble transferrin receptor/log ferritin has been proposed for reliable differential
diagnosis of these overlapping conditions (Gasche et al, 2004). However, this assay is used
primarily as a secondary measure, because it is not yet widely available and published data
exist only for pediatric IBD (Weiss & Gasche, 2010).


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Other aids to the differentiation between IDA and anemia of chronic disease, essential in
order to provide the appropriate treatment, include quantification of reticulocyte
hemoglobin and the percentage of hypochromic red cells, which indicate the availability of
iron for erythroid progenitors, as well as determination of hepcidin in serum (Weiss & Gasche,
2010). While anemia of chronic disease is mostly normochromic and normocytic, IDA more
frequently presents as microcytic and hypochromic anemia.
5.2 
CURRENT TREATMENT OF DISEASE
There is a clear unmet medical need for an alternative oral treatment for anemic patients,
particularly those who are intolerant to ferrous sulfate, to avoid the need for IV iron therapy,
regardless of the cause of the iron deficiency. The proposed new pediatric oral suspension of
ferric maltol is being developed in the treatment of iron deficiency (with or without anemia).
The first approach to correct iron deficiencies is related to diet and lifestyle. Mild iron
deficiency can be corrected by increasing the intake of iron rich food (particularly that
containing the better absorbed haem iron), and by increasing the absorption of iron by
avoiding concomitant intake of tea (for example) or by concomitant ingestion of vitamin C.
The ultimate goal of dietary changes or pharmacological treatment is the return of
hemoglobin concentrations to the age appropriate reference range. The duration of
treatment should be sufficient to normalize not only the hemoglobin value but also the iron
stores. In the case of individuals with underlying diseases associated with IDA, the primary
disease must also be addressed, of course.
The mainstay of treatment of iron deficiency anemia is oral iron supplements. Ferrous
compounds (sulfate, fumarate and gluconate), which are available both in solid and liquid
forms, are the most common due to the extremely low bioavailability of conventional ferric
preparations. The usual adult dose is 180 mg of elemental iron/day in divided doses.
Therapeutic doses can range from 100 to 200 mg of elemental iron/day, depending on
severity of symptoms, ferritin levels, age of the patient, and gastrointestinal side effects.
Intramuscular iron compounds are not widely used due to the multiple side effects and the
existence of intravenous agents.
Intravenous iron preparations are considered treatment options after the failure of oral
therapy or in specific cases in which iron stores and the degree of anemia warrant acute
therapy. They sometimes become necessary in the case of active IBD (flare ups), for example,
because chronic inflammation inhibits iron absorption in the duodenum because of the
combined actions of hepcidin and TNF
(Weiss & Gasche, 2010). The major drawback
concerning intravenous iron is that tight physiological regulation of iron absorption is
bypassed, so there is an important risk for potential iron overload and associated toxicity.
Blood transfusions are widely used as an immediate intervention for rapid correction of
severe or life threatening anemia. However, such transfusions do not correct the underlying
pathology and do not have a lasting effect. The decision on whether to administer blood


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should not, therefore, be based only on the hemoglobin level, but should also take clinical
symptoms and co morbidity into account (Weiss & Gasche, 2010).
5.3 
OVERVIEW OF TEST PRODUCT
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 hematopoiesis and storage on ferritin. European Commission marketing
authorization was granted for Ferric Maltol in February 2016 and US FDA NDA approval was
granted on 25 July 2019. The currently approved dose is 30 mg twice daily (BID), taken in the
morning and evening on an empty stomach.
Unlike OFPs, which are often given with food in order to reduce side effects, Ferric Maltol
should, be given on an empty stomach to maximize 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.
Phase I studies (ST10 01 101 and ST10 01 102) in adults confirm that following absorption,
maltol undergoes rapid and complete first pass metabolism, is bio transformed to maltol
glucuronide, and excreted in the urine. This is consistent with the known metabolism and
excretion of maltol absorbed naturally from the diet (WHO, 1980; WHO, 2006).
Phase I study (ST10 01 103) in children and adolescents, aged 10 17 years was performed to
study 3 different doses of ferric maltol (7.8 mg, 16.6 mg and 30 mg BID) over a 10 day
treatment period. All 3 doses were well tolerated and had a favorable safety profile in this
population.
A new oral suspension formulation of ferric maltol has been developed to provide an age
appropriate formulation for pediatric subjects.
5.4 
DOSE SELECTION AND RESULTS OF PREVIOUS CLINICAL STUDIES
Ferric maltol is not absorbed systemically as an intact complex and traditional PK studies may
not provide the relevant information (Barrand 1991 a, b). Therefore, a model was developed
to determine the optimal dose. Data from 6 previous studies of Ferric Maltol in subjects with
IBD and IDA were used to estimate absorption rates in the study population. Using these
data, the model suggested that in a compliant adult population, 30 mg Ferric Maltol twice
daily would result in correction of baseline anemia in the majority of subjects. This has been
confirmed by the Phase 3 studies conducted to date (see below).


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5.4.1 Phase 3 studies in adults
ST10 01 301/302 study
A Phase 3 study has been completed in adult subjects with IDA and IBD, who are intolerant of
oral iron products or are unsuitable for treatment with them (ST10 01 301 and ST10 01 302;
Gasche, 2015; Schmidt, 2016), using a dose of 30 mg BID Ferric Maltol, or 60 mg elemental
iron total daily dose. 128 subjects were randomized to 12 weeks of blinded medication (30
mg BID Ferric Maltol or matched placebo capsule) followed by a 52 week open label
extension period; during which all available subjects received Ferric Maltol at the same dose.
87% and 82% Ferric Maltol and placebo treated subjects, respectively, completed the 12
week double blind period. The difference between the treatment groups in mean Hb from
baseline to week 12 was 2.25 g/dL (ANCOVA p<0.0001). Hb increased to normal values at
week 12 in 65% of Ferric Maltol group and 10% of placebo subjects. When the placebo
subjects were transferred to Ferric Maltol treatment in the open label phase, there was a
sharp rise in Hb levels that mirrored the response in the Ferric Maltol group in the double
blind phase.
There were further increases in Hb up to 48 weeks of treatment and no
indication of any reduction in efficacy over the full 64 week treatment period.
ST10 01 303 study
A double blind, randomized, placebo controlled study in 167 patients with Iron Deficiency
Anemia in Chronic Kidney Disease was performed in a 2:1 randomization. Ferric maltol 30 mg
capsules or matching placebo were administered bid for 16 weeks followed by open label
treatment with ferric maltol 30 mg capsules for up to an additional 36 weeks.
167 patients with IDA in Chronic Kidney Disease (CKD) over 16 week double blind phase and
an open label 36 week treatment in 125 subjects demonstrated positive safety, efficacy and
tolerability. Changes in TSAT, ferritin, and serum iron concentrations indicated an
improvement in all iron parameters in the ferric maltol group compared to the placebo group
and through the open label 36 week treatment period to Week 52.
The efficacy parameters in subjects originally in the placebo group moving to the ferric maltol
group during the open label 36 week treatment period mirrored the changes seen in the
ferric maltol group patients during the double blind 16 week treatment period. No clinically
significant accumulation was observed for either plasma maltol or plasma maltol glucuronide.
The results indicated that subjects with eGFR >30 mL/min/1.73 m2 may experience a greater
treatment effect. Indeed, this would be expected due to a likely lower erythropoietin
response to anemia in the subjects with more severe renal impairment.
The most common system organ class of study drug related TEAEs during the double blind
and open label period was GI disorders. Only three subjects experienced study drug related
adverse events that led to discontinuation in the double blind phase and 5 subjects in the
open label phase. Changes in laboratory values were mainly consistent with the disease
progression and all of them were considered as not related to study drug.


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In general, ferric maltol was well tolerated with only minor differences in the safety profile
and overall GI side effects compared to placebo.
5.4.2 Phase I studies in adults
ST10 01 101 study
Another open label, randomized Phase 1 study evaluated the pharmacokinetics of Ferric
Maltol and its effect on iron indices in patients with iron deficiency (with or without anemia).
24 subjects received Ferric Maltol 30, 60, or 90 mg BID over an 8 day period. PK and iron
uptake were assessed on Days 1 and 8. Ferric maltol showed predictable pharmacokinetics,
no accumulation over 7 days, and improvements in iron uptake across the dose range 30ʹ90
mg BID (Bokemeyer, 2016).
The PK data from this study are consistent with previous data indicating that maltol is rapidly
glucuronidated and renally excreted after ST10 dosing, while iron is independently absorbed.
Across the three dosing regimens investigated, exposure to maltol glucuronide increased
dose proportionally. Serum iron concentrations and TSAT values generally increased with
higher doses, but there was no clear relationship between these parameters and exposure to
maltol or maltol glucuronide. Higher NTBI levels were detected in the higher dosing regimens.
Although the frequency of AEs was also higher with these dosing regimens, there is no
evidence that this was a consequence of elevated NTBI in these subjects. The reported AEs
were consistent with the established safety profile of ST10.
ST10 01 102 study
The study results showed that plasma and urinary PK parameters for maltol and maltol
glucuronide were consistent with rapid metabolism of maltol to maltol glucuronide, followed
by renal excretion. Total serum iron and TSAT increased after ST10 dosing, although there
was no clear relationship between either of these parameters and exposure profile to maltol
or maltol glucuronide. There was no evidence of intact ST10 in serum samples, as measured
indirectly by NTBI, and there were no findings in this sub study that affected the safety profile
of ST10.
The low serum NTBI values are consistent with the safety profile of ST10. Unsurprisingly, given
the short duration, there were no significant safety findings in this sub study.
5.4.3 Phase I study in children and adolescents
ST10 01 103 study
An open label, randomized, Phase I study was completed in 37 children and adolescents (aged
10 17) after BID oral doses of 7.8 mg, 16.6 mg or 30 mg ferric maltol (ST10) over a 10 days
treatment period. Of the 37 subjects, there were 12 subjects in the 7.8 mg dose group, 13
subjects in the 16.6 mg dose group and 12 subjects in the 30 mg dose group. The primary
objective of the study was to assess the PK and iron uptake of these 3 doses, through


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measurement of serum iron, TSAT and plasma concentrations of maltol and maltol
glucuronide.
A one compartment model with first order absorption with TLAG and first order elimination
kinetics describes plasma maltol glucuronide PK for ferric maltol according to the current
data. The results showed that dose proportionality existed over the dose range tested in this
study, although the predicted Cmax of plasma maltol glucuronide on Day 10 slightly deviated
from dose proportionality.
The exposure of iron (Cmax and AUCs) was estimated using the NCA method with the predicted
iron concentrations and then dose proportionality was assessed using a power model. The
results showed that dose proportionality for iron did not exist over the dose range tested in
this study. The Day 1 iron exposure parameters increased less than dose proportionally
probably because of the plateauing effect observed between the 16.6 mg and 30 mg doses,
and the Day 10 iron exposure parameters were comparable across the 3 doses.
A direct effect linear model without intercept fit serum TSAT according to the current data.
The predicted response parameters of TSAT (Cmax, AUC Above_B, etc) were estimated using the
NCA method with the predicted TSAT. The response time profile had a similar pattern with
iron time profile.
Safety was assessed by evaluating TEAEs, SAEs, physical examinations, vital signs, 12 lead
ECGs, and laboratory parameters. In total, 20 (54.1%) subjects experienced a TEAE: 7 (58.3%)
subjects in the 7.8 mg dose group, 6 (46.2%) subjects in the 16.6 mg dose group, and 7 (58.3%)
subjects in the 30 mg dose group. Treatment emergent adverse events were mostly mild and
no subjects had a severe TEAE. One (7.7%) subject in the 16.6 mg dose group experienced a
TEAE of tonsillitis that led to withdrawal of study drug and study discontinuation; this event
was considered by the Investigator to be moderate in severity and not related to study drug.
No subjects died or experienced an SAE during the study.
No clinically meaningful differences in mean changes from baseline in hematology or clinical
chemistry parameters were noted between dose groups. Overall, individual shifts from
normal to abnormal in hematology and clinical chemistry laboratory parameters were
considered as not related to study drug and not clinically significant.
No subjects had laboratory abnormalities that were considered as TEAEs, SAEs, or led to
withdrawal of study drug or study discontinuation There were no clinically meaningful mean
changes from baseline in vital signs results or ECG parameters, and no subjects had clinically
significant abnormal ECG results. There was 1 abnormal, clinically significant physical
examination finding for the subject who had a TEAE of tonsillitis that led to withdrawal of
study drug and study discontinuation.
Refer to the Investigator Brochure for further information.


