Clinical trial NCT02680756
Conditions: Anemia, Iron-Deficiency Inflammatory Bowel Disease Crohn's Disease
Keywords: Iron Deficiency Anaemia Crohn's Disease Deficiency Diseases Inflammatory Bowel Diseases Intestinal Diseases
Sponsor: Shield Therapeutics
Start date: 2016-01-01; Completion date: 2019-01-01
Enrollment: 250 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy of ferric maltol and intravenous iron (IVI) Ferric Carboxy Maltose in the treatment of iron deficiency anaemia (IDA) and subsequent maintenance of haemoglobin in subjects with Inflammatory Bowel Disease (IBD).

Detailed description:
A phase 3b, randomized, controlled, multicentre study with oral ferric maltol or intravenous iron (FCM), for the treatment of iron deficiency anaemia in subjects with inflammatory bowel disease.

Approximately 242 eligible subjects will be randomised (1:1) to receive one of the following treatments for the duration of the study treatment period (52 weeks):

* Oral ferric maltol, 30 mg capsule bid.
* Intravenous iron (ferric carboxy maltose) as per SPC

In the FCM arm IV iron treatment will be repeated if the subject is iron deficient at any of the study visits.

Subject participation in the study will consist of 3 periods:

* Screening: Up to 14 days
* Randomised Treatment: 52 weeks
* Post-treatment safety follow-up: 14 days after study medication discontinuation

Primary efficacy and safety of ferric maltol and Intravenous iron (ferric carboxy maltose) will be evaluated after the first 12 weeks.

End of study evaluations will occur at Week 52 or premature discontinuation.

Arms: arm 1: 30 mg capsules to be taken orally twice a day for 52 weeks arm 2: Administered as per the local summary of product characteristics (SPC)
Interventions: intervention 1: Ferric Maltol intervention 2: Ferric Carboxy Maltose
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
SAP_002.pdf: 
 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
14 Feb 2019
 
 
 
 
 
 
DOCUMENT: 
 
Statistical Analysis Plan 
 
PROTOCOL: 
 
ST10-01-304 
 
A phase 3b, randomized, controlled, multicentre study 
with oral ferric maltol (Feraccru) or intravenous iron 
(ferric carboxy maltose; FCM), for the treatment of iron 
deficiency anaemia in subjects with inflammatory bowel 
disease 
 
SAP VERSION: 
 
3.0 
 
SAP DATE:  
 
14 February 2019 
 
PROTOCOL DATE: 
10 July 2015, Version 1.0  
24 August 2015, Version 2.0 
12 February 2016, Version 3.0 
08 August 2016, Version 4.0 
25 August 2016, Version 4.2 
05 January 2017, Version 5.0 
11 July 2017, Version 6.0 
30 April 2018, Version 7.0 
 
 
 
 
 
SPONSOR:  
 
Shield TX (UK) Limited 
 
PREPARED BY: 
 
Clinipace Worldwide 
 
AUTHORS:  
 
Barbara Collins, BSc PhD 
 
 
 
 
Senior Biostatistician 
 
 
 
 
Clinipace Worldwide 
 
 
 
 
 
 
 
 
 




 
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Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
14 Feb 2019
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................................................ 5 
1 
INTRODUCTION ............................................................................................................................................. 6 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS .................................................................................... 6 
2.1 
STUDY OBJECTIVES ............................................................................................................................................ 6 
2.1.1 
Primary Objective ..................................................................................................................................... 6 
2.1.2 
Secondary Objectives ............................................................................................................................... 6 
2.2 
TREATMENT GROUP COMPARISONS ...................................................................................................................... 6 
2.3 
STUDY ENDPOINTS ............................................................................................................................................ 6 
2.3.1 
Primary Efficacy Endpoint ........................................................................................................................ 6 
2.3.2 
Secondary Efficacy Endpoints .................................................................................................................. 6 
2.3.3 
Pharmacoeconomic Endpoints ................................................................................................................. 7 
2.3.4 
Safety Endpoints ...................................................................................................................................... 8 
3 
STUDY DESIGN ............................................................................................................................................... 8 
3.1 
OVERALL STUDY DESIGN ..................................................................................................................................... 8 
3.2 
SCHEDULE OF STUDY ASSESSMENTS ...................................................................................................................... 8 
3.2.1 
Screening Period (Visit 1) ......................................................................................................................... 9 
3.2.2 
Treatment Period (Visits 2‐7) ................................................................................................................... 9 
3.2.3 
Follow‐up Period (Visit 8) ......................................................................................................................... 9 
TABLE 1. SCHEDULE OF ASSESSMENTS ................................................................................................................. 10 
4 
POWER AND SAMPLE SIZE CONSIDERATIONS .............................................................................................. 11 
5 
ANALYSIS POPULATIONS ............................................................................................................................. 11 
5.1 
RANDOMIZED POPULATION ............................................................................................................................... 11 
5.2 
SAFETY POPULATION........................................................................................................................................ 11 
5.3 
INTENTION‐TO‐TREAT (ITT) POPULATION ............................................................................................................ 11 
5.4 
PER PROTOCOL (PP) POPULATION ..................................................................................................................... 12 
6 
CONSIDERATIONS FOR DATA ANALYSIS ....................................................................................................... 12 
6.1 
GENERAL STATISTICAL CONSIDERATIONS .............................................................................................................. 12 
6.2 
PROGRAMMING ENVIRONMENT ......................................................................................................................... 12 
6.3 
STRATA AND COVARIATES ................................................................................................................................. 12 
6.4 
SUBGROUPS ................................................................................................................................................... 12 
6.5 
MULTIPLE COMPARISONS AND MULTIPLICITY ....................................................................................................... 12 
6.6 
SIGNIFICANCE LEVEL ........................................................................................................................................ 13 
6.7 
STATISTICAL NOTATION AND METHODOLOGY ....................................................................................................... 13 
7 
DATA HANDLING METHODS ........................................................................................................................ 13 
7.1 
MISSING DATA ............................................................................................................................................... 13 
7.1.1 
Date Values ............................................................................................................................................ 13 
7.1.2 
Non‐Date Values .................................................................................................................................... 14 
7.2 
VISIT WINDOWS ............................................................................................................................................. 14 
7.3 
DATA DERIVATIONS AND DEFINITIONS ................................................................................................................. 15 
8 
STUDY POPULATION .................................................................................................................................... 16 
8.1 
ANALYSIS POPULATIONS ................................................................................................................................... 16 
8.2 
SUBJECT DISPOSITION ...................................................................................................................................... 16 
8.3 
INCLUSION/EXCLUSION CRITERIA ........................................................................................................................ 16 


 
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Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
14 Feb 2019
8.4 
PROTOCOL DEVIATIONS .................................................................................................................................... 17 
8.5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................................................................................ 17 
8.6 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................................................................... 18 
8.7 
MEDICAL HISTORY ........................................................................................................................................... 18 
8.8 
SUBJECT PROGRESS AND UNSCHEDULED VISITS ..................................................................................................... 18 
8.9 
STUDY DRUG DISPOSITION ................................................................................................................................ 18 
9 
EFFICACY ANALYSES .................................................................................................................................... 19 
9.1 
PRIMARY EFFICACY ANALYSES ............................................................................................................................ 19 
9.1.1 
Primary Analysis..................................................................................................................................... 19 
9.1.2 
Sensitivity Analysis ................................................................................................................................. 21 
9.1.2.1 
Observed Cases (OC) Analysis ....................................................................................................................... 21 
9.1.2.2 
Observed Cases (OC) Repeated Measures Analysis ...................................................................................... 21 
9.2 
SECONDARY EFFICACY ANALYSES ........................................................................................................................ 22 
9.2.1 
Secondary Analysis................................................................................................................................. 22 
9.2.1.1 
Key Secondary Endpoints .............................................................................................................................. 22 
9.2.1.2 
Other Secondary Efficacy Endpoints ............................................................................................................. 24 
9.2.1.3 
Long‐term Secondary Endpoints ................................................................................................................... 25 
10 
PHARMACOECONOMIC ANALYSES .............................................................................................................. 26 
10.1 
MEDICAL OUTCOMES STUDY 36‐ITEM SHORT FORM (SF‐36) ................................................................................. 26 
10.2 
CORRECTION AND MAINTENANCE OF IDA ............................................................................................................ 27 
11 
SAFETY ANALYSES ....................................................................................................................................... 29 
11.1 
ADVERSE EVENTS ............................................................................................................................................ 29 
11.2 
LABORATORY EVALUATIONS .............................................................................................................................. 29 
11.3 
VITAL SIGNS ................................................................................................................................................... 30 
11.4 
PHYSICAL EXAMINATION ................................................................................................................................... 30 
12 
PRIMARY ANALYSIS ..................................................................................................................................... 30 
13 
FINAL ANALYSIS ........................................................................................................................................... 30 
14 
CHANGES FROM PROTOCOL ........................................................................................................................ 30 
15 
REFERENCES ................................................................................................................................................ 31 
16 
TABLE OF CONTENTS FOR DATA DISPLAYS .................................................................................................. 32 
16.1 
TABLES .......................................................................................................................................................... 32 
16.2 
FIGURES ........................................................................................................................................................ 34 
16.3 
LISTINGS ........................................................................................................................................................ 35 
 


 
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Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
14 Feb 2019
LIST OF ABBREVIATIONS 
 
 
AE  
 
Adverse event 
ANCOVA 
Analysis of Covariance 
ATC 
 
Anatomical Therapeutic Chemical 
bid 
 
Two times daily 
CD 
 
Crohn’s disease 
CI 
 
Confidence interval 
CFB 
 
Change from baseline 
CRF 
 
Case report form 
CSR 
 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
FCM 
 
Ferric carboxy maltose 
GLM  
Generalized Linear Model 
GLMM  
Generalized Linear Mixed Model 
Hb 
 
Haemoglobin 
IDA 
 
Iron deficiency anaemia 
IBD 
 
Inflammatory bowel disease 
ITT 
 
Intention-to-Treat 
IV 
 
Intravenous 
LCL 
 
Lower confidence limit 
LOCF  
Last Observation Carried Forward 
LSM 
 
Least squares mean 
MCS  
Mental Component Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
 
Mantel-Haenszel 
OC 
 
Observed Cases 
PCS 
 
Physical Component Score 
PE 
 
Pharmacoeconomic 
PI 
 
Prescribing Information 
PP 
 
Per Protocol  
SAE 
 
Serious adverse event 
SAP 
 
Statistical Analysis Plan 
SD 
 
Standard deviation 
SF-36  
Medical outcomes study 36-item short form 
TE 
 
Treatment emergent 
TEAE  
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
UC 
 
Ulcerative colitis  
WHO  
World Health Organization 
 
 
 
 
 
 
 


 
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Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
14 Feb 2019
1 
INTRODUCTION 
 
This document describes the statistical methods and data presentations to be used 
in the summary and analysis of safety, efficacy, and tolerability data from Protocol 
ST10-01-304.  Background information is provided for the overall study design and 
objectives.  The reader is referred to the study protocol and electronic case report 
forms (eCRFs) for details of study conduct and data collection. 
 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS 
 
2.1 
   Study Objectives 
 
2.1.1    Primary Objective 
 
To compare the efficacy of ferric maltol and intravenous iron (IVI, FCM) in the 
treatment and maintenance of iron deficiency anaemia in subjects with IBD. 
 
2.1.2    Secondary Objectives 
 
The secondary objectives of this study are: 
 
To evaluate the safety and tolerability of ferric maltol and intravenous iron 
(IVI, FCM) in subjects over a treatment duration of up to 52 weeks. 
 
To evaluate long-term healthcare resources utilized in the management of 
IDA in IBD. 
 
2.2 
   Treatment Group Comparisons 
 
Subjects will be randomized to one of the following two treatment arms:  
 
Oral ferric maltol, 30mg capsule twice daily (bid). 
 
Intravenous iron (IVI, FCM), administered as per the local summary of 
product characteristics. 
Comparisons will be made between these two treatment arms. 
 
2.3 
   Study Endpoints 
 
2.3.1    Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the proportion of subjects achieving either a 
≥2g/dL increase in Haemoglobin (Hb) OR normalization of Hb (>12g/dL for women, 
>13g/dL for men) at Week 12. 
 
2.3.2    Secondary Efficacy Endpoints 
 
Secondary efficacy endpoints to be evaluated at Week 12 are: 


 
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Statistical Analysis Plan 
Protocol: ST10-01-304 
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14 Feb 2019
 
Key secondary endpoints: 
 
Change in Hb concentration from baseline to Week 12 
 
Change in Hb concentration from baseline to Week 12 in subjects with a 
baseline Hb <9.5 g/dL 
Other secondary endpoints: 
 
Proportion of subjects who experience a change from baseline in Hb 
concentration ≥1.0 g/dL at Week 12 (Hb rise responder) 
 
Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase 
in Hb concentration of ≥1 g/dL at Week 12 (Hb rise responder) 
 
Proportion of subjects with Hb concentration within normal limits at Week 
12 (Hb normal limit responder) 
 
Proportion of subjects with baseline Hb concentration <9.5 g/dL that is 
within normal limits at Week 12 (Hb normal limit responder) 
 
Change in Hb concentration from baseline to Week 4 
 
Change in Hb concentration from baseline to Week 4 in subjects with a 
baseline Hb <9.5 g/dL  
 
Proportion of subjects who experience a change from baseline in Hb 
concentration  ≥2.0 g/dL at Week 12 (Hb rise responder) 
 
Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase 
in Hb concentration of ≥2 g/dL at Week 12 (Hb rise responder) 
 
Proportion of subjects who experience a change from baseline in Hb 
concentration ≥1.0 g/dL at Week 4 (Hb rise responder) 
 
Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase 
in Hb concentration of ≥1 g/dL at Week 4 (Hb rise responder) 
 
Proportion of subjects with Hb concentration within normal limits at Week 
4 (Hb normal limit responder) 
 
Proportion of subjects with baseline Hb concentration <9.5 g/dL that is 
within normal limits at Week 4 (Hb normal limit responder) 
 
Proportion of subjects who experience a change from baseline in Hb 
concentration ≥2.0 g/dL at Week 4 (Hb rise responder) 
 
Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase 
in Hb concentration of ≥2 g/dL at Week 4 (Hb rise responder) 
 
Long term efficacy endpoints i.e. proportion of subjects who are non-
anaemic at 6 and 12 months (Hb normal limit responder); normalization 
of ferritin levels at 6 and 12 months 
2.3.3    Pharmacoeconomic Endpoints 
 
Pharmacoeconomic measures include the following: 


 
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Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
14 Feb 2019
 
Number of hospital or clinic visits for administration of IV Iron. 
 
Proportion of subjects who restart IV iron during the study. 
 
Quality of life as assessed by the Medical Outcomes Study 36-item short 
form questionnaire. 
 
Correction and Maintenance of IDA  
o Repeat Hb or iron testing 
o Method of transportation to attend each visit. 
o The number of days off work or school/education to attend hospital or 
clinic visits for administration of IV Iron. 
o The time spent in the hospital or clinic receiving IV Iron. 
o The total dose of IV Iron administered over the study period.    
 
2.3.4    Safety Endpoints 
 
The safety endpoints are treatment-emergent Adverse Events (AEs), treatment-
emergent Serious Adverse Events (SAEs), AEs leading to premature discontinuation 
from the study, and adherence to study medication. 
 
 
3 
STUDY DESIGN 
 
3.1 
   Overall Study Design 
 
This study will be a Phase 3b, multicentre, open-label, active-controlled, 
randomized, parallel group prospective study to compare the efficacy and safety of 
ferric maltol to IV Iron in subjects with inflammatory bowel disease.  A total of 242 
subjects from 35-45 European sites and around 18 United States sites will be 
randomized at a ratio of 1:1 to the two treatment arms of this study. 
 
The randomization will be stratified according to screening Hb (<10g/dL or ≥ 
10g/dL for Female; < 11g/dL or ≥ 11g/dL for Male) and by IBD subgroup 
(ulcerative colitis [UC] or Crohn’s disease [CD]).  Subjects who are re-screened will 
have their re-screen Hb substituted in lieu of screening Hb for purposes of 
determining the strata for randomization. 
 
Protocol amendment 7.0 updated the study duration from 52 weeks to 12 weeks. 
For subjects who entered the study under the previous protocol for the 52 weeks 
open-label design and completed their study beyond the 12 weeks treatment 
period, the next scheduled visit will be their End of Study Visit. Otherwise, subjects 
after the eligibility screening period will enter a 12 weeks treatment period. 
 
3.2 
   Schedule of Study Assessments 
 
There will be three distinct periods in this trial: Screening, Treatment, and Post-


 
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Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
14 Feb 2019
treatment safety follow-Up. Please refer to Table 1. Schedule of Assessments below 
for details.  
 
3.2.1    Screening Period (Visit 1) 
 
A subject will enter the Screening Period (up to 14 days) upon submission of 
written informed consent to participate in the study. The subject will then complete 
the remaining screening assessments and be evaluated for eligibility to the study.  
Subjects who satisfy all inclusion and exclusion criteria for the study will be 
scheduled for Visit 2.  
 
3.2.2    Treatment Period (Visits 2-7) 
 
The Treatment Period begins on the day for which the subject receives their first 
dose of a study drug (Visit 2/Day 0) and ends on the day corresponding with Visit 7 
for those subjects enrolled prior to protocol amendment 7.0, and the day 
corresponding with Visit 4 for those subjects enrolled under protocol amendment 
7.0.  Eligible subjects will be randomized in a 1:1 ratio to receive treatment with 
either oral ferric maltol or intravenous iron.   
Subjects randomized to the oral ferric maltol treatment arm will self-administer 
study medication twice daily; first thing in the morning at least 1 hour before food 
and concomitant medications, and last thing at night before bed at least 2 hours 
after food and concomitant medications. Capsules must be taken on an empty 
stomach with water only. There should be at least an 8-hour gap between doses.  
These subjects will maintain treatment with oral ferric maltol for the duration of the 
Treatment Period. 
Subjects randomized to the intravenous iron treatment arm will receive IV Iron in 
accordance with the dosing instructions as per the local summary of product 
characteristics (SPC)/Prescribing Information (PI).  Initial dosing will be as per local 
SPC/PI, with the number of IV Iron doses administered being calculated based on 
the subject’s starting Hb and weight.  For ongoing treatment decisions, ferritin will 
be measured at Visits 4 (Week 12) and Visits 5 and 6 (Week 24, and Week 36) for 
patients prior to protocol amendment 7.0.  Subjects continuing after Week 12 who 
are iron deficient (ferritin below 100ng/mL) at any of Visits 4-6 will receive 
additional IV Iron doses according to the formula in the local SPC/PI. 
3.2.3    Follow-up Period (Visit 8) 
 
At the end of the Treatment Period, subjects will enter a 14-day Follow-up Period 
during which AEs and concomitant medications will be monitored.  At the end of the 
14-day Follow-up Period, subjects will have their Follow-up visit (Visit 8).  Visit 8 
will be conducted by telephone interview, unless the subject has an ongoing AE that 
requires physical examination or investigations for assessment/management. 
If an AE is reported or is ongoing at the time of the Follow-up visit, or if a 
significant lab abnormality is identified at the last visit prior to the Follow-up visit, 
the Investigator must follow the event until resolution or until there is a satisfactory 


 
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Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
14 Feb 2019
explanation of the changes observed. 
Table 1. Schedule of Assessments 
 
Screening 
Treatment 
8Follow-up 
Duration 
Up to 
14 days 
Week 
14 days 
 
 
0 
4 
12 
(24)15 
(36)16 
(52)17 
(54) 
9Visits 
1 
2 
3 
4 
(5) 
(6) 
(7) 
(8) 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
1Vital signs 
X 
 
 
 
 
 
 
 
2Height and weight 
X 
X 
X 
X 
(X) 
(X) 
(X) 
 
3Basic chemistry 
X 
 
 
 
 
 
 
 
4Liver function tests 
X 
 
 
 
 
 
 
 
5Haematology; Iron Markers 
X 
X 
X 
X 
(X) 
(X) 
(X) 
 
C-reactive protein 
 
X 
 
 
 
 
 
 
13Retained plasma and serum samples 
 
X 
 
X 
 
 
 
 
6Randomization 
 
X 
 
 
 
 
 
 
Collect IV Iron History/IV Iron dosing detail 
X 
X 
X 
X 
(X) 
(X) 
(X) 
 
SCCAI or CDAI12 
X12 
 
 
X 
(X) 
(X) 
(X) 
 
10Collect pharmacoeconomic (PE) and SF36 
data 
 
X 
X11 
X 
(X) 
(X) 
(X) 
 
7Pregnancy test 
X 
 
 
X 
 
 
(X) 
 
Dispense/Administer study medication 14 
 
X 
 
(X) 
(X) 
(X) 
 
 
Compliance check 
 
 
X 
X 
(X) 
(X) 
(X) 
 
Adverse events 
 
X 
X 
X 
(X) 
(X) 
(X) 
X 
Prior/Concomitant medication 
X 
X 
X 
X 
(X) 
(X) 
(X) 
X 
1  Vital signs (blood pressure & heart rate) are taken after subject has been sitting for 5 minutes.  
2  Height & weight measured during Screening, weight only at other visits. 
3 Basic chemistry: bicarbonate, BUN, creatinine, chloride, glucose, potassium, sodium, Vitamin B12 and folate, creatinine clearance (US-only). 
4 Liver function tests: ALT, AST and total bilirubin. 
5 Haematology and Iron markers all visits:  haematocrit, haemoglobin, platelets, RBC count, RBC Hb concentration; WBC count and 
     differential; total serum iron; ferritin, transferrin; TSAT.    
6 Maximum 14 days between Screening and randomization. 
7 Urine pregnancy test, kits provided by central laboratory. 
8 Follow up is conducted by telephone, unless the subject has an ongoing AE that requires physical examination or investigations for 
     assessment/management.  Visit 8 will take place 14 days after Visit 4 (week 12/Early Termination) unless subject discontinued treatment   
    early and end of study/Week 52 assessments occurred 14 days or more after the last dose. 
9 Visit Windows: Maximum of 14 days between screening and randomization.  Subjects randomized to IV Iron must complete Visit 2 ideally on 
 the day of randomisation or within 5 days.  The subject must visit to complete: 
 
 Visits 3 and 4: +/- 1 week relative to date of Visit 2/first dose administered 
 
 Visit 4 to 7: +/- 1 week relative to date of Visit 2/first dose administered 
 
 Visit 8: 14 days (+5 days) after Visit 4 (unless subject discontinued treatment early and end of study/Week 12 
  assessments occurred 14 days or more after the last dose). 
10 SF36 to be administered at Week 0 (baseline), and Week 12, 24, 36, and 52. 
11 SF36 is not collected at this visit. 


 
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Statistical Analysis Plan 
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12 For CD subjects, a CDAI diary card will be provided at Screening, for completion over the 7 days prior to scheduled Visit 2.  The screening 
     haematocrit value will be used for the screening CDAI calculation to assess eligibility prior to randomization and will also count as the 
      baseline CDAI value.  For CD subjects, CDAI diary cards will then be provided at Visits 3 and 4. Subjects who went beyond week 12 will 
receive 
CDAI 
diary 
at 
Visit 
5 
and 
6 
for 
completion 
over 
the 
7 
days 
prior 
to 
     the scheduled dates of Visit 4, 5, 6 and 7. 
13 Retained serum and plasma samples will only be collected from trial subjects at those Investigator sites who have suitable freezer facilities for  
     storage of the samples at -70°C/-80°C, prior to subsequent periodic shipping to the central laboratory on dry-ice.  Detailed instructions will be  
    provided in the Laboratory Manual. 
14. Dispense/Administer study drug: based on the randomization stratification subjects will receive FCM/Ferric Maltol on Visit 2. If subjects 
went beyond Visit 4 (Week 12) and their treatment period will be continuing according to previous protocol until the next scheduled visit. 
15. Visit 5 (Week 24) will only occur if subjects went beyond Visit 4 according to previous protocol, otherwise this will be the End of Study 
Visit. 
16. Visit 6 (Week 36) will only occur if subjects went beyond Visit 5 (week 24) according to previous protocol, otherwise this will be the End 
of Study Visit. 
17. Visit 7 (Week 52) will only occur if subjects went beyond Visit 6 (Week 36) according to previous protocol, otherwise this will be the End 
of Study Visit. 
 
4 
POWER AND SAMPLE SIZE CONSIDERATIONS 
 
This study is designed with a ‘responder %’ primary endpoint, where responder is a 
subject who either has at least 2g/dL rise in Hb from baseline or has shift from 
baseline of anaemic to non-anaemic status. The primary endpoint is the Hb 
responder rate at Week 12.  The comparator group (IV Iron) responder rate is 
assumed to be 75% and the absolute non-inferiority margin is 20%.  The non-
inferiority margin is based on clinical opinion, coupled with the fact that in a 
previous study, the response rate in the placebo arm was less than 5% at 12 
weeks. 
 
The study is powered at 90% when the true response rate in the ferric maltol arm 
is 75% (i.e., the true difference in response rate to IV Iron is 0%).  The primary 
statistical test is based on the 2-sided 95% confidence interval for the difference in 
response rates between the two treatment groups.  This requires 108 subjects per 
treatment arm.  In order to allow for protocol deviations, the sample size has been 
increased by 12% to 121 subjects per treatment arm. 
 
5 
ANALYSIS POPULATIONS 
 
5.1 
 Randomized Population 
 
The randomized population will include all subjects who are randomized. 
   
5.2 
Safety Population 
 
The Safety population will consist of all subjects who have received at least one 
dose of a study drug. Tables summarised or analysed using the safety population 
will be presented by actual treatment given. 
 
5.3 
   Intention-to-Treat (ITT) Population 
 
The ITT population will include all subjects who are randomized. However, any 
efficacy measurement obtained after a patient experienced a serious 
adverse event (SAE) of haemorrhage (defined by MedDRA under haemorrhagic 
terms), received a blood transfusion, or received intravenous iron (outwith of 


 
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Statistical Analysis Plan 
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14 Feb 2019
protocolled dose) or erythropoiesis stimulating agent will be removed from the ITT 
analysis. 
 
5.4 
   Per Protocol (PP) Population 
 
The PP population will consist of those randomized subjects who do not have major 
protocol deviations during the first 12 weeks of the study.  Protocol deviations 
occurring during the study will be classified as major or minor prior to database 
lock.  See Section 8.4 for definitions of protocol deviations. In addition, patients 
who do not attend week 12 and have no Hb result at week 12 will be excluded from 
the PP population. 
 
The ITT and PP population will be used in the primary efficacy analysis. Tables 
summarised or analysed using the ITT population will be presented by randomized 
treatment. Tables summarised or analysed using the PP population will be 
presented by actual treatment given. 
 
6 
CONSIDERATIONS FOR DATA ANALYSIS 
 
6.1 
   General Statistical Considerations 
 
All analyses described in this plan are considered a priori, in that they have been 
defined prior to locking the database.  All other analyses, if any, designed 
subsequent to locking the database, will be considered post hoc and, thereby, 
exploratory.  Post hoc analyses will be clearly identified in the Clinical Study Report. 
 
6.2 
   Programming Environment 
 
All analyses will be conducted using SAS version 9.3. 
 
6.3 
   Strata and Covariates 
 
Randomization will employ screening Hb (< 10g/dL or ≥ 10g/dL for Females; < 
11g/dL or ≥ 11g/dL for Males) and IBD subgroup (UC or CD) as binary stratification 
factors.  Unless otherwise indicated, IBD subgroup will be included as a binary 
stratification factor and baseline Hb will be included as a continuous factor in 
statistical modelling. 
 
6.4 
   Subgroups 
 
The secondary endpoint analyses involving haemoglobin (see Sections 9.2.1.1 and 
9.2.1.3) will be repeated for the subgroup of subjects with baseline Haemoglobin < 
9.5g/dL.    
 
6.5 
   Multiple Comparisons and Multiplicity 
 
There are no planned adjustments for multiple comparisons. 
 
 


 
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6.6 
   Significance Level 
 
Unless stated otherwise, all statistical tests will be two-sided, with a significance 
level of 0.05. Confidence intervals (CIs) will be calculated at the 95% level, 
reflecting a type I error rate of 0.05. 
 
6.7 
   Statistical Notation and Methodology 
 
Unless stated otherwise, the term “descriptive statistics” refers to the number of 
subjects (n), mean, median, standard deviation, minimum, and maximum for 
continuous data and frequency distributions (counts and percentages) for 
categorical data. The denominator for percentages will use the number of subjects 
in the appropriate analysis population.  Minimum and maximum values will be 
rounded to the precision of the original value, means and medians will be rounded 
to 1 decimal place greater than the precision of the original value, and standard 
deviations will be rounded to 2 decimal places greater than the precision of the 
original value. Percentages will be rounded to the nearest whole number (zeros are 
not displayed) with values of “<1%” and “>99%” shown as necessary for values 
falling near the boundaries (i.e., 0% and 100%).  P-values will be presented with a 
precision of 3 decimal places, and p-values less than 0.001 will be presented as 
“<0.001”. 
 
Unless otherwise noted, all data collected during the study will be included in data 
listings and will be sorted by site number, subject number, and then by date/time 
for each subject number.  
 
7 
DATA HANDLING METHODS 
 
7.1 
   Missing Data 
 
7.1.1    Date Values 
 
In cases of incomplete dates (e.g. AE, concomitant medication, and medical history 
start and/or stop dates), the missing component(s) will be assumed as the most 
conservative value possible.  For example, if the start date has a missing day value, 
the first day of the month will be imputed for study day computations (i.e. 
treatment-emergent status, etc.) unless it is the same month and year (only day 
missing) or year (day and month missing) as start date of treatment.  In this case, 
start date of treatment will be used, which assumes treatment emergence.  If day 
is missing for an end date, the last day of the month will be imputed.   
 
Date imputation will only be used for computational purposes such as treatment-
emergent status, etc.  Actual data values, as they appear in the original CRFs, will 
be presented within the data listings. 
 
 


 
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7.1.2    Non-Date Values 
 
Every effort will be made to obtain required data at each scheduled evaluation from 
all subjects who have been enrolled.  Missing values for the primary efficacy 
endpoint of Hb responder (i.e., a subject who either has at least 2g/dL rise in Hb 
from baseline or has shift from baseline of anaemic to non-anaemic status) at Week 
12 will be imputed using a Multiple imputation approach for the primary efficacy 
analysis on the ITT population.  If the value of Hb is missing, multiple imputation 
based on pre-treatment visits will be used in the baseline and multiple imputation 
based on post-treatment visits will be used to determine the post-baseline value to 
be used in the primary efficacy endpoint analysis on the ITT population. 
 
As additional sensitivity analyses, missing values for the primary efficacy endpoint 
on the ITT population will also be imputed using a Last Observation Carried Forward 
(LOCF) approach up to Week 12. 
 
Missing values for efficacy variables will be replaced for the secondary endpoint 
analyses, as follows: 
 
For the key endpoint, ‘Hb concentration within normal limits’, subjects not 
returning to a follow-up visit will be assumed to have Hb concentration not 
within normal limits.   
 
For the endpoint, ‘Increases in Hb concentration of ≥ 1g/dL’, subjects not 
returning to a follow-up visit will have their Hb concentration imputed using 
multiple imputation. 
 
For the endpoint, ‘Increases in Hb concentration of ≥ 2g/dL’, subjects not 
returning to a follow-up visit will have their Hb concentration imputed using 
multiple imputation. 
Missing values for the long-term secondary efficacy endpoints, normalization of Hb 
at 6 and 12 months and normalization of ferritin at 6 and 12 months, will not be 
imputed. 
Missing values for the SF-36 pharmacoeconomic analysis will be imputed by a LOCF 
approach up to Week 12.  Missing values for all other pharmacoeconomic analyses 
will be kept as missing. 
Safety data will be used according to availability, with no imputation for missing 
data. 
Imputation of data values will only be carried out, where indicated, for 
computational purposes and fitting of models.  Actual data values, as they appear 
in the original CRFs, will be shown in the data listings.  
 
7.2 
   Visit Windows 
 


 
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Subjects should attend the study visits according to Table 1. Schedule of 
Assessments. 
 
Values will be presented for all scheduled study visits according to the nominal visit 
obtained from the CRF.  If an unscheduled visit falls in a visit window with an 
existing nominal visit assessment, the nominal assessment will be used for 
summary presentation.  If no nominal visit assessment exists for a visit window 
with unscheduled visit(s), then the latest unscheduled visit within the visit window 
will be used.  If multiple nominal assessments are collected within the same visit, 
the latest value and corresponding date will be used for summary presentation. 
 
All values will be included in the data listings.  
 
7.3 
   Data Derivations and Definitions 
 
The following definitions and derivations will be used for this study: 
 
 
Baseline will be defined as the last measurement collected prior to 
administration of the first dose of a study drug.  
 
 
Change from baseline (CFB) will be calculated as:  
 
 
CFB = observed value – baseline value. 
 
 
As detailed in the protocol, the randomization visit is Visit 2 / Day 0 (the date of 
first dose with ferric maltol or FCM). 
In order to be consistent with the SDTM guidance, within SDTM and ADaM 
datasets, Study Day 1 will be the day corresponding to subject randomization, 
and Study Day -1 will be the day prior to subject randomization. 
  
 
 
Age in years will be as indicated within the CRF. 
 
 
A subject will be considered to have normalized Hb if their measured Hb is 
greater than 12.0 g/dL (females) or 13.0 g/dL (males).  
 
 
 
An AE will be considered treatment-emergent if it begins or worsens on the day 
of or after the first dose of study medication and within 14 days of the last dose 
of study medication.  AEs will be considered treatment-emergent if all or part of 
the date of onset of the AE is missing and it cannot be determined if the AE 
meets the definition for treatment-emergent. 
 
 
Concomitant medications will be those medications that began or stopped on or 
after the date corresponding with the first dose of a study drug. 
 
 
Prior medications will be those medications that ended before the date 
corresponding with the first dose of a study drug.  Concomitant and prior 
medications are mutually exclusive. 


 
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 
Study completers will be those subjects who complete the study procedures for 
all visits up to and including the Follow-up visit. 
 
 
Observed Cases (OC) will include assessments collected at each scheduled or 
unscheduled visit and will not contain imputed values. 
 
 
 
Last Observation Carried Forward (LOCF) utilizes the clinical assessment value of 
each efficacy endpoint (primary or secondary), if available, or carries-forward 
the last available assessment value. 
 
 
The non-inferiority margin is the maximum difference in the primary efficacy 
analysis between the two treatment arms we are prepared to tolerate if the 
ferric maltol treatment is not to be considered [clinically] inferior to the IV Iron 
treatment.  The non-inferiority margin for this study is 20%. 
 
8 
STUDY POPULATION 
 
Unless otherwise noted, the ITT population will be used for listings of the study 
population. ITT and PP populations will be used for summaries of the study 
population. 
 
8.1 
   Analysis Populations 
 
An analysis population listing will be provided for all enrolled subjects.  This listing 
will include, for each population detailed in Section 5, whether or not the subject 
was included in the population and the reason for being excluded from the 
population.  Number and percentage of subjects in each analysis population (ITT, 
PP, and Safety) will be summarised by treatment arm and overall (both treatment 
arms combined) for the Randomized population.  The denominators for calculating 
the percentages will be based on the subjects of the Randomized population for the 
treatment arm summarised. 
 
8.2 
   Subject Disposition 
 
Subject disposition will be presented for all screened subjects.  Number and 
percentage of subjects who enrol, complete the study, prematurely discontinue 
from the study, and reasons for study discontinuation will be summarised by 
treatment arm and overall.  The denominator for calculating percentages will be 
based on the number of screened subjects. 
 
8.3 
   Inclusion/Exclusion Criteria 
 
Inclusion and exclusion criteria failures will be included in a data listing for the ITT 
population.  
 
 


 
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8.4 
   Protocol Deviations 
 
Major deviations, for the purpose of the statistical analyses, are defined to be those 
deviations that could potentially bias either efficacy or safety conclusions of the 
study.  Subjects associated with major protocol deviations will be identified and 
flagged prior to freezing (or, locking) the database at each of the two planned 
database freeze (or, lock) timepoints (interim analysis freeze/lock and end-of-study 
freeze/lock). 
 
Major protocol deviations include, but are not limited to, the following categories: 
 
Subjects that received at least one dose of a study drug and who did not 
satisfy major inclusion/exclusion criteria. 
 
Subjects meeting conditions for withdrawal who were not withdrawn. 
 
Subjects that received a prohibited concomitant medication. 
 
Subjects that had at least one major required protocol procedure not being 
performed.  Examples of major required protocol procedures include missing 
haemoglobin results at baseline and/or at Week 12. 
 
Subjects that received the opposite study drug treatment than the one to 
which they were randomized. 
 
Repeated non-compliance in self-administration of ferric maltol study drug, 
where non-compliance is less than 80% or greater than 120% of expected 
administration of study drug. 
 
Other relevant deviations, to be judged on an individual basis.  
 
Protocol deviations will be summarised with frequency distributions (counts and 
percentages) by treatment arm, category, and deviation type (minor and major) for 
the ITT population.  The denominators for calculating percentages will be based on 
the number of subjects in the analysis population for each treatment arm and 
overall. 
 
Protocol deviations will be provided within a data listing by subject. 
 
8.5 
   Demographic and Other Baseline Characteristics 
 
The demographics listing will include year of birth, age, gender, ethnicity 
(Hispanic/Latino or non-Hispanic/Latino), race (American Indian/Alaskan Native, 
Asian, Black/African American, Native American/Pacific Islander, White, Other), and 
baseline Hb.   
 
The listing of reproductive status will include fertility status (sterile, post-
menopausal, potentially fertile), method of birth control (barrier method with 
spermicide, oral contraceptives, depot contraceptives [implants/injectables], 
injectables, intrauterine device, complete sexual abstinence, vasectomized partner, 


 
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none, other), date of last menstrual cycle, and whether it has been more than one 
year since the last menstrual cycle. 
 
The listing of randomization will include the stratification levels for IBD subgroup 
(UC or CD) and screening Hb (< 10g/dL or ≥ 10g/dL for Females; < 11g/dL or ≥ 
11g/dL for Males), the randomization date/time, assigned (planned) treatment arm, 
and the actual treatment corresponding to the study drug received. 
 
The listing of IBD status will include date (month and year) of IBD diagnosis, date 
(month and year) for each of the last 3 flares of IBD preceding randomization, and 
IBD subgroup. 
 
Demographic and baseline characteristics will be summarised using descriptive 
statistics by treatment arm and overall for the ITT and PP populations.  The 
summary will present: each of the variables included in the demographics listing, 
with the exception of year of birth; fertility status, summarised separately for males 
and females; and, the stratification levels used in randomization.  Subjects who 
report more than one racial category will be summarised in a separate derived race 
level labelled as “Multiple”. 
 
8.6 
   Prior and Concomitant Medications 
 
Prior and concomitant medications, including: all prescription iron replacement 
therapies taken in the last 12 months prior to screening; all oral ferrous treatment 
history prior to screening; and, all IV Iron treatment history prior to screening will 
be coded with the World Health Organization (WHO) drug dictionary.  Prior and 
concomitant medications will be separately summarised with descriptive statistics 
by drug Anatomical Therapeutic Chemical (ATC) Classification System (level one), 
generic name, and treatment arm for safety population.  Data listings will be 
included that show all medications by generic name and verbatim name. 
 
8.7 
   Medical History  
 
A comprehensive data listing of all medical histories and ongoing conditions 
(including start and stop dates and status at end of study) – for the immediate 5 
years preceding randomization – will be included.  Medical history codes will be 
summarised for each treatment arm and overall for both ITT and PP populations.  
 