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5.5 
RATIONALE FOR THE STUDY
Clinical studies conducted to date, provide evidence for the effectiveness of Ferric Maltol in
adult patients with ID in IBD and CKD. Study ST10 01 301/2 demonstrated that ferric maltol
is effective and well tolerated in patients who are intolerant of OFPs or are otherwise
unsuitable for OFP treatment.
The existing scientific and clinical experience with ferric maltol in the treatment of ID/IDA in
adults supports its further investigation in the treatment of iron deficiency/IDA in children
and adolescents, in line with the Pediatric Investigation Plan (PIP) for Ferric Maltol that has
been reviewed and approved by the European Medicines Agency (PIP reference: EMEA
001195 PIP 01 11) and the FDA agreed initial Pediatric Study Plan (PSP) (IND: 114832).
By performing this Phase I crossover study, the exposure of the adult solid dose
pharmaceutical form (hard capsules) and the proposed pediatric oral suspension will be
compared to confirm therapeutic interchangeability. Ferric maltol capsules and the new oral
ferric maltol suspension will also be evaluated in fasted and fed conditions.
Because it is not ethical to perform non therapeutic Phase 1 studies in children, this study is
being completed using adult volunteer subjects.
5.5.1 Study Population
The study population will be healthy male and female subjects, aged between 18 and 55 yrs,
inclusive at the time of informed consent.
5.5.2 Study Treatment Duration
A treatment period of 4 days with at least 48 hours washout period between each dose
administration.
During the crossover PK phase, subjects will be randomized in a 1:1:1:1 ratio to receive one
of the following treatment sequences. 8 subjects will be randomized to each sequence:
Sequence A:
o Period 1; single dose of 30 mg ferric maltol capsule in a fed condition
o Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 3; single dose of 30 mg ferric maltol capsule in a fasted condition
o Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
Sequence B:
o Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 2; single dose of 30 mg ferric maltol capsule in a fed condition


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o Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 4; single dose of 30 mg ferric maltol capsule in a fasted condition
Sequence C:
o Period 1; single dose of 30 mg ferric maltol capsule in a fasted condition
o Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 3; single dose of 30 mg ferric maltol capsule in a fed condition
o Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
Sequence D:
o Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 2; single dose of 30 mg ferric maltol capsule in a fasted condition
o Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 4; single dose of 30 mg ferric maltol capsule in a fed condition
5.6 
RISK BENEFIT EVALUATION
The safety of Ferric Maltol in subjects with IDA and IBD has been established in a well
controlled Phase 3 clinical study with data having been collected over 12 weeks on 128
subjects in the double blind phase and for over 12 months in some subjects in open label
follow up (Gasche, 2015; Schmidt, 2016). The safety and tolerability of Ferric Maltol in adults
with IDA in IBD study was positive, with the overall AE rate in Ferric Maltol being comparable
to the Placebo group over a 12 week period; 87% of Ferric Maltol subjects remained in the
study. This data is supported by smaller published clinical studies using higher doses of Ferric
Maltol and by preclinical studies testing Ferric Maltol in rodents (see Investigator͛s Brochure).
The safety and tolerability study with Ferric Maltol in 167 subjects with CKD and IDA have
been positive with data collected over 16 weeks in a double blind phase. The TEAE was
comparable between the active (70.1%) and placebo group (75%) with the most commons
system organ class of GI disorders. Only three subjects experienced study drug related
adverse events that led to discontinuation. Overall, Ferric Maltol resulted in clinically and
statistically significant increase in Hb compared to placebo.
Previous Phase I PK study (ST10 01 101) was performed to describe the PK and iron uptake in
24 iron deficient subjects in three different dosing regimens (30, 60, 90 mg BID). The most
commonly reported TEAEs (29.2%) were GI disorders which were consistent with the medical
history of the subjects, who were recruited from specialist GI clinics. A single SAE was


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reported which led to discontinuation of the study but was not considered to be related to
study treatment.
The study population will recruit healthy subjects, male and female aged 18 and 55 yrs
inclusive at the time of informed consent. All eligible subjects will enter a 4 Period treatment
phase with 48 hrs washout between each dose administration. Subjects will either take a 30
mg ferric maltol as a capsule or 5 ml oral suspension according to the randomized sequences
on each Period Day 1.
PK assessments will take place for subjects to assess the effect, the safety and tolerability of
ferric maltol oral suspension and capsule. Study procedure risks are related to IV cannulation
and blood sampling, with fainting, minor bleeding and bruising. The individual volume of
blood collected throughout the study (screening and PK assessment days) will not exceed
335.5 mL, which is substantially below the volume of routine blood donation.
Pregnancy testing will ensure that pregnant female subjects do not enter the study, and that
any subjects who become pregnant during the study are detected.
The information gathered from this Phase I study will be very important in establishing the
interchangeability between ferric maltol capsules and oral suspension.
The risk to the subject related to study procedures has been assessed as very low, therefore
the risk benefit is considered acceptable.
Refer to the Investigator͛s Brochure for further details on risk/benefit assessment.


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6 STUDY OBJECTIVES AND ENDPOINTS
6.1 
PRIMARY OBJECTIVE
To evaluate the pharmacokinetics (PK) of iron absorption after a single 30 mg dose of
ferric maltol administered as capsule or oral suspension (fasted and fed conditions), via
primary parameters Cmax and AUClast.
6.2 
SECONDARY OBJECTIVES
To evaluate the pharmacokinetics (PK) after a single 30 mg dose of ferric maltol
administered as a capsule or oral suspension (fasted and fed conditions); through
measurements of transferrin saturation (TSAT), baseline corrected serum iron,
transferrin, total and unsaturated iron binding capacity (TIBC and UIBC), and plasma of
maltol and maltol glucuronide.
To assess the safety and tolerability after a single dose of 30 mg Ferric Maltol
administered as a capsule or oral suspension (fasted and fed conditions); based on vital
signs, adverse events, concomitant medications and routine clinical laboratory safety
blood tests.
6.3 
PRIMARY ENDPOINTS
1. PK analysis of total serum iron concentration; Cmax, AUClast in fasted and fed
conditions
6.4 
SECONDARY ENDPOINTS
1. PK analysis of total serum iron concentration; AUCinf in fasted and fed conditions
2. PK analysis of baseline corrected serum iron concentration; Cmax, AUClast, AUCinf in
fasted and fed conditions
3. PK analysis of maltol and maltol glucuronide in plasma; Cmax, AUClast in fasted and
fed conditions
4. PK analysis of TSAT, TIBC, UIBC, transferrin; Cmax, AUClastin fasted and fed conditions
5. Treatment emergent Adverse Events (TEAEs)
6. Serious Adverse Events (SAEs)


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7. Treatment emergent Adverse Events leading to premature discontinuation of study
drug/PK assessments
8. Clinical laboratory safety blood results
9. Changes in vital signs
10. Concomitant medications
6.5 
EXPLORATORY ENDPOINTS
Not Applicable


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7 INVESTIGATIONAL PLAN
7.1 
STUDY OVERVIEW
This is a, Phase I, randomized, open label, single dose, four way crossover study, to compare
the pharmacokinetics of iron and maltol absorption from ferric maltol capsules and oral
suspension under fasted and fed conditions in adult healthy volunteers
The study will comprise of the following stages:
 Screening: up to 14 days
 Randomized treatment:
A treatment period of 4 days with at least 48 hrs washout period between dose
administration.
During the crossover PK phase, subjects will be randomized in a 1:1:1:1 ratio to receive one
of the following treatment sequences. 8 subjects will be randomized to each sequence:
Sequence A:
o Period 1; single dose of 30 mg ferric maltol capsule in a fed condition
o Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 3; single dose of 30 mg ferric maltol capsule in a fasted condition
o Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
Sequence B:
o Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 2; single dose of 30 mg ferric maltol capsule in a fed condition
o Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 4; single dose of 30 mg ferric maltol capsule in a fasted condition
Sequence C:
o Period 1; single dose of 30 mg ferric maltol capsule in a fasted condition
o Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 3; single dose of 30 mg ferric maltol capsule in a fed condition
o Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
Sequence D:
o Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 2; single dose of 30 mg ferric maltol capsule in a fasted condition


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o Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 4; single dose of 30 mg ferric maltol capsule in a fed condition
Prior to the first treatment period, subjects will arrive at the Clinical Unit on Day 1 at least
13 hrs before dosing. After at least 10 hours overnight fasting at the Clinical Unit subjects
will be randomized to one of the 4 treatment sequences. PK samples will be collected pre
dose and up to 24 hrs post dose during each period (11 times) for the measurements of
serum iron, TSAT, TIBC, UIBC, transferrin, plasma maltol and maltol glucuronide.
On Day 1 subjects will receive standardized meals as well.
Subjects will stay at the Clinical Unit during the 4 treatment and 3 washout periods and
will be discharged on Day 8 following the last PK sampling timepoint. There will be at least
48 hours washout period between dose administrations.
- 
Post treatment safety follow up: Post study telephone follow up will be conducted 3 7
days following the Period 4 treatment day.
During early discontinuation a safety follow up at the Clinical Unit will be performed 3 7
days after the last study medication.
Refer to Section 10.1 for a schematic of the study design and Section 10.2 for a detailed
schedule of assessments.
7.2 
INVESTIGATIONAL SITES
Approximately 1 2 sites
7.3 
INCLUSION AND EXCLUSION CRITERIA
No deviations to the inclusion or exclusion criteria are permitted.
7.3.1 Inclusion Criteria
All of the following criteria must be met for a subject to participate in the study:
1. Must voluntarily sign and date each Institutional Review Board (IRB) approved
informed consent form (ICF) prior to the initiation of any screening or study specific
procedures.
2. Willing and able to comply with study requirements.
3. Healthy adult subjects 18 to 55 years of age, inclusive at the time of informed consent.
4. Body Mass Index (BMI) of 18 32 kg/m2 inclusive
5. Female subjects of childbearing potential must not be planning a pregnancy or be
pregnant or lactating. All female subjects must have a negative result for the
pregnancy tests performed at screening and each treatment period.


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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 1% per year when used consistently and
correctly, such as hormonal contraception (oral, implants, injection, ring, or patch) and
intrauterine contraceptive devices (IUDs), at least 3 months prior to Screening, or a
vasectomized partner.
Note: complete abstinence from sexual intercourse is an acceptable form of
contraceptive practice.
7. Female subjects of non childbearing potential must be either surgically sterile
(hysterectomy, bilateral, tubal ligation, bilateral salpingectomy, and/or bilateral
oophorectomy at least 26 weeks before the Screening Visit) or post menopausal,
defined as spontaneous amenorrhea for at least 2 years
Male subjects with partners of childbearing potential must have had surgical
sterilization (vasectomy) at least 26 weeks prior to Screening or use a male barrier
method of contraception (i.e. male condom with spermicide) during any sexual
intercourse from Study Day 1 (beginning of confinement) until 3 months after the
Follow up Visit.
Note: Complete abstinence from sexual intercourse is an acceptable form of
contraceptive practice.
8. Male subjects must agree to abstain from sperm donation from initial study drug
administration through 3 months after administration of the last dose of study drug.
7.3.2 Exclusion criteria
A subject who meets any of the following criteria is not eligible for participation in the study.
1. Known hypersensitivity or allergy to the active substance or excipients of Ferric maltol
oral suspension or capsules;
2. Presence or history of any significant cardiovascular, gastrointestinal, hepatic, renal,
pulmonary, hematologic, endocrine, immunologic, dermatologic, neurological, or
psychiatric disease, as determined by the Investigator;
3. Presence or history of any other condition (including surgery) known to interfere with the
absorption, distribution, metabolism, or excretion of medicines;
4. Recent (within 6 months of screening) history of drug or alcohol abuse;
5. Positive screen results for drugs of abuse, alcohol at screening or Study Day 1 of Period
1;


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6. Consumption of alcohol within 72 hrs prior to study drug administration;
7. Positive test result for hepatitis B surface antigen (HBSaAg), hepatitis C virus antibody
(HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening;
8. Donation or loss of 550 mL or more blood volume or receipt of a transfusions of any blood
product within 8 weeks prior to study drug administration and 14 days for plasma
donation unless medically inadvisable;
9. Use of any over the counter medications, including herbal product within 7 days prior to
Screening until study completion. Except for ordinary pain (e.g. headache), some
analgesics (mainly paracetamol) and contraception which have no drug interactions with
the study products may be given;
10. Has received within 28 days prior to Screening intramuscular or intravenous (IV) injection
or administration of depot iron preparation;
11. Has received oral iron supplementation within 7 days prior to Screening;
12. Has concomitant disease that would significantly compromise iron absorption or
absorbed iron utilization such as swallowing disorders, gastric pH disturbance and/or
extensive small bowel resection;
13. Scheduled or expected hospitalization and/or surgery during the course of the study;
14. Diagnosed to be COVID 19 positive by polymerase chain reaction testing (SARS CoV 2 RT
PCR positive) of a respiratory specimen (preferably a nasopharyngeal swab) on Day 2;
15. Participation in any other interventional clinical study within 28 days prior to Screening;
16. Any other unspecified reason that, in the opinion of the Investigator or the Sponsor makes
the subject unsuitable for enrolment.
7.4 
CONCOMITANT MEDICATION
7.4.1 Not Permitted
 Treatment with other oral iron preparations (prescription and non prescription) within 7
days prior to screening and throughout the study period;
 Treatment with parenteral iron preparations within 28 days prior to screening and
throughout the study period;
 Oral antibiotics, which are prohibited at screening and during the study;
 Blood transfusions within 12 weeks before screening and during the study;
 Erythropoiesis stimulating agents within 28 days before screening and during the study;
 Multivitamins within 7 days prior to screening and throughout the study period;
 Other prescription or over the counter medications, including herbal products from
screening until study completion.