8.8 
   Subject Progress and Unscheduled Visits 
 
Progression for each scheduled visit will be displayed in a listing by subject.  An 
unscheduled visit listing will include the date of each visit and a description of the 
assessments performed at the visit. 
 
8.9 
   Study Drug Disposition 
 
The duration of exposure (days) to study drug will be summarised by treatment 
arm using descriptive statistics for the Safety population.  Duration of exposure will 


 
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be calculated as the difference between the last dose date of study drug and the 
first dose date of study drug plus 1 day.  Administration dates of IV Iron will be 
provided in a data listing by subject, for those subjects randomized to the IV Iron 
treatment arm. 
 
Compliance with ferric maltol will be assessed at each visit for which the study drug 
is returned by the subject, and also assessed over the entire Treatment Period.  
Compliance will be evaluated by comparing the expected number of capsules of 
ferric maltol administered – based on the total number of treatment days between 
visits and within the entire treatment period – with the actual number of capsules 
of ferric maltol taken.  If the return date is missing for a particular visit, then 
compliance will be missing for that visit.  Compliance with ferric maltol will be 
calculated for subjects of the Safety population who are randomized to the ferric 
maltol treatment arm.  Compliance values that are less than 0% will be set to 0%.  
Summaries of compliance will be presented using descriptive statistics for subjects 
of the Safety population who are randomized to the ferric maltol treatment arm.  A 
data listing of treatment compliance will be provided by subject, for those subjects 
of the Safety population who are randomized to the ferric maltol treatment arm. 
 
 
Compliance will be calculated as follows and expressed by a percentage: 
 
Compliance = (#caps disp - #caps ret) / (#caps exp to be administered), 
 
where #=number of, caps=capsules, disp=dispensed, ret=returned, exp=expected. 
 
9 
EFFICACY ANALYSES 
 
The ITT and PP populations will be used for summaries and analyses of all efficacy 
endpoints described below.   
 
In addition to the tables described in the sections below, data for efficacy variables 
will be provided in data listings by subject. 
 
9.1 
   Primary Efficacy Analyses 
 
9.1.1    Primary Analysis 
 
Haemoglobin (Hb) concentration will be collected at screening (Visit 1), pre-
randomization at Visit 2 (baseline assessment), and at each visit over the 
Treatment Period. Hb concentration (Observed Cases [OC]) will be summarised for 
the ITT and PP populations using descriptive statistics by visit for each treatment 
arm and overall.  A scatterplot of Hb concentrations (OC) at Week 12 versus 
baseline will be presented by treatment arm for the ITT and PP populations.  
 
A dichotomous variable, representing response status in the degree to which Hb 
increases relative to baseline, will be calculated for each visit over the Treatment 
Period.  Those subjects with at least 2g/dL increase in Hb from baseline or who 


 
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have normalization of Hb (>12.0 g/dL for women, >13.0 g/dL for men) will be 
classified as “Hb responders”.   
 
The null hypothesis for the primary efficacy endpoint analysis is that the proportion 
of Hb responders at Week 12 in the ferric maltol treatment arm is at least 20% 
lower than the proportion of Hb responders at Week 12 in the IV Iron treatment 
arm (i.e., ferric maltol is inferior to IV Iron for rate of Hb response at Week 12).  
The alternative hypothesis is that the proportion of Hb responders at Week 12 in 
the ferric maltol treatment arm is not worse than 20% lower than the proportion of 
Hb responders at Week 12 in the IV Iron treatment arm (i.e., ferric maltol is non-
inferior to IV Iron for rate of Hb response at Week 12). 
 
The proportion of Hb responders at Week 12 will be compared between the two 
treatment arms, by calculating a 2-sided confidence interval for difference in the 
proportions of Hb responders (risk difference) between the two treatment arms and 
comparing the lower confidence limit of this CI to the pre-specified non-inferiority 
margin.  The CI will be calculated using the Delta Method approach [1] based on a 
logistic regression model, adjusted for treatment arm, baseline Hb (below the 
observed median or at least the observed median), and IBD subgroup (UC or CD). 
 
Note that missing values for the Hb responder status at Week 12 primary efficacy 
analysis will be imputed using a multiple imputation approach for ITT population.  
BOCF will be used in the case of missing baseline data to use the screening value.  
Missing values of Hb concentration at Week 12 will be imputed using the SAS 
procedure MI. This will generate 20 complete datasets containing imputed values of 
Hb concentration at Week 12 for those missing in the original dataset.  Variables 
considered helpful in guiding this imputation are baseline (Visit 2) Hb concentration 
and treatment arm.  The code for implementing the SAS procedure MI is: 
 
PROC MI DATA = <dataset _name> NIMPUTE = 20 SEED = <seed> OUT = MI_out; 
  VAR baselineHb TreatmentArm Week12Hb; 
  EM MAXITER = 10000; 
RUN;    
 
Each model, corresponding to a given endpoint analysis, will be fitted against each 
of the imputed datasets.  The SAS procedure MIANALYZE will then be used to 
combine the individual analysis results for the given endpoint into one result. 
   
The null hypothesis for the primary efficacy analysis will be rejected (i.e., ferric 
maltol will be deemed non-inferior to IV Iron), if the LCL of the 95% CI for the 
difference (ferric maltol - IV Iron) in proportions of Hb responders at Week 12 
(BOCF) is ≥ -20% for both the ITT analysis and the PP analysis. The p-value in 
testing the aforementioned hypotheses will be equal to one minus the confidence 
coefficient corresponding to the CI for the risk difference whose LCL equals -20% 
(i.e., inverting the CI for the risk difference to a test statistic and calculating the p-
value from the test statistic). 
 
The proportion of Hb responders will be summarised for the ITT and PP populations 
using descriptive statistics by visit over the Treatment Period for each treatment 


 
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arm and overall, utilizing all available Hb responder data (i.e., OC approach).  Each 
summary will also present the proportion of Hb responders for the Week 12 visit 
(MI) using descriptive statistics, and will include the corresponding logistic 
regression model adjusted difference in the proportions of Hb responders between 
the two treatment arms, the corresponding adjusted 95% CI for the difference in 
proportions, and the adjusted p-value from testing the null hypothesis of inferiority 
in risk difference with non-inferiority margin 20%.  Finally, each summary will also 
present the estimated logistic regression model adjusted odds ratio of Hb responder 
at Week 12 (MI) between the two treatment arms and corresponding 95% CI for 
the odds ratio.  A bar plot of the Hb responder rate will be presented by visit (OC) 
and treatment arm for each assessment.  
 
9.1.2    Sensitivity Analysis 
 
Two sensitivity analyses will be performed for the primary efficacy endpoint. 
 
9.1.2.1 Observed Cases (OC) Analysis 
 
The first sensitivity analysis will include all available assessments of Hb responder 
and will not exploit imputation of missing Hb responder status (i.e., only Observed 
Cases [OC] of Hb responder status are considered here).  The primary efficacy 
endpoint analysis will be repeated using the OC approach for the ITT and PP 
populations.  The proportion of Hb responders at Week 12 (OC) will be summarised 
using descriptive statistics for each treatment arm and overall.  The summary will 
include the corresponding logistic regression model adjusted difference in the 
proportions of Hb responders (risk difference) between the two treatment arms, the 
adjusted 95% CI for the difference in proportions, and the adjusted p-value from 
testing the null hypothesis of inferiority in risk difference with non-inferiority margin 
20%.  The summary will also include the estimated adjusted odds ratio of Hb 
responder at Week 12 (OC) between the two treatment arms and corresponding 
95% CI for the odds ratio. 
 
9.1.2.2 Observed Cases (OC) Repeated Measures Analysis 
 
The second sensitivity analysis for the primary efficacy endpoint will be performed 
on the ITT and PP populations, in which Hb responder status will be analysed in a 
longitudinal analysis using a repeated measures generalized linear mixed model 
(GLMM) approach (i.e., a repeated measures logistic regression approach) for all 
available assessments of Hb (i.e., only Observed Cases [OC] of Hb responder status 
are considered here) over Visits 2 (Day 0; baseline) to 4 (Week 12).  The approach 
will fit a logistic model to the Hb responder dependent variable, where an 
unstructured working correlation structure will be specified (e.g., by way of the 
appropriate random statement within the GLIMMIX SAS procedure) to model the 
within-subjects correlation of repeated Hb responder status at Visits 3 and 4.  If the 
model fit fails to converge, alternative working correlation structures will be 
examined.  Covariates of the GLMM will include the fixed effects of treatment, 
baseline Hb, IBD subgroup, visit, and treatment-by-visit interaction.  The estimated 
adjusted odds ratio for treatment effect, and its corresponding 95% CI, from the 


 
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model will be presented by visit. 
 
To assess the sensitivity of Hb responder status over time – by way of a general 
linear model (GLM) approach – separate logistic regression models will be fitted to 
the Hb responder dependent variable at each visit during the Treatment Period up 
to Week 12, using all available assessments of Hb (i.e., only Observed Cases [OC] 
of Hb responder status are considered here).  Each model will include terms for the 
effects of treatment, baseline Hb (below the observed median or at least the 
observed median), and IBD subgroup.  The estimated adjusted odds ratio for 
treatment effect, and its corresponding 95% CI, will be presented for each model 
(i.e., by visit).  Sensitivity of Hb responder status over time will be assessed by 
comparing these by-visit treatment effect odds ratio estimates from the logistic 
regression models (the GLMs) to those obtained from the GLMM model. 
 
 
9.2 
   Secondary Efficacy Analyses 
 
9.2.1 Secondary Analysis 
 
9.2.1.1 Key Secondary Endpoints 
 
The change from baseline (CFB) in Hb concentration at Week 12 (MI) secondary 
endpoint will be analysed for the ITT population using an analysis of covariance 
(ANCOVA) model.   
 
For the multiple imputation, the code for implementing the SAS procedure 
MIANALYZE to the CFB Hb concentration at Week 12 secondary endpoint is: 
 
DATA CFB_Impute; SET MI_out;  CFBHbW12 = Week12Hb – baselineHb; RUN; 
 
PROC SORT DATA = CFB_Impute; BY _Imputation_; RUN; 
 
PROC REG DATA = CFB_Impute OUTEST = outreg COVOUT; 
  BY _Imputation_; 
  MODEL CFBHbW12 = binarybaselineHb TreatmentArm IBDGroup; 
RUN; 
 
PROC MIANALYZE DATA = outreg EDF = <complete-data degrees of freedom>; 
  MODELEFFECTS Intercept binarybaselineHb TreatmentArm IBDGroup; 
  ODS OUTPUT ParameterEstimates = parm1; 
RUN; 
 
The ANCOVA model will have terms for treatment arm, baseline Hb (below the 
observed median or at least the observed median), and IBD subgroup.  The 
treatment effect of ferric maltol compared to IV Iron will be considered using 
differences of adjusted means.  No formal statistical significance level in the 
treatment comparison will be defined, as the p-value from the ANCOVA model will 
be presented for descriptive purposes only.  A summary of CFB in Hb concentration 
(OC) will be provided using descriptive statistics for each visit over the Treatment 
Period by treatment arm and overall.  The summary will include the following 


 
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ANCOVA model estimates: adjusted means (i.e., Least-Square Means [LSMs]) of 
CFB in Hb concentration at Week 12 for each treatment arm, the difference in 
treatment arm LSMs, the corresponding 95% CIs for treatment arm specific LSMs 
and difference in treatment arm LSMs, and the p-value for the difference in 
treatment arm LSMs.  Mean CFB in Hb concentration will be plotted against visit 
(OC) by treatment arm for the ITT and PP populations. 
 
A dichotomous variable, representing status of Hb concentration relative to the 
normal limits of Hb will be calculated for each visit over the Treatment Period.  
Women with Hb concentration greater than 12 g/dL and men with Hb concentration 
greater than 13 g/dL will be classified to be within normal limits of Hb. Those 
subjects with Hb concentration within the normal limits will be classified as “Hb 
normal limit responders”.  Subjects missing Hb concentration at Week 12 will be 
assumed to have Hb concentration not within normal limits (i.e., these subjects will 
be considered Hb normal limit non-responders).  The logistic regression modelling 
and hypothesis testing for the primary analysis (Section 9.1.1) will be repeated 
here for the Hb normal limit responder at Week 12 secondary endpoint. 
 
The code for implementing the SAS procedure MIANALYZE to the Hb normal limit 
responder at Week 12 secondary endpoint for the ITT population is: 
DATA NormalHb_Impute; SET MI_out;   
  NLResponder = 0; 
  IF Gender =: ‘F’ AND Week12Hb > 12.0 THEN NLResponder = 1; 
  IF Gender =: ‘M’ AND Week12Hb > 13.0 THEN NLResponder = 1;  
RUN; 
 
PROC SORT DATA = NormalHb_Impute; BY _Imputation_; RUN; 
 
PROC LOGISTIC DATA = NormalHb_Impute; 
  MODEL NLResponder = binarybaselineHb TreatmentArm IBDGroup / covb; 
  BY _Imputation_; 
  ODS OUTPUT ParameterEstimates = lgsparms 
                      CovB                       = lgscovb; 
RUN; 
 
PROC MIANALYZE PARMS = lgsparms COVB(effectvar=stacking) = lgscovb; 
  MODELEFFECTS Intercept binarybaselineHb TreatmentArm IBDGroup; 
RUN 
 
A summary will be provided for the Hb normal limit responder secondary endpoint 
using descriptive statistics by visit over the Treatment Period for each treatment 
arm and overall, utilizing all available Hb data (i.e., OC approach).  The summary 
will also present the Hb normal limit responder rate for the Week 12 visit (MI) for 
ITT population using descriptive statistics, and will include the corresponding 
logistic regression model adjusted difference in proportions of Hb normal limit 
responders between the two treatment arms, the corresponding [Delta Method 
derived] adjusted 95% CI for the difference in proportions, and the p-value from 
testing the null hypothesis of inferiority in risk difference with non-inferiority margin 
20%.  Finally, the summary will also present the estimated logistic regression 
model adjusted odds ratio of Hb normal limit responders at Week 12 (MI) between 


 
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the two treatment arms and corresponding 95% CI for the odds ratio. 
 
9.2.1.2 Other Secondary Efficacy Endpoints 
 
The analysis for the key secondary endpoint, CFB in Hb concentration at Week 12 
(MI), will be repeated for the secondary endpoints: CFB in Hb concentration at 
Week 12 (MI) in subjects with baseline Hb <9.5 g/dL; CFB in Hb concentration at 
Week 4 (MI); and, CFB in Hb concentration at Week 4 (MI) in subjects with a 
baseline Hb <9.5 g/dL. 
 
Two dichotomous variables, each representing response for the magnitude rise in 
Hb from baseline, will be calculated for each visit during the Treatment Period from 
the Hb concentration data.  Those subjects with a rise in Hb from baseline of at 
least 1g/dL will be classified as “Hb rise responders” for the first variable; those 
subjects with a rise in Hb from baseline of at least 2g/dL will be classified as “Hb 
rise responders” for the second variable.  Separate logistic regression models will 
be fitted to each of the Hb rise responders at Week 12 variables (secondary 
endpoints) using an MI approach for the ITT populations.  Each model will include 
terms for the effects of treatment, baseline Hb (below the observed median or at 
least the observed median), and IBD subgroup.  A hypothesis test of the null 
hypothesis of inferiority for ferric maltol responder rate compared to IV Iron 
responder rate will be considered for each Hb rise responder secondary endpoint 
using a non-inferiority margin of 20%.  No formal statistical significance level to 
declare non-inferiority (i.e., rejection of the null hypothesis) of ferric maltol to IV 
Iron is defined, as CIs and p-values will be presented for descriptive purposes only.  
The p-value in testing the aforementioned hypotheses will be calculated as 
described in the primary analysis (Section 9.1.1).   
 
The above analysis will be repeated for the secondary endpoints: proportions of 
subjects with baseline Hb <9.5 g/dL that achieve an increase in Hb concentration of 
≥1 or ≥2 g/dL at Week 12; proportions of subjects who experience a change from 
baseline in Hb concentration ≥1 or ≥2 g/dL at Week 4 (MI); and, proportions of 
subjects with baseline Hb <9.5 g/dL that achieve an increase in Hb concentration of 
≥1 or ≥2 g/dL at Week 4 (MI).  In addition, the above analysis for the Hb normal 
limit responder at Week 12 key secondary endpoint will be repeated for the 
secondary endpoints: proportion of subjects with baseline Hb <9.5 g/dL that is 
within normal limits at Week 12; proportion of subjects with Hb concentration 
within normal limits at Week 4; and, proportion of subjects with baseline Hb <9.5 
g/dL that is within normal limits at Week 4 (MI). 
 
Serum ferritin will be collected at screening (Visit 1), pre-randomization at Visit 2 
(baseline assessment), and at each visit over the Treatment Period.  The above 
ANCOVA analysis will be repeated for the CFB in serum ferritin at Week 12 (MI) 
secondary endpoint.  A summary of serum ferritin and CFB in serum ferritin (OC) 
will be provided using descriptive statistics for each visit (CFB will be presented at 
each visit during the Treatment Period) by treatment arm.  The summary will 
include the following ANCOVA model estimates: adjusted means (i.e., Least 
Squares Means [LSMs]) of CFB in serum ferritin at Week 12 for each treatment 


 
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arm, the difference in treatment arm LSMs, the corresponding 95% CIs for 
treatment arm specific LSMs and difference in treatment arm LSMs, and the p-value 
for significance of the difference in treatment arm LSMs.  Normality and 
homogeneity of variances for the residuals of each ANCOVA model will be assessed 
using the procedure outlined in Section 9.2.1.1. 
 
9.2.1.3 Long-term Secondary Endpoints 
 
 
A dichotomous variable, representing anaemia status (anaemic versus non-
anaemic), will be calculated for each visit over the Treatment Period.  Women with 
Hb levels greater than 12.0 g/dL and men with Hb levels greater than 13.0 g/dL will 
be classified as non-anaemic.  Separate logistic regression models will be fitted to 
the long-term secondary endpoints, anaemia status at each visit over Visits 5-7 
(OC), for the ITT and PP populations.  Each model will include terms to capture the 
effects of treatment, baseline Hb (below the observed median or at least the 
observed median), and IBD subgroup.  The above hypothesis testing for Hb normal 
limit responder (Section 9.2.1.1) will be repeated here for the anaemia status 
secondary endpoint. 
 
A dichotomous variable, representing status of serum ferritin level relative to the 
normal limits of serum ferritin, will be calculated for each visit over the Treatment 
Period.  Women with serum ferritin between 10 and 291 ng/ml and men with serum 
ferritin between 22 and 322 ng/ml will be classified to be within normal limits of 
serum ferritin.  Those subjects with serum ferritin within the normal limits will be 
classified as “ferritin normal limit responders”.  Separate logistic regression models 
will be fitted to the long-term secondary endpoints, ferritin normal limit responder 
at each visit over Visits 5-7 (OC), for the ITT and PP populations.  Each model will 
include terms to capture the effects of treatment, baseline Hb (below the observed 
median or at least the observed median), and IBD subgroup.  The above hypothesis 
testing for rise in Hb responder (Section 9.2.1.2) will be repeated here for the 
serum ferritin normal limit responder secondary endpoint. 
 
Separate summaries will be provided for each of the binary long-term secondary 
endpoint variables defined above.  Each secondary endpoint will be summarised 
using descriptive statistics by visit over the Treatment Period for each treatment 
arm and overall, utilizing all available data (i.e., OC approach).  Each summary will 
also present the corresponding logistic regression model adjusted difference in 
proportions (risk difference) of secondary endpoint Hb responders between the two 
treatment arms, the corresponding [Delta Method derived] adjusted 95% CI for the 
difference in proportions, and the p-value from testing the null hypothesis of 
inferiority in risk difference with non-inferiority margin 20%.  Finally, each 
summary will also present the appropriate estimated logistic regression model 
adjusted odds ratio of secondary endpoint at Visits 5-7 (OC) between the two 
treatment arms and corresponding 95% CI for the odds ratio. 
 