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7.4.2 Permitted
 Oral contraceptives are allowed during the study, but the subjects must have been on a
stable dose for 3 months before randomisation;
 If necessary, medication used for treatment of any emergent AE at the discretion of the
Investigator may be given.
7.4.3 Potential Medication Interactions
Iron drug interactions of clinical significance have been reported to occur with a large number
of concomitant therapies. Concurrent ingestion of oral iron causes marked decrease in the
bioavailability of a number of drugs due to the formation of iron drug complexes (chelation
or binding of iron by the second drug). Examples of affected drugs are: IV iron, penicillamine,
bisphosphonates,
ciprofloxacin,
entacapone,
levodopa,
levofloxacin,
levothyroxine
(thyroxine) moxifloxacin, mycophenolate, norfloxacin, ofloxacin, tetracyclines, calcium and
magnesium salts, dimercaprol, chloramphenicol and methyldopa.
To minimize the potential for drug interactions, concomitant medications should be taken at
least 4 hrs after ferric maltol. The exact timing of any concomitant medication should be
recorded in the eCRF.
7.5 
INDIVIDUAL DISCONTINUATION 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 a Post Study Visit within 3 7 days at the Clinical
Unit after the last dose of study drug (if the subject agrees in the case of withdrawn consent).
Subjects may be discontinued prematurely during the study for the following reasons:
 Withdrawal of informed consent
 Unwillingness or inability to comply with protocol requirements
 Pregnancy or not using a reliable method of birth control (female subject of childbearing
potential)
 Use of prohibited concomitant medications
 Serious adverse events that are judged by the Investigator to be related to study
treatment
 Blood transfusions for any cause during the study treatment period
The reason for study drug discontinuation and the date of last dose should be recorded in the
eCRF. Subjects who discontinue treatment prematurely must return for the safety follow up


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at the Clinical Unit 3 7 days after last medication, unless informed consent is withdrawn (and
the subject do not agree to attend this visit follow up visit).
7.6 
STUDY TERMINATION
The Sponsor reserves the right to temporarily halt and/or terminate the study (or if
appropriate, individual treatment dose groups) at any time for safety, scientific or ethical
reasons including, but not limited to:
- 
Emerging safety concerns from this study, other ongoing studies with Ferric Maltol, or
new and relevant scientific information, which result in the risk benefit ratio for this
study becoming unfavorable, in the Sponsor͛s opinion.
- 
If the total number of dropouts is so high or the number of included subjects is so low
that completion of the trial will not realistically be expected within a reasonable
timeframe.
- 
If the Sponsor determines the study will no longer reveal new knowledge and
consequently is ethically no longer justifiable.
In case of an early termination of the study or temporary halt by the Sponsor, the IEC and CA
will be notified within 15 calendar days, including a detailed written explanation of the
reasons for the termination/halt.
In all circumstances connected with temporary halt and/or termination of the study, the
following principles will apply:
- 
All affected parties (such as the IEC, CA, Investigators, heads of study center/clinic
directors) must be informed as applicable according to local law.
- 
All study materials and supplies (except documentation that should remain stored at
site) must be returned to the Sponsor/designee.


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8 TREATMENT OF SUBJECTS
Healthy male and female subjects complying with the inclusion criteria and do not meet any
of the exclusion criteria will be randomly assigned to 4 treatment sequence. 8 subjects will be
randomized to each sequence:
Sequence A:
o Period 1; single dose of 30 mg ferric maltol capsule in a fed condition
o Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 3; single dose of 30 mg ferric maltol capsule in a fasted condition
o Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
Sequence B:
o Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 2; single dose of 30 mg ferric maltol capsule in a fed condition
o Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 4; single dose of 30 mg ferric maltol capsule in a fasted condition
Sequence C:
o Period 1; single dose of 30 mg ferric maltol capsule in a fasted condition
o Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 3; single dose of 30 mg ferric maltol capsule in a fed condition
o Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
Sequence D:
o Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o Period 2; single dose of 30 mg ferric maltol capsule in a fasted condition
o Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o Period 4; single dose of 30 mg ferric maltol capsule in a fed condition
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PRESENTATION
 5 ml (6 mg/ml elemental iron) ferric maltol oral suspension.
A full list of excipients can be found in the Investigator͛s Brochure.


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8.2 
COMPARATOR
 30 mg ferric maltol capsule
A full list of excipients can be found in the Investigator͛s Brochure.
8.3 
TREATMENT ASSIGNMENT AND BLINDING
The randomization procedure (created using a computer generated random permutation
procedure) will randomize the subject to one of the 4 treatment sequences to either
Sequence A Sequence B, Sequence C or Sequence D. The site will dispense the appropriate
formulation of open label ferric maltol bottles at each scheduled PK day according to the
schedule of assessments.
This is an open label study and treatment assignment is not blinded.
8.3.1 TREATMENT ASSIGNMENT AND ADMINISTRATION
Ferric maltol capsule and suspension fasted conditions:
Prior to the first treatment period, subjects will arrive at the Clinical Unit on Day 1 at least 13
hrs before dosing. Eligibility will be checked again before randomization and subjects will be
dosed after the 0 hrs baseline blood sample according to their randomized sequence.
Capsules should be taken with 240 ml potable tap water, must be swallowed whole and must
not be chewed, divided or crushed. 5 ml suspension will be measured out by using 2 x 3 ml
syringe, graduated up to 2.5 ml. Subject can take suspension with 240 ml potable tap water
if needed.
A hand and mouth check will be performed immediately after drug administration to ensure
that the study drug has been swallowed.
Water is allowed during the 10 hrs fasting but not allowed for 1 hr before and 2 hrs post dose
(except for drug administration). No food will also be allowed for at least 4 hours post dose.
Within 30 mins following the 4 hours post dose blood samples, subjects will receive a
standardized meal.
Blood samples will be taken at 11 additional times after dosing; post dose PK sample times
will be 15 mins ±2 min, 30 mins ±2 min, 45 mins ±5 min, 1 hr ±5 min, 1,5 hr ±5 min, 2 hrs ±5
min, 3 hrs ±5 min, 4 hrs ±5 min. 6 hrs ±10 min, 10 hrs ±15 min and 24 hrs ±15 min.
Standard meals will be provided to the subjects at 4, 8, 12 hrs after drug administration in the
morning. Meals will be identical in each treatment period. Iron content and time of
consumption of each meal will be recorded during the hospitalization in the eCRF.
Subjects will have the following mealtimes:
- 
Lunch will be served: approximately 4 hrs post dose
- 
Snack will be served: approximately 8 hrs post dose


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- 
Dinner will be served: approximately 12 hrs post dose
Subjects will stay in the Clinical Unit throughout the study period. During the washout,
subjects will stay at the Clinical Unit and receive standard meals. Iron content of the meals
will be measured and recorded in the eCRF.
Ferric maltol capsule and suspension fed conditions:
Prior to the first treatment period, subjects will arrive at the Clinical Unit on Day 1 at least 13
hrs before dosing. Eligibility will be checked again before randomization. Subjects will then
have their baseline blood samples taken and receive a test meal 30 minutes prior to
administration of ferric maltol. Subjects should finish their meal in 30 minutes or less;
however, ferric maltol will be administered 30 minutes after start of the meal. Capsules
should be taken with 240 ml potable tap water. Suspension can be taken with 240 ml potable
tap water if needed.
A hand and mouth check will be performed immediately after drug administration to ensure
that the study drug has been swallowed.
Water is allowed during the 10 hrs fasting but not allowed for 1 hr before and 2 hrs post dose
(except for drug administration). No food will also be allowed for at least 4 hours post dose.
Within 30 mins following the 4 hours post dose blood samples, subjects will receive a
standardized meal.
Blood samples will be taken at 11 additional times after dosing; the post dose PK sample times
will be 15 mins ±2 min, 30 mins ±2 min, 45 mins ±5 min, 1 hr ±5 min, 1,5 hr ±5 min, 2 hrs ±5
min, 3 hrs ±5 min, 4 hrs ±5 min, 6 hr ±10 min, 10 hrs ±15 min and 24 hrs ±15 min.
Standard meals will be provided to the subjects at 4, 8, 12 hrs after drug administration in the
morning. Meals will be identical in each treatment period. Iron content and time of
consumption of each meal will be recorded during the hospitalization.
Subjects will have the following meal times:
- 
Breakfast will be served 30 minutes prior to drug administration
- 
Lunch will be served: approximately 4 hrs post dose
- 
Snack will be served: approximately 8 hrs post dose
- 
Dinner will be served: approximately 12 hrs post dose
A test meal should consist of, 150, 250, and 500 600 calories protein, carbohydrate and fat
respectively. An example meal: 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with
butter, 4 ounces (113 g) of hash brown, potato and 8 ounces (227 ml) of water. Substitutions
in this test meal can be made as long as the meal provides a similar amount of calories from
protein, carbohydrate, and fat and has comparable meal volume and viscosity. If the meal is
different from the above mention, it should be documented in the eCRF.


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Subjects will stay in the Clinical Unit throughout the study period. During the washout,
subjects will stay at the Clinical Unit and receive standard meals. Iron content of the meals
will be measured and recorded in the eCRF.
8.3.2 WASHOUT PERIOD
Washout period lasts for at least 48 hrs between dose administration.
8.3.3 FOLLOW UP
Post study telephone follow up will be conducted 3 7 days following period 4 treatment day.
During early discontinuation a safety follow up at the Clinical Unit will be performed 3 7 days
after the last study medication.
8.4 
PACKAGING
Capsule: Ferric Maltol capsules will be supplied in a white polypropylene securitainer with a
tamper evident standard securitainer cap of white medium density polyethylene. Each bottle
will contain 56 capsules. Site staff will dispense 1 capsule for each subject according to the
randomization sequence group.
Oral suspension: Ferric maltol oral suspension will be supplied in 150 ml amber glass bottle
with an amber colored graduated syringe. Site staff will administer orally 5 ml oral suspension
according to the randomization sequence.
8.5 
STORAGE
Ferric maltol capsules and suspension must be stored below 25 °C and must not be frozen. In
the event that the drug is exposed to temperatures greater than or equal to 25°C, the
CRA/Sponsor should be contacted for review and further instruction.
8.6 
LABELLING
All bottles will be identified by a unique Bottle ID number. Bottles will be clearly labelled as
ferric maltol with the the strength indicated. Labels of the IMP will contain information
according to 21CFR Section 312.6.
Individual supplies packaging and labelling will be checked by the Investigator/designee
before the subject takes their dose of study medication at site on each PK day.
8.7 
TREATMENT COMPLIANCE
Subjects will be instructed to take the study drug as according to their individual
randomization sequence.
If the subject is non adherent, a decision will be made by the medical monitor and/or Sponsor
as to whether the subject should be withdrawn from the study treatment.


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The delivery of medication to the site, its use and return, as well as subject specific
compliance, will be reconciled and documented using a Drug Accountability Form in order to
monitor compliance with the medication schedule. All opened containers, together with
remaining contents, and unopened containers will be kept by the Investigator in a secure,
locked area until return to the drug supplier by the monitor or destruction by the site if agreed
with the Sponsor/designee. The Investigator will use the IMP only within the framework of
this clinical study and in accordance with the current, approved study protocol.
8.8 
CONTINUATION OF TREATMENT
The information gathered from this Phase I study will be very important in establishing the
interchangeability between ferric maltol capsules and oral suspension. Once this Phase I study
has been completed, the results will be submitted to the FDA prior to commencing the Phase
III Pediatric study. No further provisions are made for access to the study treatment under
this protocol.


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9 ENROLMENT AND RANDOMIZATION PROCEDURES
Full details of procedures will be provided in the Investigator Site File and eCRF Completion
Guidelines.
9.1 
SCREENING
Subjects will be evaluated according to the inclusion and exclusion criteria (Sections 7.3.1
and 7.3.2). Subjects will be deemed eligible for 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 subject͛s eCRF, medical notes and on the
study screening log.
A subject may be retested once for screening laboratory criteria that do not meet protocol
in/exclusion criteria initially, so long as randomization occurs no more than 14 days from
the initial Screening visit date (if eligible based on retest results).
9.2 
COVID 19 TESTING AND IMPLICATIONS ON THE TRIAL
All efforts will be made by the unit to avoid screening any subjects who might have a known
exposure to SARS CoV 2 or any symptoms suggestive of any infection with it by following
the guidelines provided by the Centers for Disease Control and Prevention (CDC) for
evaluating patients for COVID 19.
All subjects who remain qualified after their screening visit will get a respiratory specimen
(preferably a nasopharyngeal swab) on Day 2 which will be tested for SARS CoV02 RT.
Subjects diagnosed to be COVID 19 positive by the polymerase chain reaction testing will
not be admitted to the unit and excluded from the trial.
The inpatient portion of the admitted and randomized trial subjects will be conducted in
compliance with the most current guidelines for COVID 19 prevention at that time.
If there is an occurrence or suspicion (based upon signs and symptoms) of new COVID 19
infection in a subject after randomization, the subject may be withdrawn from the trial
treatment and procedures.
All COVID 19 positive test results will be recorded as an adverse event in the eCRF. The
subjects with known positive results or suspected COVID 19 will be advised to follow up
with their primary care physician or call the local health board for taking the appropriate
next steps for diagnosis and treatment of COVID 19.
Every attempt will be made to follow up with the adverse events via phone call to the
subject till known resolution or stabilization of the disease.
9.3 
RANDOMIZATION
Subjects will be assigned a unique 3 digit subject identification number at the Screening
visit.


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A final eligibility evaluation must be conducted by the Investigator/designee prior to
randomization, once the results of all Screening and Day 1 assessments are available. No
subject may begin treatment prior to being randomized. The randomization procedure
(created using a computer generated random permutation procedure) will randomize the
subject to one of the 4 treatment sequences.
9.4 
REPLACEMENT POLICY
Discontinuations after randomization for any reasons may be replaced at the discretion of
the Sponsor, in order to reach the agreed number of evaluable subjects for
pharmacokinetic endpoints. Up to a maximum of 4 subjects may be recruited to replace
early discontinuation.
9.5 
BLINDING PROCEDURES
Not applicable as this is an open label study.
9.6 
EMERGENCY UNBLINDING
Not applicable as this is an open label study.


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10 STUDY PROCEDURES
10.1 DESIGN SCHEMATICS
Subjects will be hospitalized from Period 1 Day 1 and discharged Period 4, following the 24 hrs post dose sampling.
Safety blood sampling will take place at Period 4 following the 24 hrs post dose sampling and 3 7 days post dose subjects will have a telephone safety
follow up. Subjects who discontinued early and did not withdrawn their consent, will need to attend a safety follow up 3 7 days after drug discontinuation.


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10.2 SCHEDULE OF ASSESSMENTS
PERIODS
SCREENING
PERIOD 1
Washout
PERIOD 2
Washout
PERIOD 3
Washout
PERIOD 4
Discharge 15
FOLLOW UP13
Study Day
Screening 1
2
1
1
2
3
4
5
6
7
8
10 14
Follow up
Informed Consent
X
Demographics
X
Medical History
X
Concomitant Medications and
Procedures 14
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
(X)
Vital Signs 2
X
X
X
X
X
X
(X)
ECG 16
X
Pregnancy Test 3
X
X
X
(X)
Blood sampling for Hepatitis
B, C and HIV 4
X
Urine test for drug screen 5
X
X
Alcohol breathalyzer 6
X
X
Haematology, Clinical
Chemistry and Iron markers
blood sampling 8
X
X
(X)
SARS CoV 2 RT PCR17
X
Eligibility Confirmation and
Randomization 7
X
X


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PERIODS
SCREENING
PERIOD 1
Washout
PERIOD 2
Washout
PERIOD 3
Washout
PERIOD 4
Discharge 15
FOLLOW UP13
Study Day
Screening 1
2
1
1
2
3
4
5
6
7
8
10 14
Follow up
Dispense Study Drug 10
X
X
X
X
Hospitalisation
X
Standardised supervised
meal 11
X
X
X
X
Standardised meal
X
X
X
X
X
X
X
X
Supervised morning dosing
with ferric maltol 12
X
X
X
X
PK Blood Sampling for Iron
markers, maltol/maltol
glucuronide 9
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Subject discharge of
hospitalisation 15
X
Telephone contact
X


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1. 
A subject may be retested once for screening laboratory criteria that do not meet protocol in/exclusion criteria, so long
as randomization occurs no more than 14 days from the initial screening date (if eligible based on retest results).
2. 
Vital Signs ʹsystolic/diastolic blood pressure, pulse rate and body temperature at each treatment day, to be taken after
subject has been sitting for at least 5 minutes
3. 
Pregnancy test for female subjects of childbearing potential. Serum pregnancy test at Screening and Urine pregnancy
test at Day 1 and Day 8 for female subjects of childbearing potential.
4. 
All subjects will have blood test at screening to show if they have been infected with Hepatitis C or HIV, or if they have
ever been infected with Hepatitis B and still have Hepatitis B in the subject`s system. HIV testing will be a 2 step process.
If the first test is positive, the blood will be tested again. Until the second test results are negative, subjects will not be
able to participate in the study.
5. 
Urine for drug test: 5 Panel Multi Line Test to detect amphetamines, cocaine, THC, opiates and PCP.
6. 
Breath test will be performed at Screening and at Period 1 Day 1 to measure the Breath Alcohol Content (BAC) of each
subject.
7. 
Eligibility central laboratory sampling/assessments must be completed at Screening and on Period 1 Day 1 before the
subject is randomized.
8. 
Hematology, Clinical Chemistry and screening Iron markers blood sampling
9. 
On all four PK study days, all subjects will have baseline PK blood samples collected immediately prior to Ferric Maltol
dosing (0 hr). Subjects will then have further PK blood samples collected at 11 additional times after dosing; the post
dose PK sample times will be 15 mins ±2 min, 30 mins ±2 min, 45 mins ±5 min, 1 hr ±5 min, 1,5 hr ±5 min, 2 hrs ±5 min,
3 hrs ±5 min, 4 hrs ±5 min, 6 hr ±10 min, 10 hrs ±15 min and 24 hrs ±15 min. For each individual subject, the post dose
PK blood sampling schedule will be the same on all four PK days. PK blood samples on the PK days will be: serum iron,
total and unsaturated iron binding capacity (TIBC, UIBC), transferrin, transferrin saturation (TSAT), maltol and maltol
glucuronide.
10. Drug dispensing: subjects will be randomized to either Sequence A, B, C or D
Sequence A:
o 
Period 1; single dose of 30 mg ferric maltol capsule in a fed condition
o 
Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o 
Period 3; single dose of 30 mg ferric maltol capsule in a fasted condition
o 
Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
Sequence B:
o 
Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o 
Period 2; single dose of 30 mg ferric maltol capsule in a fed condition
o 
Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o 
Period 4; single dose of 30 mg ferric maltol capsule in a fasted condition
Sequence C:
o 
Period 1; single dose of 30 mg ferric maltol capsule in a fasted condition
o 
Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o 
Period 3; single dose of 30 mg ferric maltol capsule in a fed condition
o 
Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
Sequence D:
o 
Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition
o 
Period 2; single dose of 30 mg ferric maltol capsule in a fasted condition
o 
Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition
o 
Period 4; single dose of 30 mg ferric maltol capsule in a fed condition
11. A test meal should consist of, 150, 250, and 500 600 calories protein, carbohydrate and fat respectively. An example
meal: 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces (113 g) of hash brown, potato and 8
ounces (227 ml) of water. Substitutions in this test meal can be made as long as the meal provides a similar amount of


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calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity. If the meal is different from
the above mention, it should be documented in the eCRF.
Subjects will have their test meal supervised by site staff.
12. Ferric maltol capsule and suspension fasted conditions: Prior to the first treatment period, subjects will arrive at the
Clinical Unit on Day 1 at least 13 hrs before dosing. Eligibility will be checked again before randomization and subjects
will be dosed after the 0 hrs baseline blood sample according to their randomized sequence. Capsules should be taken
with 240 ml potable tap water, must be swallowed whole and must not be chewed, divided or crushed. Suspension can
be taken with 240 ml potable tap water if needed. A hand and mouth check will be performed immediately after drug
administration to ensure that the study drug has been swallowed. Water is allowed during the 10 hrs fasting but not
allowed for 1 hr before and 2 hrs post dose (except for drug administration). No food will also be allowed for at least 4
hours post dose. Within 30 mins following the 4 hours post dose blood samples, subjects will receive a standardized
meal.
Blood samples will be taken at 11 additional times after dosing; post dose PK sample times will be 15 mins ±2 min, 30
mins ±2 min, 45 mins ±5 min, 1 hr ±5 min, 1,5 hr ±5 min, 2 hrs ±5 min, 3 hrs ±5 min, 4 hrs ±5 min. 6 hrs ±10 min, 10 hrs
±15 min and 24 hrs ±15 min.
Standard meals will be provided to the subjects at 4, 8, 12 hrs after drug administration in the morning. Meals will be
identical in each treatment period. Iron content and time of consumption of each meal will be recorded during the
hospitalization in the eCRF.
Subjects will have the following mealtimes:
- 
Lunch will be served: approximately 4 hrs post dose
- 
Snack will be served: approximately 8 hrs post dose
- 
Dinner will be served: approximately 12 hrs post dose
Ferric maltol capsule and suspension fed conditions: Prior to the first treatment period, subjects will arrive at the Clinical
Unit on Day 1 at least 13 hrs before dosing. Eligibility will be checked again before randomization. Subjects will then
have their baseline blood samples taken and receive a meal 30 minutes prior to administration of ferric maltol. Subjects
should finish their meal in 30 minutes or less; however, ferric maltol will be administered 30 minutes after start of the
meal. Capsules should be taken with 240 ml potable tap water. Suspension can be taken with 240 ml potable tap water
if needed. A hand and mouth check will be performed immediately after drug administration to ensure that the study
drug has been swallowed. Water is allowed during the 10 hrs fasting but not allowed for 1 hr before and 2 hrs post dose
(except for drug administration). No food will also be allowed for at least 4 hours post dose. Within 30 mins following
the 4 hours post dose blood samples, subjects will receive a standardized meal.
Blood samples will be taken at 11 additional times after dosing; the post dose PK sample times will be 15 mins ±2 min,
30 mins ±2 min, 45 mins ±5 min, 1 hr ±5 min, 1,5 hr ±5 min, 2 hrs ±5 min, 3 hrs ±5 min, 4 hrs ±5 min, 6 hr ±10 min, 10
hrs ±15 min and 24 hrs ±15 min.
Standard meals will be provided to the subjects at 4 and 8 hrs after drug administration in the morning. Meals will be
identical in each treatment period. Iron content and time of consumption of each meal will be recorded during the
hospitalization.
A hand and mouth check will be performed immediately after drug administration to ensure that the study drug has
been swallowed.
Subjects will have the following mealtimes:
- 
Breakfast will be served 30 minutes prior to drug administration
- 
Lunch will be served: approximately 4 hrs post dose
- 
Snack will be served: approximately 8 hrs post dose
- 
Dinner will be served: approximately 12 hrs post dose
Subjects will receive standardised meal during the study period and iron content will be measured and recorded in the
eCRF.
13. Post study telephone follow up will be conducted 3 7 days following Period 4 treatment day.  Subjects who discontinue
from the study prematurely should have final assessments conducted per /Post study Safety Follow Up at the Clinical
Unit, unless consent is withdrawn.
14. To minimize the potential for drug interactions, concomitant medications should be taken at least 4 hrs after ferric
maltol. The exact timing of any concomitant medication should be recorded in the eCRF.


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15. Subject will be discharged from the Clinical Unit following the 24 hrs blood sampling in Period 4 (Day 8), providing the
Investigator has no ongoing safety concerns
16. ECG ʹ machine reported ECG parameters and overall clinical ECG interpretation will be recorded in the eCRF. ECG to be
obtained after the subject has been supine for at least a 10 minute rest.
17. SARS CoV 2 RT PCR will be performed on Day 2. Subjects with only negative results will be able to admit to the Clinical
Unit on Day 1.
10.3 DEMOGRAPHICS AND MEDICAL HISTORY
The following will be documented at Screening and updated (if required) prior to
randomization: Date of Birth, race and ethnicity, gender, all current medical conditions, all
clinically significant medical history from the past 5 years including all malignancies,
sterilizations, hospitalizations and surgeries; the method of contraception for female subjects
of childbearing potential, if applicable. Body weight (Kg), height (m) will be measured at the
Screening visit only.
10.4 PHYSICAL EXAMINATION
A brief physical examination is to be conducted to assess safety. The examination should
include an assessment of general appearance, skin, head, eyes, ears, nose and throat,
cardiovascular, respiratory, abdominal, gastrointestinal and musculoskeletal systems.
10.5 CONCOMITANT MEDICATIONS AND PROCEDURES
The following will be documented at Screening and updated (if required) prior to
randomization: all current medications at the time of Screening or stopped within 3 months
of screening and any medical procedure performed within 3 months prior to Screening.
The following will be documented throughout the study: any medications initiated, stopped
or with dose and/or frequency changes throughout the study. Any medical procedure
performed throughout the study.
Medical procedures to be documented are any therapeutic intervention such as
surgery/biopsy, physical therapy or diagnostic assessment (e.g. blood gas measurement).
To minimize the potential for drug interactions, concomitant medications should be taken at
least 4 hrs after ferric maltol. The exact timing of any concomitant medication and its iron
content should be recorded in the eCRF.
10.6 VITAL SIGNS
Body temperature (°C), blood pressure and pulse rate will be assessed at Screening for all
subjects on all four PK days at pre dose. Blood pressure and pulse rate should be measured
after the subject has been sitting for at least 5 minutes at Screening visit and at each PK days
pre dose.


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10.7 LABORATORY ASSESSMENTS
10.7.1 Hematology and Clinical Chemistry
Routine clinical laboratory safety bloods for hematology (3.0 mL) and clinical chemistry/iron
markers (7.5 mL) evaluations will be collected at Screening to assess eligibility. Hematology
(3 mL) and clinical chemistry (5.0 mL) will be repeated at Period 4; 24 hrs post dose sampling
or at the Follow up visit for early discontinued subjects. Additional testing may be required
if any abnormal value is reported and this must be followed until it is resolved.
All analyses will be conducted by a central laboratory. Procedures for the collection,
processing, storing, and transporting of samples to the laboratory will be fully described in
the study specific Laboratory Manual.
Investigators will review, sign and date all lab results upon receipt from the central laboratory.
If a value is flagged as outside of the normal range, the Investigator must document the
abnormality as ͚clinically significant͛ (CS) or ͚non clinically significant͛ (NCS). Any lab
abnormality assessed as ͚CS͛ must be recorded as an AE if not explained by a pre existing
condition (documented in the medical history).
The signed paper copy of the laboratory report is retained at the investigational site. The
electronic data transferred from the central laboratory database to the clinical study database
will be considered source data for the derivation of summary data and listings presented in
the clinical study report.
10.7.1.1 Hematology test parameters
Red blood cell count, hemoglobin, hematocrit, white blood cell count (total and differential
(% and absolute), absolute reticulocyte count and platelet count.
10.7.1.2 Clinical Chemistry and Screening Iron Markers test parameters
Clinical Chemistry: ALT, AST, alkaline phosphatase, gamma glutamyl transpeptidase (GGT),
total bilirubin, creatinine, blood urea nitrogen (BUN), sodium, potassium, chloride, calcium,
total cholesterol, uric acid, glucose, total protein, albumin, bicarbonate, LDH, CK, triglycerides
Iron Markers: serum iron, transferrin, transferrin saturation (TSAT), total and unsaturated iron
binding capacity (TIBC, UIBC).
10.7.2 Pharmacokinetics
Blood samples for maltol and maltol glucuronide on PK days
4 ml venous blood samples will be collected in lithium heparin tubes by indwelling cannula or
venipuncture at the required times on the PK assessment days relative to the time of ferric
maltol morning dosing: pre dose then 11 further times between 0.15 to 24 hours post dose
(10.2).