Any patients who are in the PP population but have major deviations after Week 12 
will be excluded from the PP analyses of the long-tern secondary endpoints. 


 
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10 PHARMACOECONOMIC ANALYSES 
 
Unless otherwise noted, the ITT population will be used for all analyses, summaries, 
and listings of pharmacoeconomic endpoints. 
 
10.1 Medical Outcomes Study 36-item Short Form (SF-36) 
 
The SF-36 is a multipurpose, proprietary health survey with 36 questions (www.sf-
36.org).  It was constructed to survey health status in the Medical Outcomes Study 
and designed for use in clinical practice and research, health policy evaluations, and 
general population surveys.  The SF-36 includes one multi-item scale that assesses 
eight health concepts (components): 
 
Limitations in physical activities because of health problems (SF-36 Physical 
Functioning Component); 
 
Limitations in social activities because of physical or emotional problems (SF-
36 Social Functioning Component); 
 
Limitations in usual role activities because of physical health problems (SF-36 
Role-Physical Component); 
 
Bodily pain (SF-36 Bodily Pain Component); 
 
General mental health (psychological distress and well-being [SF-36 Mental 
Health Component]); 
 
Limitations in usual role activities because of emotional problems (SF-36 
Role-Emotional Component); 
 
Vitality (energy and fatigue [SF-36 Vitality Component]); and 
 
General health perceptions (SF-36 General Health Component). 
 
These eight health component scales can be further summarised into two summary 
scores, the SF-36 Mental Component Score (MCS) and the SF-36 Physical 
Component Score (PCS). 
 
The survey was constructed for self-administration by persons 14 years of age and 
older, and for administration by a trained interviewer in person or by telephone.  
The SF-36 survey will be administered at study visits as indicated in the schedule of 
assessments (Table 1), commencing pre-randomization at Visit 2.  The SF-36 
survey will be completed by the subjects in their native language.  Missing values 
for each of the 36 items of the SF-36 will employ a LOCF approach in ITT analyses 
up to Week 12.   
 
The process of computing SF-36 component scales involves several steps [4].  First, 
10 items of the survey are reverse-coded.  Next, component-specific raw scales are 
formed by way of simple summation over the item scores for the appropriate health 
component of the SF-36.  The component-specific raw scales are then transformed 
to range between 0 and 100, followed by a norm-based (z-score) transformation.  


 
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The latter transformation is carried out such that each scale is mapped to the scale 
of the 1998 general United States (US) population [4].  The two summary scores, 
MCS and PCS, are computed by aggregating norm-based component scores using 
factor score coefficients from the 1990 general US population [4].  The aggregated 
summary scores are standardized to have a mean of 50 with a standard deviation 
of 10, in the general 1998 US population [4].  The full SF-36 scoring algorithm is 
published in [4] and is the approach we take here to score the SF-36.  A summary 
of each of the 8 subscales and the 2 summary scores will be presented using 
descriptive statistics by visit (OC) for each treatment arm and overall. 
 
The change from baseline (CFB) in each of the 8 SF-36 component subscales and 
the 2 summary scores will be calculated for each visit during the Treatment Period 
(BOCF) and analysed with separate ANCOVA models.  Each ANCOVA model will 
include terms for treatment arm, baseline Hb (below the observed median or at 
least the observed median), and IBD subgroup.  A hypothesis test for the treatment 
effect of ferric maltol compared to IV Iron will be conducted using differences of 
adjusted means.  Statistical significance in the treatment comparison will be 
declared if the p-value of the hypothesis test from the ANCOVA model is less than 
or equal to 0.05.  Significance levels will not be adjusted for multiplicity.  A 
summary of CFB in each SF-36 subscale and each summary score will be provided 
using descriptive statistics for each visit during the Treatment Period (OC and 
BOCF) by treatment arm.  The summary will include the ANCOVA estimates: 
adjusted means (LSMs) of CFB in each SF-36 component and summary score for 
each treatment arm, the difference in treatment arm LSMs, corresponding 95% CIs 
for LSMs and difference in treatment arm LSMs, and the p-value for the comparison 
of treatment arm LSMs.  Normality and homogeneity of variances for the residuals 
of each ANCOVA model will be assessed using the procedure outlined in Section 
9.2.1.1. 
 
A data listing of the SF-36 questionnaire will be presented by visit and subject. 
 
10.2 Correction and Maintenance of IDA 
 
Status (yes or no) of administration of IV Iron will be documented at each visit 
(scheduled or unscheduled) over the Treatment Period for subjects randomized to 
the IV Iron treatment arm, commencing with the assessment conducted post-
randomization at Visit 2.  The total number of visits (scheduled and unscheduled) of 
administration of IV Iron over the Treatment Period will be calculated for each 
subject randomized to the IV Iron treatment arm.  A summary of administration of 
IV Iron will be provided using descriptive statistics by visit, including a visit labelled 
“unscheduled”, over all visits, and over Post-Day 0 visits.  The summaries over all 
visits and Post-Day 0 visits will capture the respective number of hospital visits for 
administration of IV Iron and restart of IV Iron pharmacoeconomic endpoints.  
Missing values of administration of IV Iron will be kept as missing in the summary.  
A data listing of dose administration will be provided by subject. 
 
Details of IV Iron dosing at the study site include: the duration of time (hours) 
spent at the study site for IV Iron administration; the dose (mg) of IV Iron 


 
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administered at the study site; and, the number of days off work (or, 
school/education or childcare) that the subject is required to miss due to 
administration of IV Iron at the study site, will be documented at each visit 
(scheduled or unscheduled) over the Treatment Period for subjects randomized to 
the IV Iron treatment arm.  A summary of these IV Iron dosing details will be 
provided using descriptive statistics by visit (including a visit labelled 
“unscheduled”).  A data listing of IV Iron dosing details will be provided by subject. 
 
Status (yes or no) of repeat Hb or Iron testing will be documented at each 
unscheduled visit over the Treatment Period.  The total number of repeat Hb or Iron 
tests over all unscheduled visits of the Treatment Period will be calculated for each 
subject and will be analysed as a repeated time-to-event approach.  A GLMM 
approach (i.e., a repeated measures Poisson regression) will be used to estimate 
the ratio (relative risk) of mean repeat Hb or Iron tests between the two treatment 
arms.  An unstructured correlation structure will be specified (e.g., by way of the 
appropriate random statement within the SAS procedure GLIMMIX) to model the 
within-subjects errors across unscheduled visits.  If the model fails to converge, 
alternative correlation structures will be examined.  The model will fit the natural 
logarithm of the mean number of repeat Hb or Iron tests to a linear combination of 
covariates (i.e., a log-linear model).  The covariates will include: the fixed effects of 
treatment, baseline Hb (below the observed median or at least the observed 
median), and IBD subgroup; and, random effects of time (elapsed time between 
consecutive unscheduled visits by subject) and treatment-by-time interaction.  A 
summary of the number of repeat Hb or Iron tests will be provided using 
descriptive statistics by treatment arm and overall.  The summary will also include 
the GLMM LSM estimate of repeat Hb or Iron tests and its 95% CI by treatment 
arm, the GLMM estimate of the ratio (relative risk) of mean repeat Hb or Iron tests 
between the two treatment arms and corresponding 95% confidence interval for 
the ratio, and the p-value from the test of null hypothesis that the mean repeat Hb 
or Iron tests are the same between the two treatment arms. 
 
The method of transportation (Public, Own transport, Hospital provided, Unknown) 
will be documented at each visit (scheduled or unscheduled) over the Treatment 
Period.  For each scheduled visit, a multinomial logistic regression modelling 
approach will be used to estimate the visit-specific relative odds of taking a given 
transportation method to that of Public (i.e., Public transportation will serve as the 
reference level) between the two treatment arms, adjusted for the effects of 
baseline Hb (below the observed median or at least the observed median) and IBD 
subgroup.  The “Unknown” method of transportation will be considered as a missing 
value of method of transportation for purposes of the modelling described here.  A 
summary of Public transportation will be presented using descriptive statistics by 
visit (including a visit labelled “unscheduled”).  The summary will also present, by 
scheduled visit, the estimated relative odds of taking a given transportation method 
to that of Public between the two treatment arms, the corresponding 95% CI for 
the odds ratio, and the p-value from testing the null hypothesis of no association 
between treatment arm and chosen transportation method. 
 
A data listing of correction and maintenance of IDA will be provided by subject.    


 
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11 SAFETY ANALYSES 
 
Unless otherwise noted, the Safety Population will be used for all analyses, 
summaries, and listings of safety endpoints.  
 
11.1    Adverse Events 
 
An AE is any unfavourable or unintended sign, symptom, or disease temporally 
associated with the use of an investigational product or protocol-imposed 
intervention, regardless of attribution.  All observed or volunteered AEs regardless 
of suspected causal relationship to the investigational product(s) will be reported. 
 
All reported terms (investigator descriptions) for AEs will be coded using the most 
recent version of the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarised with frequencies and percentages by treatment group, system organ 
classification, and preferred term.  
 
The number, intensity, relation to study medication and action taken will be 
described by incidence tables.  Subjects with multiple intensities for the same AE 
will be categorized by the maximum intensity experienced.  Subjects with instances 
of the same AE recorded as both related and unrelated to study medication will be 
categorized as related.  Subjects with multiple actions taken within the same AE will 
be categorized according to the worst case.  Actions taken are discontinued, 
interrupted, dose reduced, and none (listed from worst case to best case).  
 
The most relevant AE dataset will be the treatment emergent adverse effects 
(TEAEs), defined as those that occur on or after the day of first dose of study 
medication and up to 14 days after the last dose of study medication.  Multiple 
instances of the TEAE in each system organ class and multiple occurrences of the 
same preferred term will be counted only once per subject. When an adverse event 
occurs more than once for a subject, the maximum severity, causality, and action 
will be used.  The number and percentage of subjects in the following categories 
will be summarised by group and overall: subjects with AE, TEAE, SAE, Deaths, 
TESAE, TE Deaths, TEAE related to study treatment, TESAE related to study 
treatment, and TE deaths related to study treatment. 
 
The following tables will also be presented by treatment arm:  
‐ 
All TEAEs (including TEAEs by intensity, relation to study medication, and 
action taken) 
‐ 
Serious TEAEs  
‐ 
AEs leading to premature discontinuation of study medication. 
 
Separate data listings will be presented for all AEs, all SAEs, and all deaths. 
 
11.2    Laboratory Evaluations 
 
Clinical laboratory evaluations include the haematology, iron marker, basic 


 
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chemistry, liver function, and urine pregnancy test results (for all females of 
childbearing potential; data will be provided in a data listing).  
 
Laboratory values, change from baseline (haematology and iron markers only) will 
be summarised using descriptive statistics by category, laboratory test, and visit for 
each treatment arm and overall.  
 
Laboratory data, including normal ranges and abnormal laboratory flags, will be 
provided in data listings.  
 
11.3    Vital Signs 
 
Vital signs (blood pressure and heart rate), along with height and weight, will be 
collected at screening and will be summarised using descriptive statistics.  Vital 
signs, height, and weight will be provided in a data listing by subject.  
 
11.4    Physical Examination 
 
Findings from the screening physical examination will be listed by subject. 
 
 
12 PRIMARY ANALYSIS  
 
Not applicable 
 
13 FINAL ANALYSIS 
 
The final, complete analysis will be conducted after the last subject completes or 
discontinues the study and the resulting clinical database has been cleaned, quality 
checked, and locked.  The assignment of subjects to the analysis populations, as 
described in Section 5, will be the same as in the primary analysis. 
The final analysis will then be performed and will include all safety data and efficacy 
results up-to-and including Follow-up.  Results of this analysis will be reported in 
the CSR. 
 
 
14 CHANGES FROM PROTOCOL 
 
The Safety population is defined in the protocol as all subjects who have had at 
least one dose of study drug and one subsequent contact with the Investigator. This 
has been updated so that the safety population will only consist of subject who 
received at least one dose of a study drug for consistency with ICH definitions. 
 
A two stage analysis of the safety and efficacy data was detailed in the protocol, 
with the first stage being conducted when all subjects have completed 12 weeks of 
treatment, and the second stage being the final analysis. Due to the shortening of 
the study period, it is anticipated that when all patients have completed 12 weeks 


 
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of treatment there will be no patients ongoing in the study, and so only one 
analysis will be performed. 
 
Other pharmacoeconomic endpoints have been specified here as they are not 
explicitly mentioned in the protocol. These are: 
 
 
Quality of life as assessed by the Medical Outcomes Study 36-item short 
form questionnaire. 
 
Correction and Maintenance of IDA  
o Repeat Hb or iron testing 
o Method of transportation to attend each visit. 
o The number of days off work or school/education to attend hospital or 
clinic visits for administration of IV Iron. 
o The time spent in the hospital or clinic receiving IV Iron. 
o The dose of IV Iron administered.    
 
15 REFERENCES 
 
1. Agresti A (2002). Categorical data analysis, 2nd edition. New York: Wiley.  
2. D’Agnostino RB, Belanger A, D’Agnostino RB Jr. (1990).  A suggestion for 
using powerful informative tests of normality.  The American Statistician; 
35(3). 
3. Glaser RE (1982).  Levene’s robust test of homogeneity of variances.  
Encyclopaedia of Statistical Sciences.  New York: John Wiley and Sons; 608-
610. 
4. Ware JE, Kosinski M, Dewey JE (2000).  How to score version 2 of the SF-36 
Health Survey, Quality Metric Incorporated.   
 
 
 


 
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16 TABLE OF CONTENTS FOR DATA DISPLAYS 
 
16.1    Tables 
 
Study Population 
 
 
Table 14.1.1.1 
Summary of Analysis Populations – All Randomized Subjects 
Table 14.1.1.2 
Summary of Subject Disposition – All Screened Subjects 
Table 14.1.1.3.1 
Summary of Protocol Deviations in the First 12 Weeks – ITT 
Population 
Table 14.1.1.3.2 
Summary of Protocol Deviations After the First 12 Weeks – 
ITT Population 
Table 14.1.1.3 
Summary of Protocol Deviations – ITT Population 
Table 14.1.2.1 
Summary of Demographic Characteristics – ITT Population 
Table 14.1.2.2 
Summary of Demographic Characteristics – PP Population 
Table 14.1.3.1 
Summary of Medical History – ITT Population 
Table 14.1.3.2 
Summary of Medical History – PP Population 
 
 
Efficacy/PE 
 
 
Table 14.2.1.1 
Summary of Haemoglobin Concentration (g/dL) – ITT 
Population 
Table 14.2.1.2 
Summary of Haemoglobin Concentration (g/dL) – PP 
Population 
Table 14.2.1.3 
Summary of Haemoglobin Concentration (g/dL) in Subjects 
with Baseline Hb < 9.5 g/dL – ITT Population 
Table 14.2.1.4 
Summary of Haemoglobin Concentration (g/dL) in Subjects 
with Baseline Hb < 9.5 g/dL – PP Population 
Table 14.2.2.1 
Summary of Haemoglobin Responder Rate – ITT Population 
Table 14.2.2.2 
Summary of Haemoglobin Responder Rate – PP Population 
Table 14.2.2.3 
Statistical Analysis of Haemoglobin Responder Rate Using a 
Repeated Measures Approach – ITT Population 
Table 14.2.2.4 
Statistical Analysis of Haemoglobin Responder Rate Using a 
Repeated Measures Approach – PP Population 
Table 14.2.3.1 
Summary of Rise in Haemoglobin Responder Rate – ITT 
Population 
Table 14.2.3.2 
Summary of Rise in Haemoglobin Responder Rate – PP 
Population 
Table 14.2.3.3 
Summary of Haemoglobin Rise Responder in Subjects with 
Baseline Hb < 9.5 g/dL – ITT Population 
Table 14.2.3.4 
Summary of Haemoglobin Rise Responder in Subjects with 
Baseline Hb < 9.5 g/dL – PP Population 
Table 14.2.4.1 
Summary of Haemoglobin Normal Limit Responder Rate – 
ITT Population 
Table 14.2.4.2 
Summary of Haemoglobin Normal Limit Responder Rate – 
PP Population 
Table 14.2.4.3 
Summary of Haemoglobin Normal Limit Responder Rate in 
Subjects with Baseline Hb < 9.5 g/dL – ITT Population 


 
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Table 14.2.4.4 
Summary of Haemoglobin Normal Limit Responder Rate in 
Subjects with Baseline Hb < 9.5 g/dL – PP Population 
Table 14.2.5.1 
Summary of Anaemic Status – ITT Population  
Table 14.2.5.2 
Summary of Anaemic Status – PP Population  
Table 14.2.6.1 
Summary of Serum Ferritin Concentration (ng/ml) – ITT 
Population 
Table 14.2.6.2 
Summary of Serum Ferritin Concentration (ng/ml) – PP 
Population 
Table 14.2.7.1 
Summary of Ferritin Normal Limit Responder Rate – ITT 
Population 
Table 14.2.7.2 
Summary of Ferritin Normal Limit Responder Rate – PP 
Population 
Table 14.2.8.1 
Summary of Medical Outcomes Study SF-36 Scores – ITT 
Population 
Table 14.2.8.2 
Summary of Change from Baseline in Medical Outcomes 
Study SF-36 Scores – ITT Population 
Table 14.2.9.1 
Summary of Administration of IV Iron – ITT Population 
Table 14.2.9.2 
Summary of IV Iron Dosing Details – ITT Population 
Table 14.2.10 
Summary of Number of Repeat Haemoglobin or Iron Tests – 
ITT Population 
Table 14.2.11 
Summary of Method of Transportation by Visit – ITT 
Population 
 
 
Safety 
 
 
Table 14.3.1.1 
Overall Summary of Adverse Events 
Table 14.3.1.2.1 
Summary of Treatment-Emergent Adverse Events 
Table 14.3.1.2.2 
Summary of Treatment-Emergent Adverse Events by 
Maximum Intensity 
Table 14.3.1.2.3 
Summary of Treatment-Emergent Adverse Events by 
Relation to Study Medication 
Table 14.3.1.2.4 
Summary of Treatment-Emergent Adverse Events by Action 
Taken 
Table 14.3.1.3.1 
Summary of Study Drug Exposure 
Table 14.3.1.3.2 
Summary of Ferric Maltol Compliance by Visit 
Table 14.3.2.1 
Summary of Treatment-Emergent Serious Adverse Events 
Table 14.3.2.2 
Summary of Adverse Events Leading to Premature 
Discontinuation of Study Medication 
Table 14.3.3.1 
Summary of Prior Medications 
Table 14.3.3.2 
Summary of Concomitant Medications 
Table 14.3.4.2.1.1 
Summary of Laboratory Evaluations (Haematology) 
Table 14.3.4.2.1.2 
Summary of Laboratory Evaluations (Basic Chemistry) 
Table 14.3.4.2.1.3 
Summary of Laboratory Evaluations (Clinical Chemistry) 
Table 14.3.4.2.1.4 
Summary of Laboratory Evaluations (Liver Function) 
Table 14.3.4.3 
Summary of Vital Signs at Screening 
 
 


 
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16.2    Figures 
 
Figure 14.2.1.1 
Haemoglobin Concentration (g/dL) at Week 12 Versus 
Baseline – ITT Population 
Figure 14.2.1.2 
Mean Change from Baseline Haemoglobin Concentration 
(g/dL) by Visit – ITT Population 
Figure 14.2.1.3 
Haemoglobin Responders by Visit – ITT Population 
Figure 14.2.1.4 
Haemoglobin Concentration (g/dL) at Week 12 Versus 
Baseline – PP Population 
Figure 14.2.1.5 
Mean Change from Baseline Haemoglobin Concentration 
(g/dL) by Visit – PP Population 
Figure 14.2.1.6 
Haemoglobin Responders by Visit – PP Population 
Figure 14.2.1.7 
Haemoglobin Concentration (g/dL) at Week 24 Versus 
Baseline – ITT Population 
Figure 14.2.1.8 
Haemoglobin Concentration (g/dL) at Week 24 Versus 
Baseline – PP Population 
Figure 14.2.1.9 
Haemoglobin Concentration (g/dL) at Week 36 Versus 
Baseline – ITT Population 
Figure 14.2.1.10 
Haemoglobin Concentration (g/dL) at Week 36 Versus 
Baseline – PP Population 
Figure 14.2.1.11 
Haemoglobin Concentration (g/dL) at Week 52 Versus 
Baseline – ITT Population 
Figure 14.2.1.12 
Haemoglobin Concentration (g/dL) at Week 52 Versus 
Baseline – PP Population 
Figure 14.2.1.13 
Haemoglobin Responders (1g/dL) by Visit – ITT Population 
Figure 14.2.1.14 
Haemoglobin Responders (1g/dL) by Visit – PP Population 
Figure 14.2.2.1 
Ferritin Concentration (ng/mL) at Week 24 Versus Baseline 
– ITT Population 
Figure 14.2.2.2 
Ferritin Concentration (ng/mL) at Week 24 Versus Baseline 
– PP Population 
Figure 14.2.2.3 
Ferritin Concentration (ng/mL) at Week 24 Versus Baseline 
– ITT Population 
Figure 14.2.2.4 
Ferritin Concentration (ng/mL) at Week 24 Versus Baseline 
– PP Population 
Figure 14.2.2.5 
Ferritin Concentration (ng/mL) at Week 36 Versus Baseline 
– ITT Population 
Figure 14.2.2.6 
Ferritin Concentration (ng/mL) at Week 36 Versus Baseline 
– PP Population 
Figure 14.2.2.7 
Ferritin Concentration (ng/mL) at Week 52 Versus Baseline 
– ITT Population 
Figure 14.2.2.8 
Ferritin Concentration (ng/mL) at Week 52 Versus Baseline 
– PP Population 
 
 
 
 
 


 
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16.3    Listings 
 
Study Population 
Listing 16.2.1.1 
Listing of Subject Disposition 
Listing 16.2.1.2.1 
Listing of Scheduled Visit Dates 
Listing 16.2.1.2.2 
Listing of Unscheduled Visits 
Listing 16.2.2.1 
Listing of Informed Consent 
Listing 16.2.2.2 
Listing of Inclusion/Exclusion Criteria Deviations 
Listing 16.2.2.3 
Listing of Protocol Deviations 
Listing 16.2.3.1 
Listing of Subject Randomization 
Listing 16.2.3.2 
Listing of Analysis Populations 
Listing 16.2.4.1.1 
Listing of Demographics 
Listing 16.2.4.1.2 
Listing of Reproductive Status 
Listing 16.2.4.1.3 
Listing of IBD Status 
Listing 16.2.4.2 
Listing of Medical History 
Listing 16.2.5.1 
 Listing of Study Drug Exposure and Compliance 
Listing 16.2.5.2 
 
Listing of Overall Compliance 
 
 
Efficacy/PE 
Listing 16.2.6.1 
Listing of Haemoglobin Results 
Listing 16.2.6.2 
Listing of Ferritin Results 
Listing 16.2.6.3 
Listing of Medical Outcomes Study SF-36 Scores 
Listing 16.2.6.4 
Listing of Correction and Maintenance of IDA 
 
 
Safety 
Listing 16.2.7.1 
Listing of Adverse Events 
Listing 16.2.7.2 
Listing of Serious Adverse Events 
Listing 16.2.7.3 
Listing of Deaths 
Listing 16.2.8.1 
Listing of Laboratory Evaluations (Haematology) 
Listing 16.2.8.2 
Listing of Laboratory Evaluations (Iron Markers) 
Listing 16.2.8.3 
Listing of Laboratory Evaluations (Basic Chemistry) 
Listing 16.2.8.4 
Listing of Laboratory Evaluations (Liver Function) 
Listing 16.2.8.5 
Listing of Pregnancy Test Results 
Listing 16.2.9.1 
Listing of Vital Signs at Screening 
Listing 16.2.9.2 
Listing of Physical Examination at Screening 
Listing 16.2.9.3 
Listing of Activity Index 
Listing 16.2.9.4 
Listing of Initial Pregnancy Report 
Listing 16.2.9.5 
Listing of Follow-up Pregnancy Report 
Listing 16.2.9.6 
Listing of Prior Medications 
Listing 16.2.9.7 
Listing of Concomitant Medications 
Listing 16.2.9.8 
Listing of Medical Procedures Completed During Study 
 
 
 
 
 


 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
23 July 2020
 
 
 
 
 
 
DOCUMENT: 
 
Post-hoc Statistical Analysis Plan 
 
PROTOCOL: 
 
ST10-01-304 
 
A phase 3b, randomized, controlled, multicentre study 
with oral ferric maltol (Feraccru) or intravenous iron 
(ferric carboxy maltose; FCM), for the treatment of iron 
deficiency anaemia in subjects with inflammatory bowel 
disease 
 
SAP VERSION: 
 
Final 1.0 of Post-hoc Statistical Analysis Plan 
 
SAP DATE:  
 
23 July 2020 
 
PROTOCOL DATE: 
10 July 2015, Version 1.0  
24 August 2015, Version 2.0 
12 February 2016, Version 3.0 
08 August 2016, Version 4.0 
25 August 2016, Version 4.2 
05 January 2017, Version 5.0 
11 July 2017, Version 6.0 
30 April 2018, Version 7.0 
 
 
 
 
 
SPONSOR:  
 
Shield TX (UK) Limited 
 
PREPARED BY: 
 
Clinipace Worldwide 
 
AUTHORS:  
 
Barbara Collins, BSc PhD 
 
 
 
 
Senior Biostatistician 
 
 
 
 
Clinipace Worldwide 
 
 
 
 
 
 
 
 
 




 
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Statistical Analysis Plan 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................................................ 4 
1 
INTRODUCTION ............................................................................................................................................. 5 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS .................................................................................... 5 
3 
STUDY DESIGN ............................................................................................................................................... 5 
4 
POWER AND SAMPLE SIZE CONSIDERATIONS ................................................................................................ 5 
5 
ANALYSIS POPULATIONS ............................................................................................................................... 5 
6 
CONSIDERATIONS FOR DATA ANALYSIS ......................................................................................................... 6 
7 
DATA HANDLING METHODS .......................................................................................................................... 6 
8 
STUDY POPULATION ...................................................................................................................................... 7 
9 
EFFICACY ANALYSES ...................................................................................................................................... 8 
9.1 
PRIMARY EFFICACY ANALYSES .............................................................................................................................. 8 
9.1.1 
Primary Analysis....................................................................................................................................... 8 
9.1.2 
Sensitivity Analysis ................................................................................................................................. 10 
9.1.2.1 
Observed Cases (OC) Analysis ............................................................................................................ 10 
9.1.2.2 
Observed Cases (OC) Repeated Measures Analysis ........................................................................... 10 
9.1.2.3 
Week 12 compliance analysis ............................................................................................................ 11 
9.1.2.4 
Week 12 non-windowed analysis ...................................................................................................... 11 
9.1.2.5 
Week 12 immunosuppressant analysis ............................................................................................. 12 
9.2 
SECONDARY EFFICACY ANALYSES ........................................................................................................................ 12 
9.2.1 
Secondary Analysis ................................................................................................................................. 12 
9.2.1.1 
Key Secondary Endpoints ................................................................................................................... 12 
9.2.1.2 
Other Secondary Efficacy Endpoints .................................................................................................. 13 
9.2.1.3 
Long-term Secondary Endpoints ........................................................................................................ 14 
10 
PHARMACOECONOMIC ANALYSES .............................................................................................................. 15 
11 
FINAL ANALYSIS ........................................................................................................................................... 17 
12 
SUMMARY OF POST HOC CHANGES ............................................................................................................ 17 
13 
REFERENCES ................................................................................................................................................ 18 
14 
TABLE OF CONTENTS FOR DATA DISPLAYS .................................................................................................. 19 
14.1 
TABLES .......................................................................................................................................................... 19 
14.2 
FIGURES ........................................................................................................................................................ 20 
14.3 
LISTINGS ........................................................................................................................................................ 21 
 


 
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Statistical Analysis Plan 
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23 July 2020
LIST OF ABBREVIATIONS 
 
 
ANCOVA 
Analysis of Covariance 
CI 
 
Confidence interval 
CFB 
 
Change from baseline 
CRF 
 
Case report form 
CSR 
 
Clinical Study Report 
FCM  
Ferric carboxy maltose 
GLM  
Generalized Linear Model 
GLMM  
Generalized Linear Mixed Model 
Hb 
 
Haemoglobin 
IDA 
 
Iron deficiency anaemia 
IBD 
 
Inflammatory bowel disease 
ITT 
 
Intention-to-Treat 
IV 
 
Intravenous 
LCL 
 
Lower confidence limit 
LOCF  
Last Observation Carried Forward 
LSM 
 
Least squares mean 
MH 
 
Mantel-Haenszel 
OC 
 
Observed Cases 
PE 
 
Pharmacoeconomic 
PP 
 
Per Protocol  
SAP 
 
Statistical Analysis Plan 
SD 
 
Standard deviation 
SF-36  
Medical outcomes study 36-item short form 
UC 
 
Ulcerative colitis  
WHO  
World Health Organization 
 
 
 
 
 
 
 


 
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Statistical Analysis Plan 
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23 July 2020
1 
INTRODUCTION 
 
This document describes the statistical methods and data presentations to be used 
in the revised and post-hoc summary and analysis of efficacy data from Protocol 
ST10-01-304.  The reader is referred to the study protocol and electronic case 
report forms (eCRFs) for details of study conduct and data collection, and the final 
statistical analysis plan version 3.0 dated 14 February 2019 for background 
information and details of the original analysis where applicable. 
 
2 
STUDY OBJECTIVES, TREATMENTS, AND ENDPOINTS 
 
For details of the study objectives, treatment group comparisons and non-primary 
endpoints refer to Statistical Analysis Plan v3.0, dated 14 February 2019. 
 
The primary efficacy endpoint is the proportion of subjects achieving either a 
≥2g/dL increase in Haemoglobin (Hb) OR normalization of Hb (≥12g/dL for women, 
≥13g/dL for men based on the WHO definition (WHO/NMH/NHD/MNM/11.1) at 
Week 12 [Post-hoc change from previous SAP, noted in the original CSR, from 
>12.0 g/dL (women) or 13.0 g/dL (men)]. 
 
Note: the WHO definition of Hb normal limit (≥12g/dL for women, ≥13g/dL for 
men) was applied in the primary efficacy endpoint but not the secondary efficacy 
endpoints in the original analysis for CSR v1.0. 
 
In this post-hoc analysis, all secondary endpoints that use normal limits will also be 
based on the WHO definition. 
 
3 
STUDY DESIGN 
 
For details of the overall study design and the schedule of study assessments, refer 
to Statistical Analysis Plan v3.0, dated 14 February 2019. 
 
4 
POWER AND SAMPLE SIZE CONSIDERATIONS 
 
Refer to Statistical Analysis Plan v3.0, dated 14 February 2019. 
 
5 
ANALYSIS POPULATIONS 
 
For details of the randomized, safety, and ITT populations, refer to Statistical 
Analysis Plan v3.0, dated 14 February 2019, Section 5.1 to 5.3. 
 
For details of the PP population, refer to Statistical Analysis Plan v3.0, dated 14 
February 2019, Section 5.4 and Section 8 below. To clarify, data of the subjects 
with major protocol deviations occurring after Week 12 were excluded from the PP 
analysis of the long-term endpoints from that point of deviation onwards in the 
original analysis for CSR v1.0. 
 


 
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23 July 2020
Patients data are re-evaluated with a focus on visit window, drug compliance, 
missing data, and the allowance of immunosuppressants. A re-evaluated PP 
population is defined for the post hoc analyses. 
 
Two sensitivity PP population will be determined for the analysis of the primary 
efficacy data: 
 
The modified PP population for compliance (mPP compliance) contains all patients 
from the re-evaluated PP population, along with all patients who are only excluded 
from the re-evaluated PP population due to compliance issues.  
 
The modified PP population for windowing (mPP windowing) contains all patients 
from the re-evaluated PP population, along with all patients who are only excluded 
from the re-evaluated PP population due to Week 12 windowing issues for 
haemoglobin.  
 
Data of the subjects with major protocol deviations occurring after Week 12 are 
excluded from the re-evaluated PP analysis of the long-term endpoints from that 
point of deviation onwards. 
 
 
 
6 
CONSIDERATIONS FOR DATA ANALYSIS 
 
For details of the programming environment, strata and covariates, subgroups, 
multiple comparisons and multiplicity, significance level, and statistical notation and 
methodology, refer to Statistical Analysis Plan v3.0, dated 14 February 2019. 
 
Any analysis based on the PP population in the original SAP will be rerun based on 
the re-evaluated PP population. 
 
Post hoc analyses will be clearly identified as such both in this document and in the 
Clinical Study Report. Any outputs that are generated post hoc due to re-
evaluations of the statistical methods or re-evaluated PP populations will be labelled 
“Post-Hoc” followed by the month/year run and the table number, Eg “Post Hoc July 
2020 Table 14.1.1”. Outputs that are updated due to a correction in methods to 
that described in the Statistical Analysis Plan v3.0, dated 14 February 2019 will be 
labelled “Revised” followed by the month/year run and the table number, Eg 
“Revised July 2020 Table 14.1.1”.   
 
7 
DATA HANDLING METHODS 
 
For details of the data handling methods, refer to Statistical Analysis Plan v3.0, 
dated 14 February 2019. 
Missing data for adherence to ferric maltol (i.e. no returned bottles and no pill 
count) will not be imputed and will not be assumed to be zero adherence or all 
tablets taken. 


 
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The code for implementing the SAS procedure MI is: 
 
PROC MI DATA = <dataset _name> NIMPUTE = 20 SEED = <seed> OUT = MI_out; 
  VAR baselineHbtrans gender ibd Week4Hbtrans Week12Hbtrans; 
  EM MAXITER = 10000; 
RUN;    
 
For the multiple imputation, the code for implementing the SAS procedure 
MIANALYZE to the CFB Hb concentration at Week 12 secondary endpoint is: 
 
DATA CFB_Impute; SET MI_out;  CFBHbW12 = Week12Hb – baselineHb; RUN; 
 
PROC SORT DATA = CFB_Impute; BY _Imputation_; RUN; 
 
PROC REG DATA = CFB_Impute OUTEST = outreg COVOUT; 
  BY _Imputation_; 
  MODEL CFBHbW12 = binarybaselineHb TreatmentArm IBDGroup; 
RUN; 
 
PROC MIANALYZE DATA = outreg EDF = <complete-data degrees of freedom>; 
  MODELEFFECTS Intercept binarybaselineHb TreatmentArm IBDGroup; 
  ODS OUTPUT ParameterEstimates = parm1; 
RUN; 
 
The code for implementing the SAS procedure MIANALYZE to the Hb normal limit 
responder at Week 12 secondary endpoint for the ITT population is: 
DATA NormalHb_Impute; SET MI_out;   
  NLResponder = 0; 
  IF Gender =: ‘F’ AND Week12Hb => 12.0 THEN NLResponder = 1; 
  IF Gender =: ‘M’ AND Week12Hb => 13.0 THEN NLResponder = 1;  
RUN; 
 
PROC SORT DATA = NormalHb_Impute; BY _Imputation_; RUN; 
 
PROC LOGISTIC DATA = NormalHb_Impute; 
  MODEL NLResponder = binarybaselineHb TreatmentArm IBDGroup / covb; 
  BY _Imputation_; 
  ODS OUTPUT ParameterEstimates = lgsparms 
                      CovB                       = lgscovb; 
RUN; 
 
PROC MIANALYZE PARMS = lgsparms COVB(effectvar=stacking) = lgscovb; 
  MODELEFFECTS Intercept binarybaselineHb TreatmentArm IBDGroup; 
RUN 
 
 
8 
STUDY POPULATION 
 
For details of the listings and summaries for the study population, refer to 
Statistical Analysis Plan v3.0, dated 14 February 2019. 
 


 
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In addition to the existing categories described in Statistical Analysis Plan v3.0, 
dated 14 February 2019, additional major protocol deviations include the following 
categories: 
 
Repeated non-compliance in self-administration of ferric maltol study drug, 
where non-compliance is less than 80% or greater than 120% of expected 
administration of study drug in the first 12 weeks. Where data were missing 
the compliance may be assessed based on individual visit pill returns, where 
data exists the compliance would be based on the average compliance in the 
first 12 weeks of study. 
 
Subjects that had a Week 12 haemoglobin value measured more than 2 
weeks (+/- 14 days) outside the planned Week 12 assessment, ie an 
additional 1 week window beyond the 1 week window in the schedule of 
assessments. 
 
IV Iron subjects who did not follow the specific country dosing regimens. An 
IV iron dose up to Week 12 that was >2 or <.5 times the calculated dose 
based on weight and Hb and per the local Prescribing Information, will not be 
included in the re-evaluated PP population. 
 
Immunosuppressant use will not be a criterion for exclusion from the re-
evaluated PP population, based on protocol version 6, dated 11 July 2017.  
 
Protocol deviations deemed to be major, but not recorded on the database, will be 
included by means of a spreadsheet which will be agreed by Shield and Clinipace 
based on the minutes of the subject evaluability meeting.  
 
No imputation was performed for missing data in compliance calculations. 
 
9 
EFFICACY ANALYSES 
 
 
9.1 
   Primary Efficacy Analyses 
 
9.1.1    Primary Analysis 
 
Haemoglobin (Hb) concentration will be summarised at screening (Visit 1), pre-
randomization at Visit 2 (baseline assessment), and at each visit over the 
Treatment Period. Hb concentration (Observed Cases [OC]) will be summarised for 
the ITT (post hoc table 14.2.1.1) and re-evaluated PP (post hoc table 14.2.1.2) 
populations using descriptive statistics by visit for each treatment arm and overall.  
A scatterplot of Hb concentrations (OC) at each visit versus baseline will be 
presented by treatment arm for the re-evaluated PP population (post hoc figures 
14.2.1.4, 14.2.1.5.1, 14.2.1.5.2, 14.2.1.6, 14.2.1.8, 14.2.1.10, 14.2.1.12.1, 
14.2.1.12.2).  
 
A dichotomous variable, representing response status in the degree to which Hb 
increases relative to baseline, will be calculated for each visit over the Treatment 
Period.  Those subjects with at least 2g/dL increase in Hb from baseline or who 


 
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have normalization of Hb from baseline (≥12.0 g/dL for women, ≥13.0 g/dL for 
men) will be classified as “Hb responders”.  [Post-hoc change from > 12.0 g/dL for 
women or > 13.0 g/dL for men].  A shift from baseline of anaemic to non-anaemic 
status (ie Hb concentration shift from below to within the normal limits will be 
classified as “Hb normal limit responders”.  [Post-hoc change to align Hb normal 
limit responder definition with the definition given in section 2]. Patients who are 
normal at baseline cannot be classified as a responder. Ferric maltol patients who 
take IV Iron cannot be classified as responders after the intake of IV iron. 
 
The null hypothesis for the primary efficacy endpoint analysis is that the proportion 
of Hb responders at Week 12 in the ferric maltol treatment arm is at least 20% 
lower than the proportion of Hb responders at Week 12 in the IV Iron treatment 
arm (i.e., ferric maltol is inferior to IV Iron for rate of Hb response at Week 12).  
The alternative hypothesis is that the proportion of Hb responders at Week 12 in 
the ferric maltol treatment arm is not worse than 20% lower than the proportion of 
Hb responders at Week 12 in the IV Iron treatment arm (i.e., ferric maltol is non-
inferior to IV Iron for rate of Hb response at Week 12). 
 
The proportion of Hb responders at Week 12 will be compared between the two 
treatment arms, by calculating a 2-sided confidence interval for difference in the 
proportions of Hb responders (risk difference) between the two treatment arms and 
comparing the lower confidence limit of this CI to the pre-specified non-inferiority 
margin.  The CI will be calculated using the Delta Method approach [1] based on a 
logistic regression model, adjusted for treatment arm, baseline Hb (below the 
observed median or at least the observed median), and IBD subgroup (UC or CD). 
Note: For the CI calculation in the primary efficacy endpoint, the risk difference 
model was applied in the original analysis for CSR v1.0. The analysis method will be 
corrected to the Delta Method approach in the current post hoc analysis. 
 