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Following collection and mixing, blood samples will be centrifuged, and the resultant plasma
samples separated and stored at 20°C at the study site, prior to collection and onward
transfer to the central laboratory on dry ice for subsequent assay of maltol and maltol
glucuronide plasma concentrations using appropriately validated bioanalytical methods. Full
details of the required sample collection, processing and handling logistics will be specified in
the study specific Laboratory Manual. Samples will be destroyed at the end of the study, once
all analyses are complete.
Blood samples for iron markers on PK days
2.5 mL venous blood samples will be collected in serum separator tubes (SST) by indwelling
cannula or venipuncture at the following times on the PK assessment days, relative to the
time of ferric maltol dosing: pre dose then 11 further times between 0.15 24 hours post dose
(same times as blood samples for maltol/maltol glucuronide for each individual, section 10.2).
Following collection and mixing, blood samples will be centrifuged, and the resultant serum
samples separated and split into 1 primary (ambient) and 1 frozen ( 20°C) aliquots at each
timepoint. Ambient serum samples will be shipped to the central laboratory for subsequent
assay of serum iron, transferrin, transferrin saturation (TSAT), total and unsaturated iron
binding capacity (TIBC, UIBC).
Full details of the required sample collection, processing and handling logistics will be
specified in the study specific Laboratory Manual. Samples will be destroyed at the end of
the study, once all analyses are complete.
10.7.3 Hepatitis B, C and HIV test
All subjects will have blood test (5 ml) at screening to show if they have been infected with
Hepatitis C or HIV, or if they have ever been infected with Hepatitis B and still have Hepatitis
B in the subject`s system. HIV testing will be a 2 step process. If the first test is positive, the
blood will be tested again. Until the second test results are negative, subjects will not be able
to participate in the study.
10.7.4 Urine Drug test
A 5 panel Multi Line Test will also be conducted at Screening to detect amphetamines,
cocaine, THC, opiates and PCP.
10.7.5 Pregnancy Test
Females of childbearing potential only. A serum pregnancy test should be conducted at the
Screening visit to assess eligibility using the test kits provided by the central laboratory. A
urine pregnancy test will be conducted at Period 1, Day 1 and Period 4 Day 8 following the
24 hrs post dose blood sampling.


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Full details of the required sample collection and processing procedures will be described in
the study specific Laboratory Manual.
10.7.6 Breath Alcohol Content Test
Each subject will have a breath alcohol content test at screening and Period 1, Day 1.
10.7.7 COVID 19 Testing
COVID 19 polymerase chain reaction testing (SARS CoV 2 RT PCR) of a respiratory specimen
(preferably a nasopharyngeal swab) will be performed on Day 2.
10.7.8 ECG
Machine reported standard ECG with overall clinical ECG interpretation will be recorded at Screening
in the eCRF.
10.7.9 Overall blood volume
The individual volume of blood collected throughout the study (Screening, PK assessment and
Safety Follow up) will be approximately 335.5 ml.
Number of blood samples
Total number of samples per period: 12 PK timepoints, 1 pre dose and 11 post dose.
Volume per blood sample
Screening: 15.5 ml
Total blood volume per PK day including 24 hrs post dose (Period 1, Period 2, Period 3): 78 ml
Total blood volume per PK day including 24 hrs post dose (Period 4, including safety follow
up blood samples): 86 ml
Total blood volume per subject: 335.5 ml


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11 SAFETY
11.1 DEFINITIONS
11.1.1 ADVERSE EVENT (AE)
An AE is any untoward medical occurrence in a subject administered a pharmaceutical
product and does not necessarily have a causal relationship with this treatment. An AE can
therefore be any unfavorable or unintended sign or symptom, intercurrent illness, injury, or
any concomitant impairment of the subject͛s 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:
ͻ 
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.
ͻ 
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.
ͻ 
Events considered by the Investigator to be related to study mandated procedures.
ͻ 
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.
ͻ 
Signs, symptoms of a suspected drug interaction.
ͻ 
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:
ͻ 
Medical or surgical procedure, e.g., surgery, appendectomy, endoscopy, tooth
extraction, transfusion (as these are treatments for an AE). However, the event
resulting in the procedure is the AE (e.g. appendicitis, abdominal pain).
ͻ 
Pre existing disease or medical condition documented at baseline that does not
worsen.


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ͻ 
Situations in which an adverse change did not occur, e.g., hospitalizations for
cosmetic elective surgery or for social and/or convenience reasons.
ͻ 
Anticipated day to day fluctuations or seasonal fluctuations (e.g. allergic rhinitis) of
pre existing disease(s) or condition(s) documented at baseline.
ͻ 
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 subject͛s condition.
ͻ 
Overdose of either study drug or concomitant medication without any signs or
symptoms.
11.1.2 SERIOUS ADVERSE EVENT (SAE)
An SAE is any untoward medical occurrence between the time of consent and the subject͛s
final visit that:
ͻ 
is fatal,
ͻ 
is life threatening,
ͻ 
requires inpatient hospitalization or prolongation of existing hospitalization,
ͻ 
results in persistent or significant disability/incapacity,
ͻ 
results in a congenital anomaly/birth defect or
ͻ 
is otherwise judged as medically significant (may jeopardize 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 hospitalization: Subject has to stay in hospital at least overnight. The following
reasons for hospitalizations are not considered AEs, and therefore not SAEs:
 Hospitalizations 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., hospitalization 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., hospitalization for chemotherapy for cancer, elective hip replacement for
arthritis, vein stripping for preventive and/or cosmetic purpose.
Prolongation of hospitalization: Complications that occur during hospitalization are AEs.
However, if a complication prolongs hospitalization or would have required hospitalization 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 hospitalization. When in


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doubt as to whether ͞prolongation of hospitalization͟ was necessary, the AE should be
considered serious.
Significant disability: The term significant disability means that there is a substantial
disruption of a person͛s 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 hospitalization 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 hospitalization, or development of drug
dependency or drug abuse.
SAE related to study mandated procedures: Such SAEs are defined as SAEs that appear to
have a reasonable possibility of causal relationship (i.e., a relationship cannot be ruled out)
to
study mandated
procedures
(excluding
administration
of
study
drug)
such
as
discontinuation of subject's previous treatment during a washout period, or complication of
a mandated invasive procedure (e.g., blood sampling, heart catheterization), or car accident
on the way to the hospital for a study visit, etc.
11.2 REPORTING AND DOCUMENTATION
AEs should be documented in terms of a medical diagnosis. When this is not possible, the AE
should be documented in terms of signs and/or symptoms observed by the Investigator or
reported by the subject at each study visit.
Any pre existing conditions or signs and/or symptoms present in a subject prior to the start
of the study should be recorded on the Medical History CRF.
All SAEs that occur after informed consent is obtained through study completion or
premature discontinuation must be reported on the SAE form in the CRF and reported within
24 hours to the Sponsor. All AEs occurring from the time of the first dose of study treatment
through study completion or premature discontinuation must be reported on the AE form in
the CRF. For AEs related to COVID 19 testing, see section 9.2.
Any SAE that occurs during the clinical study or within two weeks of receiving the last dose of
study drug, whether or not related to the study drug, must be reported to the Sponsor.


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


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As soon as the Sponsor is informed about an SAE, an evaluation and potential reporting to
central IRBs/IECs, Competent Authorities (CA) and other concerned parties will occur as
required. The Investigator will be responsible for reporting to any local IRB/IEC as required.
11.2.2 Non Immediate Reporting
AEs that do not qualify for immediate reporting will be documented in the eCRF and reported
in the Clinical Study Report (CSR).
11.3 EVALUATION
AEs and the corresponding entries in the eCRF will be reviewed by the Investigator or qualified
member of the study staff. Adverse events, toxicities and medical surgery/history will be
categorized by primary system organ class (SOC) and preferred term using the MedDRA
dictionary. Toxicities will also be graded as mild, moderate or severe.
11.3.1 Intensity
The intensity will be rated by the Investigator as ͞mild͟, ͞moderate͟ or ͞severe͟:
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
subject͛s 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 hospitalization.
11.3.2 Causality
The following should be considered when evaluating the relationship of AEs and SAEs to the
study treatment:
Not related: There is not a possibility that the event has been caused by the product under
investigation. Consideration should be given to factors, including but not limited to, a lack of
reasonable temporal relationship between administration of the drug and the event, the
presence of a biologically implausible relationship between the product and the AE (e.g. the
event occurred before administration of drug), or the presence of a more likely alternative
explanation for the AE.


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Related: There is a possibility that the event may have been caused by the product under
investigation. Consideration should be given to factors, including but not limited to a positive
re challenge, a reasonable temporal sequence between administration of the drug and the
event, a known response pattern of the suspected drug, improvement following
discontinuation or dose reduction, a biologically plausible relationship between the drug and
the AE or a lack of an alternative explanation for the AE.
11.3.3 Outcome
The outcome of each AE has to be assessed as follows:
ͻ 
Fatal: The AE resulted in death (͞Death͟ is recorded as an outcome, not as the AE)
ͻ 
Ongoing/Not resolved: The AE has not resolved
ͻ 
Recovered with sequelae: Resolution of the AE has occurred, but the subject retains
some sequelae
ͻ 
Recovered: The AE fully resolved with no observable residual effects
ͻ 
Unknown: The outcome of the AE is not known as the subject did not return for
follow up and attempts to locate the subject and/or to obtain follow up information
were unsuccessful (lost to follow up).
11.4 RE EXPOSURE
If an AE requires discontinuation of IMP and is judged to be treatment related by the
Investigator or by the Sponsor, re exposure is not allowed. If an AE requires dose reduction
or discontinuation of IMP and is judged by the Investigator or by the Sponsor to be unrelated
to investigational products, the decision to re introduce the medication or to increase the
dose of the medication requires prior approval of the Sponsor or designee.
11.5 SAFETY ENDPOINTS
During the study, safety endpoints will be treatment emergent AEs and SAEs, including
clinically significant changes from baseline in vital signs, physical examination and routine
clinical laboratory abnormalities.


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12 STATISTICAL CONSIDERATIONS
12.1 SAMPLE SIZE AND POWER CALCULATIONS
The sample size is based on the comparisons of each of the primary PK parameters Cmax and
AUClast for total serum iron between the formulations, within each of the two conditions: fed
and fasted. Each comparison will be made via the ratio of the two values of the parameter
between the formulations. The 90% confidence interval (CI) for this ratio will be reported.
For each of the two comparisons (suspension vs capsule (fed condition); suspension vs
capsule (fasted condition)) the CIs for two parameter ratios (Cmax and AUClast) for serum iron
will be calculated, making a total of 4 CIs. If these ratios were all independent, and the
probability of being within (80%, 125%) was 80% for each, then the probability that all 4 would
fall within the required limits would be (80%)4 = 41%. With individual probabilities of 90%,
the combined probability would be 66%. However, if the ratios were positively correlated,
the combined probabilities would be higher.
Data from a previous study (ST10 01 101) were used to provide estimates of the standard
deviations (SDs) of the logs of the within subject ratios of the parameters Cmax and AUClast, for
both total serum iron and TSAT. Assuming the SD is no greater than 0.38, if the true ratio is 1,
31 subjects would provide a probability of at least 80% of all 4 CIs lying within (80%, 125%).
The aim of the study is to demonstrate that the 4 CIs for serum iron are all within (80%, 125%).
As the SD, and the degree of correlation, are uncertain, 32 subjects will be recruited to the
study.
12.2 STATISTICAL METHODS
For each of serum iron, maltol, maltol glucuronide, TSAT, TIBC, UBIC and transferrin,
concentration data will be listed for each individual subject, by formulation / condition. The
concentration data will be summarized, for each formulation / condition, at each time point
by using the following descriptive statistics: n (the number of subjects), arithmetic mean,
standard deviation (SD), geometric mean, coefficient of variation (CV), median, minimum and
maximum, and a 90% confidence interval (CI) for the mean.
Concentration time courses of each component will be graphically displayed per subject.
Plots of the geometric mean and its 90% CI, by formulation, will be provided, overlaid, for
each condition separately.
For serum iron, baseline corrected serum iron, maltol, maltol glucuronide, TSAT, TIBC, UIBC
and transferrin, PK parameters (Cmax, Tmax, AUClast, AUCinf,
z, t½) will be calculated by non
compartmental analysis and listed by subject and by period.
The parameters will be
summarized, for each formulation / condition, by using the following descriptive statistics: n,
arithmetic mean, SD, geometric mean, CV, median, minimum and maximum.


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For each analyte, the within subject ratios between capsule and suspension of Cmax, AUClast
and AUCinf will be also be calculated and listed per subject, for each of the fed and fasted
conditions separately.
These ratios will be summarized by n, geometric mean and a 90%
confidence interval for the mean.
Other endpoints and safety data will be listed and summarized for each formulation.
Full details will be specified in the Analysis Plan prior to database lock.
All secondary endpoints will be summarized by formulation / condition:
1. Treatment emergent Adverse Events (TEAEs)
2. Serious Adverse Events (SAEs)
3. Treatment emergent Adverse Events leading to premature discontinuation of study
drug/PK assessments
4. Routine clinical laboratory safety blood results
5. Changes in vital signs
6. Concomitant medications
12.2.1 Sensitivity Analyses
Any planned sensitivity analyses will be documented in the SAP prior to database lock.
12.2.2 Imputation of Missing Data
All data will be used according to availability, with no imputation for missing data.
12.3 DEFINITION OF POPULATIONS
12.3.1 Randomized Population
All subjects who are randomized.
12.3.2 Safety Population
All subjects who have had at least one dose of study drug and one subsequent contact with
the Investigator will be analyzed for safety.
12.3.3 Full Analysis Set
All subjects who have had at least one dose of study drug and who have at least one evaluable
post dose PK sample will be included in the FAS population. This population will be utilized
for the PK Analysis.