Post-hoc change: Note that missing values for the Hb responder status at Week 12 
primary efficacy analysis will be imputed using a multiple imputation (MI) approach 
for ITT population.    Missing values of Hb concentration at Week 12 will be imputed 
using the SAS procedure MI. This will generate 20 complete datasets containing 
imputed values of Hb concentration at Week 12 for those missing in the original 
dataset.  Variables considered helpful in guiding this imputation are deviation of 
baseline (Visit 2) Hb concentration from response threshold, deviation of Week 4 Hb 
concentration from response threshold, gender and IBD subgroup. A separate 
model will be computed for each treatment arm.   
 
The Week 12 imputed value will then be back transformed from the Week 12 
deviation from the response threshold.  
 
Each model, corresponding to a given endpoint analysis, will be fitted against each 
of the imputed datasets.  The SAS procedure MIANALYZE will then be used to 
combine the individual analysis results for the given endpoint into one result.  
   
The null hypothesis for the primary efficacy analysis will be rejected (i.e., ferric 
maltol will be deemed non-inferior to IV Iron), if the LCL of the 95% CI for the 


 
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difference (ferric maltol – IV Iron) in proportions of Hb responders at Week 12 is ≥ 
-20% for both the ITT analysis and the re-evaluated PP analysis. The p-value in 
testing the aforementioned hypotheses will be equal to one minus the confidence 
coefficient corresponding to the CI for the risk difference whose LCL equals -20% 
(i.e., inverting the CI for the risk difference to a test statistic and calculating the p-
value from the test statistic). 
 
The proportion of Hb responders will be summarised for the ITT and re-evaluated 
PP populations using descriptive statistics by visit over the Treatment Period for 
each treatment arm and overall, utilizing all available Hb responder data (i.e., OC 
approach).  Each summary will also present the proportion of Hb responders for the 
Week 12 visit (MI) using descriptive statistics, and will include the corresponding 
logistic regression model adjusted difference in the proportions of Hb responders 
between the two treatment arms, the corresponding adjusted 95% CI for the 
difference in proportions, and the adjusted p-value from testing the null hypothesis 
of inferiority in risk difference with non-inferiority margin 20%.  Finally, each 
summary will also present the estimated logistic regression model adjusted odds 
ratio of Hb responder at Week 12 (MI) between the two treatment arms and 
corresponding 95% CI for the odds ratio(post hoc tables 14.2.2.1 and 14.2.2.2).  A 
bar plot of the Hb responder rate will be presented by visit (OC) and treatment arm 
for each assessment for the re-evaluated PP population (post hoc figure 14.2.1.6).  
 
9.1.2    Sensitivity Analysis 
 
Two sensitivity analyses will be performed for the primary efficacy endpoint; in 
addition, three post-hoc sensitivity analyses will be performed using the re-
evaluated PP population. 
 
9.1.2.1 Observed Cases (OC) Analysis 
 
The first sensitivity analysis will include all available assessments of Hb responder 
and will not exploit imputation of missing Hb responder status (i.e., only Observed 
Cases [OC] of Hb responder status are considered here).  The primary efficacy 
endpoint analysis will be repeated using the OC approach for the ITT population.  
The proportion of Hb responders at Week 12 (OC) will be summarised using 
descriptive statistics for each treatment arm and overall.  The summary will include 
the corresponding logistic regression model adjusted difference in the proportions 
of Hb responders (risk difference) between the two treatment arms, the adjusted 
95% CI for the difference in proportions, and the adjusted p-value from testing the 
null hypothesis of inferiority in risk difference with non-inferiority margin 20%.  The 
summary will also include the estimated adjusted odds ratio of Hb responder at 
Week 12 (OC) between the two treatment arms and corresponding 95% CI for the 
odds ratio. (post hoc table 14.2.2.1) 
 
9.1.2.2 Observed Cases (OC) Repeated Measures Analysis 
 
The second sensitivity analysis for the primary efficacy endpoint will be performed 
on the ITT and re-evaluated PP populations, in which Hb responder status will be 


 
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analysed in a longitudinal analysis using a repeated measures generalized linear 
mixed model (GLMM) approach (i.e., a repeated measures logistic regression 
approach) for all available assessments of Hb (i.e., only Observed Cases [OC] of Hb 
responder status are considered here) over Visits 2 (Day 0; baseline) to 4 (Week 
12).   
 
Post-hoc change: The approach will fit a logistic model to the Hb responder 
dependent variable, where an unstructured working correlation structure will be 
specified for each arm (e.g., by way of the appropriate random statement within 
the GLIMMIX SAS procedure) to model the within-subjects correlation of repeated 
Hb responder status at Visits 3 and 4.  If the model fit fails to converge, an auto-
regressive(1) structure will be specified. If this also fails to converge, alternative 
working correlation structures will be examined.  Covariates of the GLMM will 
include the fixed effects of treatment, baseline Hb (below the observed median or 
at least the observed median)”, IBD subgroup, visit as a categorical variable, and 
treatment-by-visit interaction.  The estimated adjusted odds ratio for treatment 
effect, and its corresponding 95% CI, from the model will be presented by visit. 
 
To assess the sensitivity of Hb responder status over time – by way of a general 
linear model (GLM) approach – separate logistic regression models will be fitted to 
the Hb responder dependent variable at each visit during the Treatment Period up 
to Week 12, using all available assessments of Hb (i.e., only Observed Cases [OC] 
of Hb responder status are considered here).  Each model will include terms for the 
effects of treatment, baseline Hb (below the observed median or at least the 
observed median), and IBD subgroup.  The estimated adjusted odds ratio for 
treatment effect, and its corresponding 95% CI, will be presented for each model 
(i.e., by visit).  Sensitivity of Hb responder status over time will be assessed by 
comparing these by-visit treatment effect odds ratio estimates from the logistic 
regression models (the GLMs) to those obtained from the GLMM model. (post hoc 
tables 14.2.2.3 and 14.2.2.4) 
 
9.1.2.3 Week 12 compliance analysis 
 
Post hoc change: The first post-hoc sensitivity analysis will be performed on the 
mPP compliance population (post hoc table 14.2.2.5). The analysis performed will 
be the same as for the primary efficacy. This analysis is relevant to HEOR and more 
of the real-world interpretation of the data. In addition, a waterfall plot of overall 
compliance in the first 12 weeks based on this subset of patients will be included 
(post hoc figure 14.3.2.3). 
 
9.1.2.4 Week 12 non-windowed analysis  
 
Post hoc change: The second post-hoc sensitivity analysis will be performed on the 
mPP windowing population (post hoc table 14.2.2.6). Patients will be considered as 
a responder if they have a haemoglobin response at any point up to and including 
Week 12 visit. The analysis performed will be the same as for the primary efficacy. 
 


 
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9.1.2.5 Week 12 immunosuppressant analysis  
 
Post hoc change: The third post-hoc sensitivity analysis will be performed on the 
re-evaluated PP population. Patients will be included into subgroups based on the 
protocol version they first consented under (prior to version 6, version 6 onwards) 
(post hoc table 14.2.2.7).  The analysis performed for each subgroup will be the 
same as for the primary efficacy. 
 
9.2 
   Secondary Efficacy Analyses 
 
9.2.1 Secondary Analysis 
 
9.2.1.1 
Key Secondary Endpoints 
 
The change from baseline (CFB) in Hb concentration at Week 12 (MI) secondary 
endpoint will be analysed for the ITT population using an analysis of covariance 
(ANCOVA) model.   
 
The ANCOVA model will have terms for treatment arm, baseline Hb (below the 
observed median or at least the observed median), and IBD subgroup.  The 
treatment effect of ferric maltol compared to IV Iron will be considered using 
differences of adjusted means.  No formal statistical significance level in the 
treatment comparison will be defined, as the p-value from the ANCOVA model will 
be presented for descriptive purposes only.  A summary of CFB in Hb concentration 
(OC) will be provided using descriptive statistics for each visit over the Treatment 
Period by treatment arm and overall.  The summary will include the following 
ANCOVA model estimates: adjusted means (i.e., Least-Square Means [LSMs]) of 
CFB in Hb concentration at Week 12 for each treatment arm, the difference in 
treatment arm LSMs, the corresponding 95% CIs for treatment arm specific LSMs 
and difference in treatment arm LSMs, and the p-value for the difference in 
treatment arm LSMs (post hoc table 14.2.2.1).  Mean CFB in Hb concentration will 
be plotted against visit (OC) by treatment arm for the re-evaluated PP populations 
(post hoc figures 14.2.1.5.1 and 14.2.1.5.2). 
 
A dichotomous variable, representing status of Hb concentration relative to the 
normal limits of Hb will be calculated for each visit over the Treatment Period.  
Female subjects with Hb concentration greater than or equal to 12 g/dL and male 
subjects with Hb concentration greater than or equal to 13 g/dL will be classified to 
be within normal limits of Hb [Post-hoc change from >12.0 g/dL (females) or >13.0 
g/dL (males)]. Those subjects with a shift from baseline of anaemic to non-anaemic 
status (ie Hb concentration shift from below to within the normal limits will be 
classified as “Hb normal limit responders”.  [Post-hoc change to align Hb normal 
limit responder definition with the definition given in section 2]. Subjects missing 
Hb concentration at Week 12 will be assumed to have Hb concentration not within 
normal limits (i.e., these subjects will be considered Hb normal limit non-
responders).  The logistic regression modelling and hypothesis testing for the 
primary analysis (Section 9.1.1) will be repeated here for the Hb normal limit 
responder at Week 12 secondary endpoint. 


 
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A summary will be provided for the Hb normal limit responder secondary endpoint 
using descriptive statistics by visit over the Treatment Period for each treatment 
arm and overall, utilizing all available Hb data (i.e., OC approach).  The summary 
will also present the Hb normal limit responder rate for the Week 12 visit (MI) for 
ITT population using descriptive statistics, and will include the corresponding 
logistic regression model adjusted difference in proportions of Hb normal limit 
responders between the two treatment arms, the corresponding [Delta Method 
derived] adjusted 95% CI for the difference in proportions, and the p-value from 
testing the null hypothesis of inferiority in risk difference with non-inferiority margin 
20%.  Finally, the summary will also present the estimated logistic regression 
model adjusted odds ratio of Hb normal limit responders at Week 12 (MI) between 
the two treatment arms and corresponding 95% CI for the odds ratio (post hoc 
tables 14.2.4.1 and 14.2.4.2). 
Note: For the CI calculation in the secondary efficacy endpoints, the risk difference 
model was applied in the original analysis for CSR v1.0. The analysis method will be 
corrected to the Delta Method approach in the current post hoc analysis. 
 
9.2.1.2 
Other Secondary Efficacy Endpoints 
 
The analysis for the key secondary endpoint, CFB in Hb concentration at Week 12 
(MI), will be repeated for the secondary endpoints: CFB in Hb concentration at 
Week 12 (MI) in subjects with baseline Hb <9.5 g/dL; CFB in Hb concentration at 
Week 4 (MI); and, CFB in Hb concentration at Week 4 (MI) in subjects with a 
baseline Hb <9.5 g/dL (post hoc tables 14.2.1.3 and 14.2.1.4). 
 
Two dichotomous variables, each representing response for the magnitude rise in 
Hb from baseline, will be calculated for each visit during the Treatment Period from 
the Hb concentration data.  Those subjects with a rise in Hb from baseline of at 
least 1g/dL will be classified as “Hb rise responders” for the first variable; those 
subjects with a rise in Hb from baseline of at least 2g/dL will be classified as “Hb 
rise responders” for the second variable.  Separate logistic regression models will 
be fitted to each of the Hb rise responders at Week 12 variables (secondary 
endpoints) using an MI approach for the ITT populations.  Each model will include 
terms for the effects of treatment, baseline Hb (below the observed median or at 
least the observed median), and IBD subgroup.  A hypothesis test of the null 
hypothesis of inferiority for ferric maltol responder rate compared to IV Iron 
responder rate will be considered for each Hb rise responder secondary endpoint 
using a non-inferiority margin of 20%.  No formal statistical significance level to 
declare non-inferiority (i.e., rejection of the null hypothesis) of ferric maltol to IV 
Iron is defined, as Cis and p-values will be presented for descriptive purposes only.  
The p-value in testing the aforementioned hypotheses will be calculated as 
described in the primary analysis (Section 9.1.1).   
 
The above analysis will be repeated for the secondary endpoints: proportions of 
subjects with baseline Hb <9.5 g/dL that achieve an increase in Hb concentration of 
≥1 or ≥2 g/dL at Week 12; proportions of subjects who experience a change from 
baseline in Hb concentration ≥1 or ≥2 g/dL at Week 4 (MI); and, proportions of 


 
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subjects with baseline Hb <9.5 g/dL that achieve an increase in Hb concentration of 
≥1 or ≥2 g/dL at Week 4 (MI) (post hoc tables 14.2.3.1 to 14.2.3.4).  In addition, 
the above analysis for the Hb normal limit responder at Week 12 key secondary 
endpoint will be repeated for the secondary endpoints: proportion of subjects with 
baseline Hb <9.5 g/dL that is within normal limits at Week 12; proportion of 
subjects with Hb concentration within normal limits at Week 4; and, proportion of 
subjects with baseline Hb <9.5 g/dL that is within normal limits at Week 4 (MI) 
(post hoc tables 14.2.4.1 to 14.2.3.4). 
 
A bar plot of the Hb responder rate (1g/dL) will be presented by visit (OC) and 
treatment arm for each assessment for the re-evaluated PP population (post hoc 
figure 14.2.1.14). 
 
Serum ferritin will be collected at screening (Visit 1), pre-randomization at Visit 2 
(baseline assessment), and at each visit over the Treatment Period.  The above 
ANCOVA analysis will be repeated for the CFB in serum ferritin at Week 12 (MI) 
secondary endpoint.  A summary of serum ferritin and CFB in serum ferritin (OC) 
will be provided using descriptive statistics for each visit (CFB will be presented at 
each visit during the Treatment Period) by treatment arm.  The summary will 
include the following ANCOVA model estimates: adjusted means (i.e., Least 
Squares Means [LSMs]) of CFB in serum ferritin at Week 12 for each treatment 
arm, the difference in treatment arm LSMs, the corresponding 95% Cis for 
treatment arm specific LSMs and difference in treatment arm LSMs, and the p-value 
for significance of the difference in treatment arm LSMs.  Normality and 
homogeneity of variances for the residuals of each ANCOVA model will be assessed 
using the procedure outlined in Section 9.2.1.1. (post hoc table 14.2.6.2).  
 
9.2.1.3 
Long-term Secondary Endpoints 
 
 
A dichotomous variable, representing anaemia status (anaemic versus non-
anaemic), will be calculated for each visit over the Treatment Period.  Female 
subjects with Hb levels greater than or equal to 12.0 g/dL and male subjects with 
Hb levels greater than or equal to 13.0 g/dL will be classified as non-anaemic [Post-
hoc change from >12.0 g/dL (females) or >13.0 g/dL (males)].  Separate logistic 
regression models will be fitted to the long-term secondary endpoints, anaemia 
status at each visit over Visits 5-7 (OC), for the ITT and re-evaluated PP 
populations.  Each model will include terms to capture the effects of treatment, 
baseline Hb (below the observed median or at least the observed median), and IBD 
subgroup.  The above hypothesis testing for Hb normal limit responder (Section 
9.2.1.1) will be repeated here for the anaemia status secondary endpoint (revised 
table 14.2.5.1 and post hoc table 14.2.5.2). 
 
A dichotomous variable, representing status of serum ferritin level relative to the 
normal limits of serum ferritin, will be calculated for each visit over the Treatment 
Period. Female subjects with serum ferritin between 10 and 291 ng/ml and male 
subjects with serum ferritin between 22 and 322 ng/ml will be classified to be 
within normal limits of serum ferritin.  Those subjects with serum ferritin within the 


 
Page 15 of 21 
 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
23 July 2020
normal limits will be classified as “ferritin normal limit responders”.  Separate 
logistic regression models will be fitted to the long-term secondary endpoints, 
ferritin normal limit responder at each visit over Visits 5-7 (OC), for the ITT and re-
evaluated PP populations.  Each model will include terms to capture the effects of 
treatment, baseline Hb (below the observed median or at least the observed 
median), and IBD subgroup.  The above hypothesis testing for rise in Hb responder 
(Section 9.2.1.2) will be repeated here for the serum ferritin normal limit responder 
secondary endpoint. (post hoc table 14.2.7.2) 
 
A scatterplot of serum ferritin concentrations (OC) at each visit versus baseline will 
be presented by treatment arm for the re-evaluated PP population (post hoc figures 
14.2.2.2, 14.2.2.4, 14.2.2.6, 14.2.2.8.1, 14.2.2.8.2, 14.2.2.10.1, 14.2.2.10.2).  
 
Separate summaries will be provided for each of the binary long-term secondary 
endpoint variables defined above.  Each secondary endpoint will be summarised 
using descriptive statistics by visit over the Treatment Period for each treatment 
arm and overall, utilizing all available data (i.e., OC approach).  Each summary will 
also present the corresponding logistic regression model adjusted difference in 
proportions (risk difference) of secondary endpoint Hb responders between the two 
treatment arms, the corresponding [Delta Method derived] adjusted 95% CI for the 
difference in proportions, and the p-value from testing the null hypothesis of 
inferiority in risk difference with non-inferiority margin 20%.  Finally, each 
summary will also present the appropriate estimated logistic regression model 
adjusted odds ratio of secondary endpoint at Visits 5-7 (OC) between the two 
treatment arms and corresponding 95% CI for the odds ratio. 
Note: For the CI calculation in the long term secondary efficacy endpoint, the risk 
difference model was applied in the original analysis for CSR v1.0. The analysis 
method will be corrected to the Delta Method approach in the current post hoc 
analysis. 
 
Any patients who are in the re-evaluated PP population but have major deviations 
after Week 12 will be excluded from the re-evaluated PP analyses of the long-term 
secondary endpoints from the date of the major deviation onwards. 
 
10 PHARMACOECONOMIC ANALYSES 
 
For details of the pharmacoeconomic analyses, refer to Statistical Analysis Plan 
v3.0, dated 14 February 2019. 
 
The IV iron quantity that should have been prescribed was also calculated based on 
Weight and Hb and the local FCM Prescribing Information 
 
Post hoc analysis: The total amount of IV Iron taken by patients who completed 52 
weeks of treatment will be summarised for the IV Iron group using descriptive 
statistics on the safety population. (post hoc table 14.2.12) 
 
Post hoc analysis: A Kaplan-Meier plot of the time to first additional IV Iron will be 
provided for both ITT and re-evaluated PP population. The time to first additional IV 


 
Page 16 of 21 
 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
23 July 2020
Iron will be the time from first treatment to first additional or rescue IV iron taken 
on or after Visit 4. Patients originally consented under amendment 7 will be 
excluded from this plot. Patients who do not receive additional or rescue IV Iron will 
be censored at the end of study visit. (post hoc figure 14.3.2.2) 
 
Post hoc listing: A listing for all patients detailing the amount of IV Iron up to Week 
12 in subjects in the IV Iron group will be provided, detailing whether patients 
received the country specific amounts up to Week 12 and also if they received more 
than the maximum weekly amount at any point up to Week 12. A summary of this 
data will be provided, indicating the number of patients who were dosed as 
planned, those who were not but were considered minor deviations, and those who 
were not but were considered major deviations (post hoc table 14.2.13). 
 