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13 ETHICAL CONSIDERATIONS
The Sponsor and Investigator must comply with this protocol, all applicable national and local
regulations including International Conference on Harmonization (ICH) and Good Clinical
Practice (GCP).
13.1 DECLARATION OF HELSINKI
The Sponsor and the Investigator must comply with the principles set forth by the Declaration
of Helsinki dated October 2008.
13.2 INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE
The Investigator must ensure that the IRB/IEC has approved the protocol, the Information
Sheet and Consent 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/IEC.
Prior to activation of a site and provision of IMP, the Sponsor must receive documentation to
demonstrate IRB/IEC approval of the required study documents and must have completed a
comprehensive site initiation training with the Investigator and site staff.
A progress report must be submitted to the IRB/IEC at least annually and more frequently if
required by the IRB/IEC.
On completion or termination of the study the Investigator or Sponsor must submit a closeout
letter to the IRB/IEC (as required). A copy of the CSR synopsis will also be sent in accordance
with local laws.
13.3 SUBJECT INFORMATION AND INFORMED CONSENT
IRB/IEC approval of the written information sheet and consent 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 forms.
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.


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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 at
site. A description of the consent process must be documented in the subject͛s medical
record.
13.4 SUBJECT DATA PROTECTION
Prior to any study test being conducted, including Screening tests, the subject must provide
authorization as required by local law, eg. PHI. Subjects will not be identified by name (or
initials) in the eCRF or any study reports. Data will be used for research purposes only. Every
effort will be made to keep the subject͛s personal medical data confidential. All data will be
used for research purposes only.
13.5 SUBJECT INSURANCE
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow
applicable local compensation laws.
13.6 CONFLICT OF INTEREST
Investigators should address any potential conflicts of interest (e.g. financial interest in the
Sponsor) with the subject before the subject makes a decision to participate in the study.
13.7 REGISTRATION OF STUDY AND DISCLOSURE OF RESULTS
The Sponsor will register the study on all required registries (e.g. clinicaltrials.gov) and will
post study results regardless of outcome on publicly accessible websites in accordance with
the applicable laws and regulations.


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


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14.4 STUDY FUNDING
Shield TX (UK) Limited is the Sponsor and provides funding for the conduct of this study. All
financial details are provided in clinical trial agreements between the institution, Investigator
and Sponsor.
14.5 CONTRACT RESEARCH ORGANIZATION (CRO)
A CRO (Medpace Inc.) will be contracted to be responsible for administrative aspects of the
study including, but not limited to, site selection and qualification, study set up, site initiation,
monitoring, data management including clinical database and electronic CRF provisioning,
statistics and programming and study reporting. Vendors will also be contracted to cover
supportive services such as a central laboratory, bioanalysis of PK samples and IMP
production/labelling.
14.6 AMENDMENTS TO THE STUDY PROTOCOL
The study will be conducted in compliance with this Protocol, as approved by all relevant
parties. Should any amendments to the protocol be deemed necessary, this will be resolved
by mutual written agreement between the Principal Investigator and the Sponsor.
Any significant changes to the protocol shall be submitted to the IRB/IEC and Regulatory
Authorities and must be approved prior to implementation as required by local law.
However, the Sponsor may, at any time, amend this protocol to eliminate an apparent
immediate hazard to a subject. In this case, appropriate communications and notifications to
the IRB/IEC and Regulatory Authorities will occur as required by local law.
Amendments to the Information Sheet and Consent Form will be made if impacted by an
amendment to the study protocol which will also be submitted and approved to the IRB/IEC
as required by local law.
14.7 STUDY STOPPING RULES
The Sponsor may terminate this study at any time. In consultation with the Investigator it is
normal procedure to review the emerging clinical and safety data (section 7.6). As a result of
this review it may be necessary to stop the study before all subjects have completed the study.
In this case, all subjects will be followed up for safety assessments.
The Sponsor will notify the IRB/IEC of discontinuation of the study and the reason for doing
so.
14.8 END OF STUDY
The end of study is the date of the last subject, last visit for final collection of data.


Protocol ST10 01 104, Version 2.0, 15 Jul 2020
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14.9 RETENTION OF RECORDS
The Investigator must retain the informed consent documentation, disposition of the IMP,
hard copy eCRFs, medical records and other source data for at least 25 years after completion
or discontinuation of the trial or for at least 2 years after the granting of the last marketing
authorization in the EC (when there are no pending or contemplated marketing applications
in the EC) or for at least 2 years after formal discontinuation of clinical development of the
investigational product. Prior to proceeding with destruction of records, the Investigator must
notify the Sponsor in writing and receive written 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.
14.10 SECURITY AND PUBLICATIONS
This study protocol remains the Sponsor property until the final fulfilment of the contract and
may only be passed on to registration authorities and license partners with the Sponsor /
Applicant͛s approval. The study site will treat all knowledge about the study product and/or
its manufacturer with strictest confidentiality.
The Sponsor ensures that substances used in the manufacture of the IMP are generally known
in pharmaceutical science and have been released by the appropriate national authorities for
use in medications, cosmetics or food.
Publication rights will be described in the Investigator contract. The study site͛s 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 licensing partners or specialist groups.


Protocol ST10 01 104, Version 2.0, 15 Jul 2020
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15 REFERENCES
Barrand MA, Callingham BA. Evidence for regulatory control of iron uptake from ferric maltol
across the small intestine of the rat. Br J Pharmacol 1991a: 102: 408 14.
Barrand MA, Callingham BA, Dobbin P, Hider RC. Dissociation of a ferric maltol complex and
its subsequent metabolism during absorption across the small intestine of the rat. Br J
Pharmacol 1991b; 102: 723 9.
British Columbia Guidelines and Protocols. Iron deficiency
investigation and management.
Effective date: 15 June 2010.
Bokemeyer B, Krummenerl A, Maaser C, Howaldt S, Mroß M, Mallard N. Randomized Open
Label Phase 1 Study of the Pharmacokinetics of Ferric Maltol in Inflammatory Bowel Disease
Patients with Iron Deficiency. Eur J Drug Metab Pharmacokinet. 2017 Apr;42(2):229 238.
Food Effect Bioavailability and Fed Bioequivalence Studies ʹ Guidance for Industry
U.S.
Department of Health and Human Services Food and Drug Administration Center for Drug
Evaluation and Research (CDER), December 2002
Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anemia, and inflammatory bowel diseases. Gut
2004; 53: 1190 7.
Gasche C, Ahmad T, Tulassay Z, Baumgart DC, Bokemeyer B, Büning C, Howaldt S, Stallmach
A; AEGIS Study Group.
Ferric maltol is effective in correcting iron deficiency anemia in
patients with inflammatory bowel disease: results from a phase 3 clinical trial program.
Inflamm Bowel Dis. 2015; 21(3): 579 88
Latest version of the Investigator͛s Brochure for Ferric Maltol (ST10 021, ST10).
Mamula P, Piccoli DA, Peck SN, Markowitz JE, Baldassano RN. Total dose intravenous infusion
of iron dextran for iron deficiency anemia in children with inflammatory bowel disease. J
Pediatr Gastroenterol Nutr 2002; 34: 286 90.
Schmidt C, Ahmad T, Tulassay Z, Baumgart DC, Bokemeyer B, Howaldt S, Stallmach A, Büning
C; AEGIS Study Group.. Ferric maltol therapy for iron deficiency anemia in patients with
inflammatory bowel disease: long term extension data from a Phase 3 study. Aliment
Pharmacol Ther. 2016; 44(3):259 70.
Thayu M, Mamula P. Treatment of iron deficiency anemia in pediatric inflammatory bowel
disease. Curr Treat Options Gastroenterol 2005; 8: 411 7
Weiss G, Gasche C. Pathogenesis and treatment of anemia in inflammatory bowel disease.
Haematologica 2010; 95: 175 8.
World Health Organization (WHO): Toxicological evaluation of certain food additives.
International Programme on Chemical Safety IPCS. WHO Food Additives Series 1980; No. 16:
123 129.
World Health Organization (WHO): Evaluation of certain food additives. Sixty fifth report of
the Joint FAO / WHO Expert Committee on Food Additives. WHO Technical Report Series
2006; No. 934: 36 41.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
A randomized, open-label, single dose, four-way 
crossover, Phase I study to compare the 
pharmacokinetics of ferric maltol capsules and oral 
suspension under fasted and fed conditions in adult 
healthy volunteers 
 
Protocol Number: 
ST10‐01‐104 
Protocol Version/Date: 
Version 2.0, 15 July 2020  
Investigational Product: Ferric Maltol (ST10)  
 
 
Sponsor: 
Shield TX (UK) Limited, Northern Design Center, Baltic 
Business Quarter, Gateshead Quays, NE8 3DF United 
Kingdom 
 
 
SAP Version/Date: 
Version 1.0, 15 October 2020  
 
 
CONFIDENTIAL 
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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Statistical Analysis Plan 
Protocol ST10‐01‐104 
 
Version 1.0, 15 October 2020 
 
Page 3 of 19 
VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
15 Oct 2020 
Initial approved version. 
 
 


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Statistical Analysis Plan 
Protocol ST10‐01‐104 
 
Version 1.0, 15 October 2020 
 
Page 4 of 19 
TABLE OF CONTENTS 
1 
Introduction ............................................................................................................................ 8 
2 
Study Overview...................................................................................................................... 8 
2.1 
Study Objectives ............................................................................................................. 8 
2.1.1 
Primary Objective .................................................................................................... 8 
2.1.2 
Secondary Objectives ............................................................................................. 8 
2.2 
Study Design .................................................................................................................. 8 
2.2.1 
Study Overview ....................................................................................................... 8 
2.2.2 
Treatment Assignment and Blinding ..................................................................... 10 
2.2.3 
Study Drug ............................................................................................................ 10 
2.2.4 
Sample Size Determination ................................................................................... 10 
2.3 
Study Endpoints ........................................................................................................... 11 
2.3.1 
Primary PK Endpoints ........................................................................................... 11 
2.3.2 
Secondary PK Endpoints ...................................................................................... 11 
2.3.3 
Safety Endpoints ................................................................................................... 11 
3 
Statistical Methodology ........................................................................................................ 11 
3.1 
General Considerations ................................................................................................ 11 
3.1.1 
Other Data Handling Approaches ......................................................................... 12 
3.1.2 
Analysis Day .......................................................................................................... 12 
3.1.3 
Handling of Dropouts and Missing Data ................................................................ 12 
3.2 
Baseline ........................................................................................................................ 12 
3.3 
Analysis Populations .................................................................................................... 12 
3.3.1 
Randomized Population ........................................................................................ 12 
3.3.2 
Safety Population .................................................................................................. 12 
3.3.3 
Full Analysis Set (FAS) Population ....................................................................... 13 
3.4 
Subject Data and Study Conduct ................................................................................. 13 
3.4.1 
Subject Disposition ................................................................................................ 13 
3.4.2 
Protocol Deviations ............................................................................................... 13 
3.4.3 
Analysis Populations ............................................................................................. 13 
3.4.4 
Demographics ....................................................................................................... 13 
3.4.5 
Medical History ...................................................................................................... 14 
3.4.6 
Prior and Concomitant Medications ...................................................................... 14 
3.5 
Pharmacokinetic Assessment ...................................................................................... 14 
3.5.1 
PK blood sampling ................................................................................................ 14 
3.5.2 
Handling missing PK data or concentration below the lower limit of quantification
 
14 
3.5.3 
PK Concentrations ................................................................................................ 15 
3.5.4 
PK Parameters ...................................................................................................... 15 
3.5.5 
PK analysis ............................................................................................................ 16 


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Statistical Analysis Plan 
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Version 1.0, 15 October 2020 
 
Page 5 of 19 
3.6 
Safety Assessment ....................................................................................................... 17 
3.6.1 
Adverse Events (AEs) ........................................................................................... 17 
3.6.2 
Treatment-Emergent Adverse Event ..................................................................... 17 
3.6.3 
Safety Laboratory .................................................................................................. 18 
3.6.4 
Vital Signs ............................................................................................................. 18 
3.6.5 
ECG ....................................................................................................................... 18 
3.6.6 
Physical Examinations .......................................................................................... 18 
4 
Data Safety Monitoring Board .............................................................................................. 18 
5 
Interim Analysis ................................................................................................................... 19 
6 
Programming Specifications ................................................................................................ 19 
 
 
 


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Statistical Analysis Plan 
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Version 1.0, 15 October 2020 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration Curve 
𝐴𝑈𝐶(0−𝑖𝑛𝑓) 
Area Under the Plasma Concentration Curve for 0‐infinity  
𝐴𝑈𝐶𝑙𝑎𝑠𝑡 
Area Under the Plasma Concentration Curve from 0 up to the last 
measurable concentration (non-below) quantification limit after dosing 
BID 
Twice Daily 
BUN 
Blood Urea Nitrogen 
BP 
Blood pressure 
C 
Celsius 
CA 
Competent Authority 
CD 
Crohn’s Disease 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
𝐶𝑚𝑎𝑥 
Maximum Observed Concentration 
COVID-19 
Coronavirus Disease 2019  
CRA 
Clinical Research Associate 
CRF/eCRF 
Case Report Form/electronic Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CV 
Coefficient Variation 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma‐Glutamyl Transpeptidase 
GI 
Gastrointestinal 
hr 
Hour 
Hb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
IBD 
Inflammatory Bowel Disease 
ICH 
International Conference on Harmonization 
ID 
Iron Deficiency 
IDA 
Iron Deficiency Anemia 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medical Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine Contraceptive Devices 
IV 
Intravenous 
MAA 
Marketing Authorization Application 