Country specific guidance is detailed below: 
 
Country 
Hb 
(g/dl) 
Patient 
weight 
maximum by 
weight 
Maximum 
weekly dose 
Maximum recommended 
dose for a course 
Germany
<10 
between 35 
and 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
≥10 
between 35 
and 70 kg 
20 mg/kg 
1000 mg 
1000 mg 
<10 
over 70 kg 
20 mg/kg 
1000 mg 
2000 mg 
≥10 
over 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
Belgium 
<10 
between 35 
and 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
≥10 
between 35 
and 70 kg 
20 mg/kg 
1000 mg 
1000 mg 
<10 
≥ 70 kg 
20 mg/kg 
1000 mg 
2000 mg 
≥10 
≥ 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
France 
<10 
< 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
≥10 
< 70 kg 
20 mg/kg 
1000 mg 
1000 mg 
<10 
≥ 70 kg 
20 mg/kg 
1000 mg 
2000 mg 
≥10 
≥ 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
Spain 
<10 
between 35 
and 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
≥10 
between 35 
and 70 kg 
20 mg/kg 
1000 mg 
1000 mg 
<10 
≥ 70 kg 
20 mg/kg 
1000 mg 
2000 mg 
≥10 
≥ 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
Hungary 
<10 
between 35 
and 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
10-< 14  
between 35 
and 70 kg 
20 mg/kg 
1000 mg 
1000 mg 
≥14 
between 35 
and 70 kg 
20 mg/kg 
500 mg 
500 mg 
<10 
≥ 70 kg 
20 mg/kg 
1000 mg 
2000 mg 


 
Page 17 of 21 
 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
23 July 2020
10-< 14  
≥ 70 kg 
20 mg/kg 
1000 mg 
1500 mg 
≥14 
≥ 70 kg 
20 mg/kg 
500 mg 
500 mg 
USA 
  
≥ 50 kg 
  
750 mg 
1500mg in 2 doses 
separated 7 days apart. 
750 mg x2 
  
<50 kg 
15 mg/kg 
15 mg/kg 
15 mg/kg 2 doses 
separated by 7 days 
 
 
11 FINAL ANALYSIS 
 
The corrections and updates to the analyses will be performed and will include data 
as described above.  Results of this analysis will be reported in version 2 of the 
CSR. 
 
 
12 SUMMARY OF POST HOC CHANGES 
 
The definition of Hb normalisation, for Hb responder, normal limit responder and 
anaemic response has been updated to align with the WHO definition. 
 
The visit window around the haemoglobin evaluation at week 12 has been extended 
from 1 week, as in the schedule of visits, to 2 weeks, as per protocol Version 1. 
 
IV Iron subjects who did not follow the specific country dosing regimens were 
considered to be major protocol deviations. (Based on at least 2x deviation from 
recommended dosing) 
 
Dose changes or initiation of immunosuppressants was permitted in Protocol 
Version 6 and later; this rule was applied to all patients included in earlier Protocol 
versions. 
  
Protocol deviations deemed to be major, but not recorded on the database, will be 
included by means of a spreadsheet which will be agreed by Shield and Clinipace 
based on the minutes of the subject evaluability meeting 
 
The following summaries and analyses were included post-hoc: 
 
The total amount of IV Iron taken by patients who completed 52 weeks of 
treatment will be summarised for the IV Iron group using descriptive statistics.  
 
A Kaplan-Meier plot of the time to first additional IV Iron will be provided for 
both ITT and re-evaluated PP population. The time to first additional IV Iron will 
be the time from first treatment to first additional or rescue IV iron taken on or 
after Visit 4. Patients originally consented under amendment 7 will be excluded 
from this plot. Patients who do not receive additional or rescue IV Iron will be 
censored at the end of study visit. 
 


 
Page 18 of 21 
 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
23 July 2020
A listing detailing the amount of IV Iron up to Week 12 in subjects in the IV Iron 
group will be provided, detailing whether patients received the country specific 
amounts up to Week 12 and also if they received more than the maximum 
weekly amount at any point up to Week 12. A summary of this data will be 
provided, indicating the number of patients who were dosed as planned, those 
who were not but were considered minor deviations, and those who were not 
but were considered major deviations. 
 
A sensitivity analysis will be performed on the mPP compliance population. The 
analysis performed will be the same as for the primary efficacy. This analysis is 
relevant to HEOR and more of the real-world interpretation of the data.  In 
addition, a waterfall plot of overall compliance in the first 12 weeks based on 
this subset of patients will be included. 
 
A sensitivity analysis will be performed on the mPP windowing population 
containing all patients from the re-evaluated PP population, along with all 
patients who are only excluded from the re-evaluated PP population due to 
haemoglobin windowing issues will be included. Patients will be considered as a 
responder if they have a haemoglobin response at any point up to the Week 12 
visit. The analysis performed will be the same as for the primary efficacy. 
 
A sensitivity analysis will be performed on the re-evaluated PP population. 
Patients will be included into subgroups based on the protocol version they first 
consented under (prior to version 6, version 6 onwards).  The analysis 
performed for each subgroup will be the same as for the primary efficacy. 
 
13 REFERENCES 
 
1. Agresti A (2002). Categorical data analysis, 2nd edition. New York: Wiley.  
 
 


 
Page 19 of 21 
 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
23 July 2020
14 TABLE OF CONTENTS FOR DATA DISPLAYS 
 
14.1    Tables 
 
Study Population
Post hoc Table 
14.1.1.1
Summary of Analysis Populations – All Randomized 
Subjects
Post hoc Table 
14.1.1.3.1
Summary of Protocol Deviations in the First 12 Weeks –
ITT Population
Post hoc Table 
14.1.1.3.2 
Summary of Protocol Deviations After the First 12 Weeks –
ITT Population 
Post hoc Table 
14.1.2.2 
Summary of Demographic Characteristics – Re-evaluated 
PP Population 
Post hoc Table 
14.1.3.2
Summary of Medical History – Re-evaluated PP Population
Efficacy/PE
Post hoc Table 
14.2.1.1 
Summary of Haemoglobin Concentration (g/dL) – ITT 
Population 
Post hoc Table 
14.2.1.2
Summary of Haemoglobin Concentration (g/dL) – Re-
evaluated PP Population
Post hoc Table 
14.2.1.3
Summary of Haemoglobin Concentration (g/dL) in 
Subjects with Baseline Hb < 9.5 g/dL – ITT Population
Post hoc Table 
14.2.1.4 
Summary of Haemoglobin Concentration (g/dL) in 
Subjects with Baseline Hb < 9.5 g/dL – Re-evaluated PP 
Population
Post-hoc Table 
14.2.2.1
Summary of Haemoglobin Responder Rate – ITT 
Population
Post hoc Table 
14.2.2.2
Summary of Haemoglobin Responder Rate – Re-evaluated 
PP Population
Post hoc Table 
14.2.2.3 
Statistical Analysis of Haemoglobin Responder Rate Using 
a Repeated Measures Approach – ITT Population 
Post hoc Table 
14.2.2.4 
Statistical Analysis of Haemoglobin Responder Rate Using 
a Repeated Measures Approach – Re-evaluated PP 
Population
Post hoc Table 
14.2.2.5 
Summary of Haemoglobin Responder Rate – mPP
Compliance Population 
Post hoc Table 
14.2.2.6 
Summary of Haemoglobin Responder Rate – mPP 
Windowing Population 
Post hoc table 
14.2.2.7
Summary of Haemoglobin Responder Rate – Protocol 
Version Subgroup - Re-evaluated PP Population
Post-hoc Table 
14.2.3.1
Summary of Rise in Haemoglobin Responder Rate – ITT 
Population
Post-hoc Table 
14.2.3.2
Summary of Rise in Haemoglobin Responder Rate – Re-
evaluated PP Population


 
Page 20 of 21 
 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
23 July 2020
Post-hoc Table 
14.2.3.3 
Summary of Haemoglobin Rise Responder in Subjects with 
Baseline Hb < 9.5 g/dL – ITT Population 
Post-hoc Table 
14.2.3.4 
Summary of Haemoglobin Rise Responder in Subjects with 
Baseline Hb < 9.5 g/dL – Re-evaluated PP Population 
Post-hoc Table 
14.2.4.1
Summary of Haemoglobin Normal Limit Responder Rate –
ITT Population
Post-hoc Table 
14.2.4.2
Summary of Haemoglobin Normal Limit Responder Rate –
Re-evaluated PP Population
Post-hoc Table 
14.2.4.3
Summary of Haemoglobin Normal Limit Responder Rate in 
Subjects with Baseline Hb < 9.5 g/dL – ITT Population
Post-hoc Table 
14.2.4.4 
Summary of Haemoglobin Normal Limit Responder Rate in 
Subjects with Baseline Hb < 9.5 g/dL – Re-evaluated PP 
Population
Revised Table 
14.2.5.1
Summary of Anaemic Status – ITT Population 
Post-hoc Table 
14.2.5.2 
Summary of Anaemic Status – Re-evaluated PP Population 
Post-hoc Table 
14.2.6.2 
Summary of Serum Ferritin Concentration (ng/ml) – Re-
evaluated PP Population 
Post-hoc Table 
14.2.7.2 
Summary of Ferritin Normal Limit Responder Rate – Re-
evaluated PP Population 
Post hoc Table 
14.2.12
Total Amount of IV Iron in Patients who Completed 52 
Weeks of Study – Safety Population
Post hoc Table 
14.2.13
Planned vs Actual Amount of IV Iron up to Week 12 –
Safety Population
 
 
14.2    Figures 
 
Post hoc Figure 
14.2.1.4
Haemoglobin Concentration (g/dL) at Week 12 Versus 
Baseline – Re-evaluated PP Population
Post hoc Figure 
14.2.1.5.1 
Mean Change from Baseline Haemoglobin Concentration 
(g/dL) by Visit – Re-evaluated PP Population 
Post hoc Figure 
14.2.1.5.2 
Mean Change from Baseline Haemoglobin Concentration 
(g/dL) by Visit with Early Termination – Re-evaluated PP 
Population
Post hoc Figure 
14.2.1.6 
Haemoglobin Responders by Visit – Re-evaluated PP 
Population 
Post hoc Figure 
14.2.1.8 
Haemoglobin Concentration (g/dL) at Week 24 Versus 
Baseline – Re-evaluated PP Population 
Post hoc Figure 
14.2.1.10
Haemoglobin Concentration (g/dL) at Week 36 Versus 
Baseline – Re-evaluated PP Population
Post hoc Figure 
14.2.1.12.1
Haemoglobin Concentration (g/dL) at Week 52 Versus 
Baseline – Re-evaluated PP Population
Post hoc Figure 
14.2.1.12.2
Haemoglobin Concentration (g/dL) at Week 52/Early 
Termination Versus Baseline – Re-evaluated PP Population


 
Page 21 of 21 
 
Statistical Analysis Plan 
Protocol: ST10-01-304 
Shield TX (UK) Limited
23 July 2020
Post hoc Figure 
14.2.1.14 
Haemoglobin Responders (1g/dL) by Visit – Re-evaluated 
PP Population 
Post hoc Figure 
14.2.2.2 
Ferritin Concentration (ng/mL) at Week 12 Versus 
Baseline – Re-evaluated PP Population 
Post hoc Figure 
14.2.2.4
Ferritin Concentration (ng/mL) at Week 24 Versus 
Baseline – Re-evaluated PP Population
Post hoc Figure 
14.2.2.6
Ferritin Concentration (ng/mL) at Week 36 Versus 
Baseline – Re-evaluated PP Population
Post hoc Figure 
14.2.2.8.1
Ferritin Concentration (ng/mL) at Week 52 Versus 
Baseline – Re-evaluated PP Population
Post hoc Figure 
14.2.2.8.2 
Ferritin Concentration (ng/mL) at Week 52/Early 
Termination Versus Baseline – Re-evaluated PP Population 
Post hoc Figure 
14.2.2.10.1 
Mean Change from Baseline Ferritin Concentration 
(ng/mL) by Visit – Re-evaluated PP Population 
Post hoc Figure 
14.2.2.10.2 
Mean Change from Baseline Ferritin Concentration 
(ng/mL) by Visit with Early Termination – Re-evaluated PP 
Population 
Post hoc Figure 
14.3.2.2 
Time to First Additional IV Iron – Re-evaluated PP 
Population 
Post hoc Figure 
14.3.2.3 
Waterfall Plot of Compliance in the First 12 Weeks –
Safety Population 
 
 
 
 
 
14.3    Listings 
 
Study Population
Post hoc Listing 
16.2.2.3 
Listing of Protocol Deviations
Post hoc Listing 
16.2.3.2
Listing of Analysis Populations
Post Hoc Listing 
16.2.5.4
Listing of Planned vs IV Administration In First 12 Weeks
Efficacy/PE
Post hoc Listing 
16.2.6.1 
Listing of Haemoglobin Results
Post hoc Listing 
16.2.6.2 
Listing of Ferritin Results
Post hoc Listing 
16.2.6.4
Listing of Correction and Maintenance of IDA
 

Prot_000.pdf: 
 
 
 
ST10‐01‐304 Clinical Study Protocol 
 
 
 
 
Version 7.0  30 Apr 2018 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 1 of 62  
 
 
 
 
CLINICAL STUDY PROTOCOL 
A phase 3b, randomized, controlled, multicentre study with oral ferric maltol (Feraccru) or 
intravenous iron (ferric carboxymaltose; FCM), for the treatment of iron deficiency anaemia in 
subjects with inflammatory bowel disease 
 
Protocol Number: 
ST10‐01‐304  
EudraCT Number: 
2015‐002496‐26  
Test Drug: 
 
Ferric maltol 
IND Number:   
114832 
 
 
Sponsor: 
 
 
Shield TX (UK) Limited 
 
 
Sponsor Address:                    Northern Design Centre  
Baltic Business Quarter  
Gateshead Quays  
NE8 3DF 
United Kingdom 
 
Tel:                                            +44 (0)191 511 8500 
 
 
 
              
EU Legal Representative:  
Not Applicable 
 
 
 
 
 
Version/Date:  
 
Version 7.0 / 30 Apr 2018 
 
 
 
 
 
Confidentiality Statement 
 
The information contained in this document is provided in confidence.  It is understood that 
this information will not be disclosed to others without prior agreement of Shield TX (UK) 
Limited, according to the statement in the clinical study protocol, and in accordance with the 
confidentiality agreement. 




 
 
 
ST10‐01‐304 Clinical Study Protocol 
 
 
 
 
Version 7.0  30 Apr 2018 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 3 of 62  
 
2 
SYNOPSIS 
 
Title / Study Number 
 
A phase 3b, randomized, controlled, multicentre study with oral ferric 
maltol (Feraccru) or intravenous iron (ferric carboxymaltose, FCM), 
for  the  treatment  of  iron  deficiency  anaemia  in  subjects  with 
inflammatory bowel disease (IBD) 
ST10‐01 304 
Phase  
Phase 3b 
Objectives 
Primary Objective 
To  compare  the  efficacy  of  ferric  maltol  and  intravenous  iron  (IVI, 
FCM) in the treatment and maintenance of iron deficiency anaemia 
(IDA) in subjects with IBD  
 
Secondary Objective 
To  evaluate  the  safety  and  tolerability  of  ferric  maltol  and  IVI  in 
subjects over a treatment duration of up to 52 weeks. 
To  evaluate  long‐term  healthcare  resources  utilized  in  the 
management of IDA in IBD. 
Study Design 
 
Prospective, multicentre, randomized, controlled Phase 3b study 
 
Screening: Up to 14 days 
 
Randomized treatment:  
 
12 weeks treatment period  
 
subjects entered in the 52 weeks treatment period will finish 
their randomized treatment at week 12, unless they went 
beyond this visit. If so, the next scheduled visit will be their 
last treatment visit.  
 
End of study: Week 12/premature discontinuation or next 
scheduled visit if subjects went beyond Week 12.  
 
Post‐treatment safety follow‐up: 14 days (2 weeks) after End of 
Study visit or premature discontinuation of ferric maltol or FCM 
 
Number of 
Subjects/Treatments 
Approximately 242 subjects with IDA and IBD will be randomized at a 
ratio of 1:1 into one of the following treatment arms: 
 
Oral ferric maltol, 30 mg capsule twice daily (bid) 
 
Intravenous iron (ferric carboxymaltose), administered as per the 
local summary of product characteristics (SPC/PI) 
 
Diagnosis/Inclusion Criteria 
All of the following criteria must be met to randomize a subject in the 
study: 
1. Subjects must be competent to understand the information 
given  in  the  Independent  Ethics  Committee  (IEC)  or 
Institutional Review Board (IRB) approved informed consent 


 
 
 
ST10‐01‐304 Clinical Study Protocol 
 
 
 
 
Version 7.0  30 Apr 2018 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Page 4 of 62  
 
form and must sign and date the informed consent prior to 
any study mandated procedure  
2. Subjects  must  be  willing  and  able  to  comply  with  study 
requirements  
3. Age ≥ 18 years 
4. Subjects must have a confirmed diagnosis of IBD (endoscopic 
and/or biopsy) 
5. Subjects  must  be  considered  suitable  for  intravenous  iron 
treatment by the Investigator  
6. Subjects must have iron deficiency anaemia defined by the 
following criteria: 
a.  Hb 8.0 g/dL and ≤11.0 g/dL for women OR a Hb 8.0 
g/dL and ≤12.0 g/dL for men 
b. AND Ferritin <30ng/ml OR Ferritin <100 ng/ml WITH 
Transferrin saturation (TSAT) <20%. 
7. 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 implants, injectables, some intrauterine 
contraceptive devices (IUDs), complete sexual abstinence, or 
a vasectomized partner.  Oral contraceptive medications are 
allowed  in  this  study.    Female  subjects  who  are  surgically 
sterile  (bilateral  tubal  ligation,  bilateral  oophorectomy  or 
hysterectomy) or postmenopausal (defined as no menstrual 
period  within  1  year  of  screening)  are  also  allowed  to 
participate. 
 
Exclusion Criteria 
 
A subject who meets any of the following criteria is not eligible for 
participation in the study. 
1. Subject  with  anaemia  due  to  any  cause  other  than  iron 
deficiency, including, but not limited to, 
a. Untreated  or  untreatable  severe  malabsorption 
syndrome 
b. Immunosuppressant use.  Immunosuppressants are 
permitted so long as there is no clinical evidence or 
suspicion of the immunosuppressant contributing to 
the subject’s anaemia or affecting erythropoiesis.  
Variations to dosing are permitted at the discretion of 
the investigator so long as there is no clinical evidence 
or suspicion of the immunosuppressant contributing 
to the subject’s anaemia or affecting erythropoiesis 
2. Subject who has received prior to screening 


 
 
 
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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
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a. Within 8 weeks intramuscular or intravenous (IV) iron 
or administration of depot iron preparation 
b. Within 2 weeks a blood transfusion 
c. Oral iron supplementation, taken specifically to treat 
anaemia,  within  the  previous  4  weeks  (Over  the 
Counter  (OTC)  multivitamins  containing  iron  are 
permitted)  
3. Subjects with active inflammatory bowel disease as defined 
by a SCCAI (Simple Clinical Colitis Activity Index) score greater 
than 5 at Screening or a CDAI (Crohn’s Disease Activity Index) 
score greater than 300 in the Screening period (as assessed 
using the Screening haematocrit (HCT) and CDAI diary card 
completed  by  the  subject  for  7  days  prior  to  planned 
randomization). 
4. Subjects with known hypersensitivity or allergy to either the 
active  substance  or  excipients  of  ferric  maltol  capsules  or 
ferric carboxymaltose solution for IV administration 
5. Subjects who have had serious adverse reactions to previous 
doses of ferric carboxymaltose or any other intravenous iron 
6. Subjects  with  contraindication  for  treatment  with  iron 
preparations,  e.g.  hemochromatosis,  chronic  hemolytic 
disease,  sideroblastic  anaemia,  thalassemia,  or  lead 
intoxication induced anaemia. 
7. Subjects  with  vitamin  B12  or  folic  acid  deficiency  as 
determined  by  the  central  laboratory  screening  results. 
Subjects may start vitamin B12 or folate replacement and 
rescreen after at least 2 weeks.  
8. Subjects who are pregnant or breast feeding.  
9. Concomitant  medical  conditions  with  significant  active 
bleeding likely to initiate or prolong anaemia. 
10. Participation in any other interventional clinical study within 
30 days prior to screening. 
11. Subject  with  cardiovascular,  liver,  renal,  haematologic, 
gastrointestinal,  immunologic,  endocrine,  metabolic,  or 
central  nervous  system  disease  that,  in  the  opinion  of  the 
Investigator, may adversely affect the safety of the subject or 
severely  limit  the  lifespan  of  the  subject  (i.e.  unlikely  to 
complete the full duration of the study). 
12. Subject with significant neurologic or psychiatric symptoms 
resulting in disorientation, memory impairment, or inability 
to  report  accurately  that  might  interfere  with  treatment 
compliance,  study  conduct  or  interpretation  of  the  results 
(e.g., Alzheimer’s disease, schizophrenia or other psychosis, 
active or current alcohol or drug abuse). 
13. Subject  who  is  an  inmate  of  a  psychiatric  ward,  prison,  or 
other state institution. 