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Statistical Analysis Plan 
Protocol ST10‐01‐104 
 
Version 1.0, 15 October 2020 
 
Page 7 of 19 
Abbreviation 
Definition 
NCS 
Non‐Clinically Significant 
NTBI 
Non‐Transferrin Bound Iron 
OFP 
Oral Ferrous Product 
PHI 
Protected Health Information 
PIP 
Pediatric Investigational Plan 
PK 
Pharmacokinetics 
PSP 
Pediatric Study Plan 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2-
RT-PCR 
Severe Acute Respiratory Syndrome–
associated Coronavirus RealTime Reverse Transcriptase–
Polymerase Chain Reaction 
SD 
Standard Deviation 
TEAE 
Treatment‐emergent Adverse event 
TESAE 
Treatment‐emergent Serious Adverse event 
TIBC 
Total Iron Binding Capacity 
TLAG 
The delay between the time of dosing and time of appearance of  
concentration in the sampling compartment 
𝑇𝑚𝑎𝑥 
Time to Maximum Plasma Concentration 
TNF-a 
Tumor Necrosis Factor alpha 
TSAT 
Transferrin Saturation 
𝑇1/2 
Apparent terminal elimination half‐life 
UC 
Ulcerative Colitis 
UIBC 
Unsaturated Iron Binding Capacity 
WHO 
World Health Organization 
yrs 
Years 
𝜆𝑧 
Apparent terminal elimination rate constant, determined by linear 
regression of the terminal points of the ln-linear plasma concentration-time 
curve 
 
 
 


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Statistical Analysis Plan 
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Version 1.0, 15 October 2020 
 
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1 INTRODUCTION 
This statistical analysis plan (SAP) provides a detailed, technical elaboration of the statistical 
analyses of pharmacokinetic (PK) and safety data as described in the study protocol 2.0 dated 
15 July 2020. Specifications for tables, listings, and figures are contained in a separate 
document. Any deviation from this analysis plan will be substantiated by sound statistical/PK/PD 
rationale and will be documented in the final clinical study report.  
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective is to evaluate the pharmacokinetics (PK) of iron absorption after a single 
30 mg dose of ferric maltol administered as capsule or oral suspension in fasted and fed 
conditions, via primary parameters 𝐶𝑚𝑎𝑥 and 𝐴𝑈𝐶𝑙𝑎𝑠𝑡. 
  
2.1.2 Secondary Objectives 
The secondary objectives are: 
To evaluate the pharmacokinetics (PK) after a single 30 mg dose of ferric maltol administered 
as a capsule or oral suspension (fasted and fed conditions); through measurements of 
transferrin saturation (TSAT), baseline corrected serum iron, transferrin, total and unsaturated 
iron binding capacity (TIBC and UIBC), and plasma of maltol and maltol glucuronide. 
To assess the safety and tolerability of ferric maltol after a single dose of 30 mg administered as 
a capsule or oral suspension (fasted and fed conditions); based on vital signs, adverse events, 
concomitant medications and routine clinical laboratory safety blood tests. 
2.2 Study Design 
2.2.1 Study Overview 
This is a Phase I, randomized, open-label, single dose, four-way crossover study, to compare 
the pharmacokinetics of iron and maltol absorption from ferric maltol capsules and oral 
suspension formulations under fasted and fed conditions in adult healthy volunteers. 
A total of 32 eligible subjects will be randomized at a ratio of 1:1:1:1 to receive one of the 
following treatment sequences comprised of four treatment periods. Treatment periods will last 
4 days with at least 48 hours washout period between each dose administration. Eight subjects 
will be randomized to each treatment sequence:   
Sequence A:   
 
Period 1; single dose of 30 mg ferric maltol capsule in a fed condition   
 
Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition   
 
Period 3; single dose of 30 mg ferric maltol capsule in a fasted condition   
 
Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition 
Sequence B:   


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Statistical Analysis Plan 
Protocol ST10‐01‐104 
 
Version 1.0, 15 October 2020 
 
Page 9 of 19 
 
Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition    
 
Period 2; single dose of 30 mg ferric maltol capsule in a fed condition   
 
Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition  
 
Period 4; single dose of 30 mg ferric maltol capsule in a fasted condition   
Sequence C:    
 
Period 1; single dose of 30 mg ferric maltol capsule in a fasted condition   
 
Period 2; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition   
 
Period 3; single dose of 30 mg ferric maltol capsule in a fed condition   
 
Period 4; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition   
Sequence D:    
 
Period 1; single dose of 30 mg (5 ml) ferric maltol suspension in a fed condition   
 
Period 2; single dose of 30 mg ferric maltol capsule in a fasted condition  
 
Period 3; single dose of 30 mg (5 ml) ferric maltol suspension in a fasted condition   
 
Period 4; single dose of 30 mg ferric maltol capsule in a fed condition   
The planned study consists of three study phases: 
1. Screening Phase; 
2. Treatment Phase; 
3. Follow-Up Phase.  
Table 1 contains details of the study periods, study visits and timing of the visits.  
Table 1 Study Visits 
Phase 
Period 
Study Visit 
Study Day 
Screening 
Screening 
1 
-14 to -1 
Treatment 
 
 
 
Treatment Period 1 
2 
1 
Treatment Period 2 
3 
3 
Treatment Period 3 
4 
5 
Treatment Period 4 
5 
7 
Follow-Up 
Follow-Up 
6 
10-14 
The Screening Phase will consist of one visit: Study Visit 1 (Screening) scheduled to take place 
within 14 days prior to the planned Treatment Phase for each subject. The purpose of this visit 
is to determine subject eligibility for the study.  
Prior to the first treatment period, subjects will arrive at the Clinical Unit on Day ‐1 at least 13 
hours before dosing. After at least 10 hours overnight fasting at the Clinical Unit subjects will be 
randomized to one of the 4 treatment sequences. PK samples will be collected pre‐dose and up 
to 24 hours post‐dose during each period (12 times including pre‐dose) for the measurements of 
serum iron, TSAT, TIBC, UIBC, transferrin, plasma maltol and maltol glucuronide.    
There will be at least 48 hours washout period between dose administrations. Subjects will fast 
at least 10 hours prior to each treatment period dosing.    


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Statistical Analysis Plan 
Protocol ST10‐01‐104 
 
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Subjects will stay at the Clinical Unit during the 4 treatment and 3 washout periods and will be 
discharged on Day 8 following the last PK sampling timepoint.   
Post study telephone follow‐up will be conducted 3‐7 days following Treatment Period 4. During 
early discontinuation a safety follow up at the Clinical Unit will be performed 3‐7 days after the 
last study medication.    
The schedule of procedures can be found in Table 10.2 from Protocol. 
2.2.2 Treatment Assignment and Blinding 
This is an open label study and treatment assignment is not blinded. 
The randomization procedure (created using a computer‐generated random permutation 
procedure) will randomize the subject to one of the 4 treatment sequences to either Sequence A 
Sequence B, Sequence C or Sequence D. The site will dispense the appropriate formulation of 
open‐label ferric maltol bottles at each scheduled PK day according to the schedule of 
assessments. The randomization scheme will be programmed by Medpace independent 
statistician using SAS®. Detailed randomization methods and procedures are described in a 
stand-alone document. 
2.2.3 Study Drug 
Investigational Medicinal Product 
Ferric maltol oral suspension: oral suspension containing 30 mg elemental iron, in the 
form of 231.5 mg ferric maltol, in 5 ml suspension.      
Comparator 
Ferric maltol capsules: gelatin capsules with 30 mg elemental iron, in the form of 231.5 
mg ferric maltol. 
2.2.4 Sample Size Determination 
The sample size is based on the comparisons of each of the primary PK parameters 𝐶𝑚𝑎𝑥 and 
𝐴𝑈𝐶𝑙𝑎𝑠𝑡 for total serum iron between the formulations for each of the two conditions: fed and 
fasted. Each comparison will be made via the ratio of the two values of the parameter between 
the formulations. The 90% confidence interval (CI) for this ratio will be reported.   
Thus, there are 4 primary endpoints:   
In fed condition  
𝐶𝑚𝑎𝑥 (suspension) / 𝐶𝑚𝑎𝑥 (capsule)  
𝐴𝑈𝐶𝑙𝑎𝑠𝑡 (suspension) / 𝐴𝑈𝐶𝑙𝑎𝑠𝑡 (capsule)  
In fasted condition  
𝐶𝑚𝑎𝑥 (suspension) / 𝐶𝑚𝑎𝑥 (capsule)  
𝐴𝑈𝐶𝑙𝑎𝑠𝑡 (suspension) / 𝐴𝑈𝐶𝑙𝑎𝑠𝑡 (capsule)    
Data from a previous study (ST10‐01‐101) were used to provide estimates of the standard 
deviations (SDs) of the logs of the within‐subject ratios of the parameters 𝐶𝑚𝑎𝑥 and 𝐴𝑈𝐶𝑙𝑎𝑠𝑡 
(between formulations). Assuming the SD is no greater than 0.38, and that the true ratio is 1, 20 
subjects would provide a probability of at least 80% of each individual confidence interval lying 


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within (80%, 125%). Further if all the 4 ratios to be reported are independent, 31 subjects would 
provide probability of at least 80% of all 4 confidence intervals lying within (80%, 125%). As the 
SD is uncertain, 32 subjects will be recruited in the study.      
The target recruitment number is 32 and up to an additional 4 may be recruited to replace early 
withdrawing subjects. 
2.3 Study Endpoints 
2.3.1 Primary PK Endpoints 
PK analysis of total serum iron concentration; 𝐶𝑚𝑎𝑥 and 𝐴𝑈𝐶𝑙𝑎𝑠𝑡 in fasted and fed conditions.  
2.3.2 Secondary PK Endpoints 
1. PK analysis of total serum iron concentration; 𝐴𝑈𝐶𝑖𝑛𝑓 in fasted and fed conditions     
2. PK analysis of baseline corrected serum iron concentration; 𝐶𝑚𝑎𝑥, 𝐴𝑈𝐶𝑙𝑎𝑠𝑡, 𝐴𝑈𝐶𝑖𝑛𝑓 in 
fasted and fed conditions     
3. PK analysis of maltol and maltol glucuronide in plasma; 𝐶𝑚𝑎𝑥, 𝐴𝑈𝐶𝑙𝑎𝑠𝑡 in fasted and fed 
conditions    
4. PK analysis of TSAT, TIBC, UIBC, transferrin; 𝐶𝑚𝑎𝑥, 𝐴𝑈𝐶𝑙𝑎𝑠𝑡 in fasted and fed conditions     
2.3.3 Safety Endpoints 
1. Treatment‐emergent Adverse Events (AEs)      
2. Serious Adverse Events (SAEs)      
3. Treatment‐emergent Adverse Events leading to premature discontinuation of study 
drug/PK assessments      
4. Clinical laboratory safety blood results      
5. Changes in vital signs      
6. Concomitant medications  
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
All available data will be presented in subject data listings, which will be sorted by treatment 
sequence group, subject identifier and where appropriate, visit number and visit/assessment 
date. 
Listings will contain data for all attended visits whether scheduled or unscheduled and visits will 
be listed in the order in which they were attended. Tables will summarize data for all attended 
visits. 
Formulation / condition groups will be displayed in all output using the following labels: 
 
Ferric Maltol Capsule/Fed 
 
Ferric Maltol Suspension/Fed 
 
Ferric Maltol Capsule/Fasted 


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 
Ferric Maltol Suspension/Fasted 
Treatment sequence groups will be displayed in all output using the following labels: 
 
Ferric Maltol Sequence A 
 
Ferric Maltol Sequence B 
 
Ferric Maltol Sequence C 
 
Ferric Maltol Sequence D 
3.1.1 Other Data Handling Approaches 
In general, descriptive statistics (n, mean, standard deviation (SD), median, maximum and 
minimum) will be used to summarize the continuous data. Discrete measures will be 
summarized using counts and percentages (derived from the number of non-missing 
observations); the number of non-missing (n) observations will also be presented.   
Unless otherwise stated, descriptive statistics showing the mean or median will be displayed to 
one more decimal place than the original data; the standard deviation will be displayed to two 
decimal places more than the original data and minimum and maximum values will be displayed 
to the same number of decimal places as the original data.   
All fractional numeric values will be printed with a zero to the left of the decimal point (e.g., 0.12, 
0.3 etc.). Percentage values will be printed with one digit to the right of the decimal point (e.g., 
52.3%, 8.9% etc.). 
3.1.2 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug. The day of the first dose 
of study drug will be Day 1, and the day immediately before Day 1 will be Day -1. There will be 
no Day 0. 
3.1.3 Handling of Dropouts and Missing Data 
All data will be used according to availability, with no imputation for missing data. 
3.2 Baseline  
 
Baseline is defined as reading or measurements at Day 1 prior to study drug administration of 
each period. If the reading at Day 1 predose is missing, the last reading before first dosing will 
be set as baseline.  
3.3 Analysis Populations 
3.3.1 Randomized Population 
All subjects who are randomized. 
3.3.2 Safety Population 
All subjects who have had at least one dose of study drug and one subsequent contact with the 
Investigator will be analyzed for safety. 


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3.3.3 Full Analysis Set (FAS) Population 
All subjects who have had at least one dose of study drug and who have at least one evaluable 
post‐dose PK sample will be included in the FAS Population. This population will be utilized for 
the PK analysis. 
3.4 Subject Data and Study Conduct 
3.4.1 Subject Disposition 
Subject disposition will be presented for the Randomized Population. The number and 
percentage of subjects in each of the following categories will be summarized by treatment 
sequence and overall, as appropriate: 
 
Randomized; 
 
Dosed; 
 
Completed each treatment period; 
 
Completed the study;  
 
Prematurely discontinued the study and reasons for study discontinuation; and 
 
Prematurely discontinued the study due to COVID-19 pandemic. 
3.4.2 Protocol Deviations 
Protocol deviations will be summarized with frequency distributions (counts and percentages) by 
treatment sequence group and category for the FAS and Randomized Population. The 
denominators for calculating percentages will be based on the number of subjects in the FAS 
and Randomized Population for each treatment sequence group and overall.  
Protocol deviations will be listed by treatment sequence for the Randomized Population. 
3.4.3 Analysis Populations 
Counts and percentages of subjects in each analysis population will be summarized by 
treatment sequence, formulation / condition and in total based on the Randomized Population.  
3.4.4 Demographics 
The following demographic and baseline characteristics will be listed and summarized by 
treatment sequence and formulation / condition with descriptive statistics or counts and 
percentages of subjects for the Randomized Population and repeated for all other analysis 
populations if they are different from the Randomized Population: 
 
Age (years)  
 
Sex 
 
Childbearing potential  
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
 
Race (Asian, American Indian or Alaska Native, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other) 
 
Height (cm) 
 
Weight (kg) 
 
Body Mass Index (BMI) (kg/m2) 


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3.4.5 Medical History 
Medical history reported terms will be coded to system organ class and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. Medical history by system 
organ class and preferred term will be summarized by treatment sequence and in total for the 
Safety Population as well as listed 
3.4.6 Prior and Concomitant Medications 
Prior and concomitant medications will be coded with the World Health Organization Drug 
Dictionary Global B3 September 2018 version.    
Prior medications will be defined as those medications (both prescribed and OTC) taken prior to 
the first dose of study drug in each treatment sequence. Medications taken at and after the time 
of first dose during the study will be defined as concomitant medications. Each treatment period 
will be defined as the period from the date and time of study drug dosing up to but not including 
the date and time of study drug dosing for the next treatment period (or end of study for the last 
treatment period). Concomitant medications taken at any time during a treatment period will be 
attributed to the corresponding treatment. 
Concomitant medications will be summarized by formulation / condition for the Safety 
Population. All prior and concomitant medications will be listed. 
3.5 Pharmacokinetic Assessment 
3.5.1 PK blood sampling 
PK samples were to be collected on Day 1 to Day 8, pre-dose and post-dose according to the 
PK Sample Schedule Group that the subject was assigned to. 
On all four PK study days, all subjects will have baseline PK blood samples collected 
immediately prior to Ferric Maltol dosing (0 hr). Subjects will then have further PK blood 
samples collected at 11 additional times after dosing; the post-dose PK sample times will be 15 
mins ±2 min, 30 mins ±2 min, 45 mins ±5 min, 1 hr ±5 min, 1.5 hr ±5 min, 2 hrs ± 5 min, 3 hrs ± 
5 min, 4 hrs ± 5 min, 6 hr ±10 min, 10 hrs ±15 min and 24 hrs ±15 min.   
For each individual subject, the post‐dose PK blood sampling schedule will be the same on all 
four PK days. PK blood samples on the PK days will be: serum iron, total and unsaturated iron 
binding capacity (TIBC, UIBC), transferrin, transferrin saturation (TSAT), maltol and maltol 
glucuronide. 
3.5.2 Handling missing PK data or concentration below the lower limit of quantification 
If the actual sampling time is missing, but a valid concentration value has been measured, the 
concentration value will be flagged, and the scheduled time point may be used for the 
calculation of PK parameters. If the dosing history information for a subject is missing, the 
sampling for that subject relative to the missing dose will not be included in the analysis. 
Missing concentrations related to serum iron, TSAT, transferrin, TIBC, and UIBC will not be 
imputed or used in the analysis. If the dosing history information for a patient is missing, the 
sampling for that patient relative to the missing dose will not be included in the analysis. 


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For maltol and maltol glucuronide, all drug concentration below the quantifiable limit (BQL) are 
treated as zero. When more than half (>50%) of the values at a single timepoint are BQL, mean 
and median values are reported as BQL. Standard deviation and %CV are not reported; 
maximum and minimum values are reported as observed (including BQL). If, as the result of the 
calculation (eg. dose normalization, descriptive statistics) a concentration value is less than the 
LLOQ the value should be reported as <LLOQ value. The following general rules will be applied 
for the concentration summary (including tabulation and plotting) for each period: 
 
Mean concentrations at any individual time point will only be calculated if at least half of 
the subjects have valid values (i.e. quantifiable and not missing) at this time point for 
each formulation / condition. 
 
In cases where a mean value is not calculated, due to the above criterion not being met, 
the mean value will be set to missing for mean plotting purposes and to BLQ for 
summary table. 
 
BLQ will be set to zero for maltol and maltol glucuronide and to LLOQ for other analytes 
for the calculation of these mean values if applicable. 
3.5.3 PK Concentrations 
The observed values for maltol, maltol glucuronide, serum iron, baseline corrected serum iron, 
TSAT, TIBC, UBIC, and transferrin will be summarized by formulation / condition and by 
visit/timepoint for FAS Population using the following descriptive statistics: n (the number of 
subjects), arithmetic mean, standard deviation (SD), geometric mean, coefficient of variation 
(CV), median, minimum and maximum, and a 90% confidence interval (CI) for the mean.  
The observed data for maltol, maltol glucuronide, serum iron (uncorrected and baseline 
corrected), TSAT, TIBC, UBIC, and transferrin will also be listed by formulation / condition group 
for each individual subject for FAS Population.  
For maltol, maltol glucuronide, serum iron (uncorrected and baseline corrected), TSAT, TIBC, 
UIBC, and transferrin the mean observed plasma concentrations will be plotted on a linear and 
semi-logarithmic scale against nominal time range by formulation / condition. Geometric mean 
observed plasma concentrations and 90% CI will be plotted on a linear scale against nominal 
time range by formulation/condition. Individual observed concentrations be plotted on a linear 
and semi-logarithmic scale against actual timepoint for each formulation/condition.  
3.5.4 PK Parameters 
For serum iron, baseline corrected serum iron, maltol, maltol glucuronide, TSAT, TIBC, UIBC 
and transferrin, the following parameters will be calculated by non-compartmental analysis.  


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Parameters 
Description 
Cmax 
Maximum plasma concentration directly from data 
Tmax 
Time to reach maximum concentration directly from data 
λz 
Apparent first-order terminal elimination rate constant (serum iron, maltol, and 
maltol glucuronide only) 
t½ 
Terminal elimination half-life, calculated as ln(2)/ λz (serum iron, maltol, and 
maltol glucuronide only) 
AUClast 
Area under the plasma concentration versus time curve from time zero to last. 
AUCinf 
Area under the plasma concentration versus time curve from time zero 
extrapolated to infinity time (serum iron, maltol, and maltol glucuronide only) 
The actual collection times will be used for the calculation of PK parameters. The Linear Up Log 
Down method (equivalent to the Linear Up/Log Down option in WinNonlin® Professional) will be 
used in the computation of AUC, if applicable. 
The apparent terminal elimination rate constant (λz), will not be presented for subjects who do 
not exhibit a terminal elimination phase in their concentration-time profiles. In order to estimate 
λz, linear regression of concentration in logarithm scale versus time will be performed using at 
least 3 data points. Uniform weighting will be selected to perform the regression analysis to 
estimate λz.  
Generally, the λz will not be assigned if one of the following happens:  
1. Tmax is one of the 3 last data points,  
2. The adjusted regression coefficient (R-squared) is less than 0.80,  
3. The AUCextrap exceeds 20%,  
4. The estimated elimination rate indicates a positive slope, or  
5. The terminal elimination phase is not linear (as appears in a semi-logarithmic scale) based on 
visual inspection. 
If the λz is not assigned, the values of associated PK parameters (e.g. λz, AUCinf, or t½) will not 
be calculated. 
Parameters will be listed by treatment sequence group for each individual subject and 
summarized by formulation/condition using the following descriptive statistics: n (the number of 
subjects), arithmetic mean, SD (standard deviation), geometric mean, geometric CV (coefficient 
of variation), median, minimum and maximum.   
3.5.5 PK analysis 
To compare the pharmacokinetics of ferric maltol capsules and oral suspension under fasted 
and fed conditions, a subject must have a calculable PK parameter for both formulations under 
fasted or fed condition.  
An ANOVA model will be performed on the ln-transformed PK parameters (Cmax, AUClast and 
AUCinf) of the two formulations including terms for sequence (treatment sequence), treatment 
(formulation/condition), and period as fixed effects, and subjects nested within a sequence as a 


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random effect. The estimates will be back-transformed into original scale. The point estimates 
for ratios and the corresponding 90% CIs will be provided. 
The PK parameters analyses will be based on the FAS Population. 
The sample SAS code for this analysis is included here for α = 0.10: 
proc mixed; 
class subject treatment sequence period; 
model logPKvar = treatment sequence period /ddfm=Satterthwaite; random 
subject(sequence); 
lsmeans treatment/pdiff cl alpha=0.1; 
run; 
3.6  Safety Assessment 
Safety analyses will be performed based on the Safety Population. Safety will be evaluated 
through assessments of AEs, treatment emergent adverse events (TEAEs), ECG, vital signs, 
physical examinations and clinical laboratory tests. 
3.6.1 Adverse Events (AEs) 
An adverse event is defined as any untoward medical occurrence in a subject regardless of its 
causal relationship to study treatment. An adverse event can be any unfavorable and 
unintended sign (including any CS abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study drug, whether or not it is considered to be study 
drug-related. 
Adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA) Version 21.1.   
The Investigator will grade the intensity of the adverse event as mild, moderate, or severe. 
The relationship of an adverse event to study drug will be assessed as: related and not related. 
3.6.2 Treatment-Emergent Adverse Event  
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges, having been 
absent prior to the study, or an AE that worsens in severity after the first dose of study drug in 
this study. Each treatment period will be defined as the period from the date and time of study 
drug dosing up to but not including the date and time of study drug dosing for the next treatment 
period (or end of study for the last treatment period).  TEAEs that started during a treatment 
period will be attributed to the corresponding treatment. TEAEs will be summarized by MedDRA 
system organ class (SOC) and preferred term (PT) for each formulation / condition and overall. 
The number and percentage of subjects experiencing TEAEs, and the number of TEAEs will be 
tabulated. Subjects reporting more than one adverse event for a given MedDRA preferred term 
will be counted only once for that term using the most severe incident. Subjects reporting more 
than one type of event within a system organ class (SOC) will be counted only once for that 
SOC. The following summaries of adverse events will be presented for each part:  
 
Overall summary of TEAEs by formulation / condition with a breakdown by AE maximum 
severity;  
 
TEAEs by SOC and PT by formulation / condition;  


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 
TEAEs by SOC, PT, and relationship to study drug by formulation / condition;  
 
TEAEs by SOC, PT, and maximum severity by formulation / condition; and   
 
TEAEs by SOC, PT, maximum severity, and the relationship to study drug by formulation 
/ condition. 
Separate listings will be prepared for SAEs, AEs leading to death and AEs leading to study 
discontinuation. 
3.6.3 Safety Laboratory 
Blood samples for safety laboratory will be collected at Screening and Day 8/ET.  
Safety laboratory values and changes from baseline will be summarized at each scheduled visit 
by treatment sequence. A table summarizing abnormal values of safety laboratory tests will also 
be presented. All safety laboratory data, including normal ranges and abnormal laboratory flags, 
will be provided in data listings. 
Pregnancy test results, drug and alcohol testing results, hepatitis and HIV test results, and 
COVID-19 test results will be listed.   
3.6.4 Vital Signs 
Vital signs including blood pressure, pulse rate, temperature, and respiratory rate will be 
measured at Screening, Day -1, Day 1, Day 3, Day 5, Day 7, and Safety Follow-Up/ET. Height, 
weight, and body mass index (BMI) will be measured at Screening only. 
Vital signs values and changes from baseline will be summarized at each scheduled visit by 
treatment sequence.   
All vital signs data will be listed. 
3.6.5 ECG 
Electrocardiograms will be performed at Screening. 
Continuous ECG parameters (heart rate, PR interval, RR interval, QRS duration, QT interval, 
and QTcF interval) values and overall interpretation will be summarized at Screening by 
treatment sequence. 
All ECG data will be listed. 
3.6.6 Physical Examinations 
Physical examinations will be performed at Screening, Day 8, and Safety Follow-Up/ET. 
Physical examination results by body system will be summarized at each scheduled visit by 
treatment sequence. 
Findings from the physical examinations will be listed. 
4 DATA SAFETY MONITORING BOARD 
There are no provisions for a Data Safety Monitoring Board for this study. 


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5 INTERIM ANALYSIS 
No interim analysis is planned for this study. 
6 PROGRAMMING SPECIFICATIONS 
The creation of analysis datasets and all statistical analyses will be performed using SAS® 
Version 9.4. Medpace standard operating procedures GL-DS-02-S3 and GL-DS-03-S2 will be 
followed for the generation and validation of all programs and outputs. 
Phoenix WinNonlin version 7.0 or higher will be used in the determination of the PK terminal 
phase and the calculation of PK parameters. Medpace standard operating procedures GL-DS-
26-S1 and GL-DS-27-S1 will be followed for conducting NCA analysis and statistical analysis. 
Detailed Programming Specifications will be provided in a separate document.