 
 
 
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14. Subject  who  is  an  Investigator  or  any  other  team  member 
involved directly or indirectly in the conduct of the clinical 
study. 
15. Subjects with severe renal impairment: creatinine clearance < 
30 mL/min. (Applicable to US sites Only) 
 
Concomitant Medication 
 
Iron preparations other than ferric maltol or ferric carboxy 
maltose (FCM) are prohibited at baseline and during study, 
with the exception of: 
 
Over the Counter (OTC) oral 
supplements/multivitamin type preparations which 
may be taken, however Subjects are encouraged to 
keep to the same dose during the course of this 
study 
 
Blood transfusions or donations are prohibited. 
 
Erythropoiesis‐stimulating agents (ESAs) are permitted during 
the study, but the subject must have been on a stable dose 
for the preceeding 3 months before randomization. 
 
Vitamin  B12  and  folic  acid  supplements/replacement  are 
allowed during the study.  
 
Immunosuppressants  are  permitted  so  long  as  there  is  no 
clinical  evidence  or  suspicion  of  the  immunosuppressant 
contributing  to  the  subject’s  anaemia  or  affecting 
erythropoiesis.  Variations  to  dosing  are  permitted  at  the 
discretion of the investigator so long as there is no clinical 
evidence 
or 
suspicion 
of 
the 
immunosuppressant 
contributing 
to 
the 
subjects 
anaemia 
or 
affecting 
erythropoiesis. 
 
Investigational Medicinal 
Product  
 
Ferric maltol 30 mg capsules bid 
Comparator Therapy 
Intravenous iron as ferric carboxy maltose (FCM) 
Study Endpoints 
 
 
 
The primary endpoint of this study is:  
 
Proportion of subjects achieving either a 2g/dL increase in 
Hb  OR  normalization  of  Hb  (>12g/dL  women,  >13g/dL 
men) at Week 12 
Secondary efficacy endpoints will include the following 
 
Change in Hb concentration from baseline to Week 12 
 
Change in Hb concentration from baseline to Week 12 in 
subjects with a baseline Hb <9.5 g/dL 
 
Proportion  of  subjects  who  experience  a  change  from 
baseline in Hb concentration ≥1.0 g/dL at Week 12 


 
 
 
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 
Proportion of subjects with baseline Hb <9.5g/dL that 
achieve an increase in Hb concentration of ≥1 g/dL at 
Week 12  
 
Proportion  of  subjects  with  Hb  concentration  within 
normal limits at Week 12 
 
Proportion  of  subjects  with  baseline  Hb  concentration 
<9.5 g/dL that is within normal limits at Week 12 
 
Change in Hb concentration from baseline to Week 4 
 
Change in Hb concentration from baseline to Week 4 in 
subjects with a baseline Hb <9.5 g/dL  
 
Proportion  of  subjects  who  experience  a  change  from 
baseline in Hb concentration ≥2.0 g/dL at Week 12 
 
Proportion of subjects with baseline Hb <9.5g/dL that 
achieve an increase in Hb concentration of ≥2 g/dL at 
Week 12  
 
Proportion  of  subjects  who  experience  a  change  from 
baseline in Hb concentration ≥1.0 g/dL at Week 4 
 
Proportion of subjects with baseline Hb <9.5g/dL that 
achieve an increase in Hb concentration of ≥1 g/dL at 
Week 4  
 
Proportion  of  subjects  with  Hb  concentration  within 
normal limits at Week 4  
 
Proportion  of  subjects  with  baseline  Hb  concentration 
<9.5 g/dL that is within normal limits at Week 4 
 
Proportion  of  subjects  who  experience  a  change  from 
baseline in Hb concentration ≥2.0 g/dL at Week 4 
 
Proportion of subjects with baseline Hb <9.5g/dL that 
achieve an increase in Hb concentration of ≥2 g/dL at 
Week 4 
 
Long term efficacy endpoints i.e. proportion of subjects 
who are non‐anaemic at 6 and 12 months; normalization 
of ferritin levels at 6 and 12 months 
Secondary safety endpoints 
 
Treatment‐emergent Adverse Events (AEs)  
 
Treatment‐emergent Serious Adverse Events (SAEs) 
 
Adverse Events leading to premature discontinuation of 
study drug 
 
Adherence to study medication 
 
Pharmacoeconomic endpoints 
 
Number of hospital or clinic visits for administration of IV 
iron 


 
 
 
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 
Proportion of subjects who restart FCM during the study 
 
Other pharmacoeconomic endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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3 
ABBREVIATION INDEX 
AE 
adverse event 
ALT 
Alanine aminotransferase  
AMG 
Arzneimittelgesetz 
ANCOVA 
analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
area under the plasma concentration‐time curve 
bid 
twice daily  
BOCF 
Baseline Observation Carried Forward 
BP 
blood pressure 
BUN 
blood urea nitrogen  
BW 
body weight 
C 
Celsius 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
Cmax 
maximum observed plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C‐reactive protein 
CS 
clinically significant 
ESA 
Erythropoiesis‐stimulating agent 
FCM 
Ferric carboxy maltose 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
h  
Hour 
Hb 
Haemoglobin 
HCT 
Haematocrit 
HDPE 
High density polyethylene 
HR 
heart rate 
IBD  
inflammatory bowel disease 
IBDQ 
Inflammatory Bowel Disease Questionnaire  
ICH 
International Conference on Harmonization  
IDA 
iron deficiency anaemia 
IEC 
Independent Ethics Committee  
IMP 
Investigational Medical Product  
IRB 
Institutional Review Board  
ISF 
Investigator Site File 
ITT 
intention‐to‐treat  
IUD 
intrauterine contraceptive devices  
IV 
Intravenous 
IVI 
Intravenous iron 
LCL 
lower confidence limit 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
NCS 
non‐clinically significant 
OFP 
oral ferrous products 


 
 
 
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OTC 
Over the counter 
PE 
Pharmacoeconomics 
PI 
Prescribing Information 
PK 
Pharmacokinetic 
PP 
per protocol 
QOL 
quality of life 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
SCCAI 
Simple Clinical Colitis Activity Index 
SF‐36 
Medical outcomes study 36‐item short form   
SIV 
Site Initiation Visit 
SOC 
System Organ Class 
SOP 
standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction  
TIBC 
total iron binding capacity 
TEAE 
Treatment‐emergent adverse event 
t1/2term 
apparent terminal elimination half‐life 
Tmax 
the actual sampling time to reach the maximum observed plasma 
concentration 
TSAT 
transferrin saturation 
UC 
ulcerative colitis 
WBC 
White blood cell 
WHO 
World Health Organization  


 
 
 
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4 
TABLE OF CONTENTS 
1 
PROTOCOL APPROVALS ........................................................................................................... 2 
2 
SYNOPSIS ................................................................................................................................. 3 
3 
ABBREVIATION INDEX .............................................................................................................. 9 
4 
TABLE OF CONTENTS .............................................................................................................. 11 
5 
BACKGROUND INFORMATION ............................................................................................... 15 
5.1 
Iron Deficiency Anaemia in Inflamatory Bowel Disease ........................................................ 15 
5.2 
Investigational Medical Product (investigational drug) ........................................................ 15 
5.3 
Results from previous clinical studies ................................................................................... 16 
5.4 
Rationale for the study .......................................................................................................... 18 
5.4.1 
Medical and regulatory background ............................................................................. 18 
5.4.2 
Population ..................................................................................................................... 18 
5.4.3 
Study Design .................................................................................................................. 18 
5.4.4 
Comparator Drugs ......................................................................................................... 20 
5.5 
Dose Selection and Treatment Duration ............................................................................... 20 
5.6 
Risk‐benefit evaluation .......................................................................................................... 21 
6 
Study objectives .................................................................................................................... 22 
6.1 
Primary Objective .................................................................................................................. 22 
6.2 
Secondary Objective .............................................................................................................. 22 
7 
Investigational plan ............................................................................................................... 22 
7.1 
Study description ................................................................................................................... 22 
7.2 
Investigational sites ............................................................................................................... 23 
7.3 
Study variables ...................................................................................................................... 23 
7.3.1 
Primary Efficacy variables .............................................................................................. 23 
7.3.2 
Primary Safety variables ................................................................................................ 23 
7.4 
Selection and withdrawal of subjects .................................................................................... 23 
7.4.1 
Inclusion criteria ............................................................................................................ 23 
7.4.2 
Exclusion criteria ........................................................................................................... 24 
7.4.3 
Concomitant medication at baseline and during the study .......................................... 25 
7.4.4 
Advice regarding potential ferric maltol drug interactions ........................................... 26 
7.4.5 
Rescreening ................................................................................................................... 26 
7.4.6 
Individual discontinuation criteria ................................................................................. 26 
7.4.7 
Subject selection ........................................................................................................... 26 


 
 
 
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7.4.8 
Replacement policy ....................................................................................................... 27 
8 
Study drugs ............................................................................................................................ 27 
8.1 
Investigational Medical Product ............................................................................................ 27 
8.2 
Packaging ............................................................................................................................... 27 
8.3 
Labelling ................................................................................................................................. 27 
8.4 
Storage .................................................................................................................................. 28 
8.5 
Treatment Assignment and Blinding ..................................................................................... 28 
8.5.1 
Treatment assignment .................................................................................................. 28 
8.5.2 
Subject screening and Randomization number ............................................................ 28 
8.5.3 
Maintenance of the randomization code ...................................................................... 28 
8.5.4 
Emergency unblinding ................................................................................................... 28 
8.6 
Treatment compliance .......................................................................................................... 28 
9 
Study procedures ................................................................................................................... 30 
9.1 
Schedule of assessments ....................................................................................................... 30 
9.2 
Treatment procedures by visit .............................................................................................. 32 
9.2.1 
Screening visit (Visit 1/between Day ‐14 and Day ‐1) ................................................... 32 
9.2.2 
Randomization visit (Visit 2/ Day 0) .............................................................................. 32 
9.2.3 
Visit 3 (Week 4) ............................................................................................................. 33 
9.2.4 
Visit 4 (Week 12) or End of Study .................................................................................. 34 
9.2.5 
Visit 5 (Week 24) or End of Study .................................................................................. 35 
9.2.6 
Visit 6 (Week 36) or End of Study .................................................................................. 35 
9.2.7 
Visit 7 (Week 52) or End of study visit ........................................................................... 36 
9.2.8 
Telephone follow up ...................................................................................................... 36 
9.2.9 
Premature Discontinuation ........................................................................................... 36 
10  Assessments .......................................................................................................................... 36 
10.1 
Efficacy ................................................................................................................................... 36 
10.1.1 
Haemoglobin ................................................................................................................. 36 
10.2 
Safety ..................................................................................................................................... 37 
10.2.1 
Definitions ..................................................................................................................... 37 
10.2.2 
Adverse Event ................................................................................................................ 37 
10.2.3 
Serious Adverse Event ................................................................................................... 38 


 
 
 
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10.2.4 
Reporting and Documentation ...................................................................................... 39 
10.2.5 
Immediate reporting ..................................................................................................... 40 
10.2.6 
Non‐immediate reporting ............................................................................................. 40 
10.2.7 
Evaluation ...................................................................................................................... 40 
10.2.8 
Intensity ......................................................................................................................... 40 
10.2.9 
Causality ........................................................................................................................ 40 
10.2.10  Outcome ........................................................................................................................ 41 
10.2.11  Re‐exposure ................................................................................................................... 41 
10.2.12  Clinical laboratory .......................................................................................................... 41 
10.3 
Pharmacoeconomics Collection ............................................................................................ 42 
10.3.1 
Medical outcomes study 36‐item short form ................................................................ 42 
10.3.2 
Pharmacoeconomics ..................................................................................................... 43 
10.4 
Baseline parameters and concomitant medications ............................................................. 43 
10.4.1 
Baseline demographics and disease characteristics ..................................................... 43 
10.4.2 
Concomitant medications ............................................................................................. 43 
11  Endpoints .............................................................................................................................. 44 
11.1 
Primary Efficacy endpoint ..................................................................................................... 44 
11.2 
Secondary Efficacy endpoints ................................................................................................ 44 
11.3 
Secondary safety Endpoints .................................................................................................. 45 
12  Statistical considerations ....................................................................................................... 45 
12.1 
General Considerations ......................................................................................................... 45 
12.2 
Sample size and power calculations ...................................................................................... 45 
12.3 
Statistical methods ................................................................................................................ 46 
12.3.1 
Primary endpoint analysis ............................................................................................. 46 
12.3.2 
Secondary and Exploratory Analyses ............................................................................ 46 
12.3.3 
Sensitivity analyses ........................................................................................................ 46 
12.3.4 
Imputation of Missing Data ........................................................................................... 47 
12.3.5 
Safety analyses .............................................................................................................. 47 
Adverse Events .............................................................................................................................. 47 
Laboratory variables ...................................................................................................................... 47 
12.3.6 
Pharmacoeconomic Analysis ......................................................................................... 47 


 
 
 
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12.3.7 
Statisical Analysis ........................................................................................................... 47 
12.4 
Definition of Populations ....................................................................................................... 48 
12.4.1 
Randomised Population ................................................................................................ 48 
12.4.2 
Safety population .......................................................................................................... 48 
12.4.3 
Intention‐to‐treat population (Full analysis set) ........................................................... 48 
12.4.4 
Per protocol population ................................................................................................ 48 
12.5 
Software applied ................................................................................................................... 48 
12.6 
Quality Control ...................................................................................................................... 48 
13  Data management ................................................................................................................. 48 
14  Ethical considerations ............................................................................................................ 48 
14.1 
Subject information and informed consent .......................................................................... 48 
14.2 
Institutional review board / Independent ethics committee ................................................ 49 
14.3 
Subject insurance .................................................................................................................. 49 
15  Study management ................................................................................................................ 49 
15.1 
Legal requirements ................................................................................................................ 49 
15.2 
Data collection ....................................................................................................................... 49 
15.2.1 
Case Report Forms ........................................................................................................ 50 
15.2.2 
Source documents ......................................................................................................... 50 
15.2.3 
Confidential subject identification list and screening log ............................................. 50 
15.3 
Access to data ........................................................................................................................ 50 
15.4 
Monitoring ............................................................................................................................. 50 
15.5 
Amendments ......................................................................................................................... 51 
15.6 
Audits ..................................................................................................................................... 51 
15.7 
Confidentiality agreement ..................................................................................................... 51 
15.8 
Notice to the local and national authorities .......................................................................... 51 
15.9 
Retention of records .............................................................................................................. 51 
15.10  Investigator meeting ............................................................................................................. 52 
15.11  Security and publications ...................................................................................................... 52 
16  References ............................................................................................................................. 53 
17  Appendices ............................................................................................................................ 55 
17.1 
Scoring system for the Simple Clinical Colitis Activity Index ................................................. 55 
17.2 
Scoring System for the Crohn’s Disease Activity Index ......................................................... 56 
17.3 
SF‐36 quality of life questionnaire ........................................................................................ 57 
17.4 
World Medical Association Declaration of Helsinki .............................................................. 58 


 
 
 
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5 
BACKGROUND INFORMATION 
5.1 
IRON DEFICIENCY ANAEMIA IN INFLAMATORY BOWEL DISEASE 
Inflammatory bowel disease (IBD) is a chronic relapsing condition of the gut characterised by 
inflammation of the mucosal and sub‐mucosal tissues.  The exact aetiology is unknown but 
there is a significant auto‐immune component to disease activity.  Disease symptoms depend 
on whether the IBD is predominantly small intestine (Crohn’s Disease; CD) or large bowel 
(ulcerative colitis; UC), but abdominal pain, diarrhoea and malabsorption occur frequently in 
both.  
Anaemia is a serious systemic complication and a key symptom of IBD.  Other recognised co‐
morbidities  of  chronic  stable  IBD  include  abnormal  bone  mineral  density,  sclerosing 
cholangitis and uveitis.  Anaemia is, however, by far the most common clinical presentation, 
such that specific guidelines were published in December 2007 for the management of iron 
deficiency and anaemia in inflammatory bowel diseases (IBD) including UC and CD (Gasche, 
2007).  An update to these guidelines were published in 2015 (Dignass, 2015). 
Iron deficiency anaemia (IDA) in IBD is primarily caused by chronic blood loss from inflamed 
mucosa  and/or  iron  malabsorption  during  both  active  and  inactive  stages  of  the  disease 
(Bergamaschi, 2010).  In addition, chronic abdominal pain and nausea often result in poor 
dietary  intake,  whilst  mucosal  inflammation  in  the  gastro‐intestinal  tract  may  lead  to 
inadequate  nutrient  absorption  (Wilson,  2004).    While  in  normal  subjects,  daily  iron  loss 
averages 1‐2 mg and is replaced by absorption of the same amount from food sources; in 
subjects with iron deficiency associated with UC, the iron loss will likely exceed the subject’s 
capacity for iron absorption from a normal diet (Wilson, 2004). Less frequently, anaemia may 
be  drug‐induced  (sulfasalazine,  thiopurines),  or  arise  from  haemolysis  or  myelodysplastic 
syndrome (Gasche, 2006).  Anaemia of these aetiologies, however, is not treatable with iron 
replacement therapy. 
Because it is associated with substantial impairment of quality of life (QOL), anaemia in IBD 
deserves  greater  proactive  management  by  gastroenterologists  than  generally  received 
(Wells,  2006).    Characteristic  symptoms  include  chronic  fatigue,  headache,  and  subtle 
impairment  of  cognitive  function.    Reasons  for  not  treating  anaemia  effectively  include 
intolerance  to  oral  iron  therapies  and  difficulty  in  delivery  and/or  risks  associated  with 
parenteral iron (Biancone, 2008). 
Diagnosis of iron deficiency in IBD is based in principle on laboratory blood parameters.  Low 
haemoglobin (Hb) in the setting of a reduced mean corpuscular volume is usually the initial 
finding on a routine complete blood count. According to World Health Organization (WHO) 
criteria, anaemia is defined by Hb levels lower than 13.0 g/dl for males and lower than 12.0 
g/dl for females (Blanc, 1968).  Haemoglobin levels below 10 g/dl are considered indicative of 
severe anaemia (Gasche, 2007).   
The aim of pharmacologic treatment is to correct the IDA, with the ultimate goal of having the 
serum Hb return to the reference range.  Furthermore, it is expected that correcting the 
anaemia will ameliorate the associated clinical symptoms.   
5.2 
INVESTIGATIONAL MEDICAL PRODUCT (INVESTIGATIONAL DRUG) 
Treatment of iron deficiency should begin with dietary replacement (i.e., fortified cereals and 
breads, red meat, beans, green leafy vegetables).  However, when diet alone is inadequate to 
restore  iron  stores  and  Hb  to  normal  levels,  or  when  anaemia  is  moderate  or  severe, 


 
 
 
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treatment with exogenous iron supplements should be implemented (Blanc, 1968). Ferrous 
sulphate is available in multiple formulations and dosages, but is typically taken as 300 mg 
tablets (60 mg elemental iron) and ferrous gluconate as 320 mg tablets (36 mg elemental iron) 
three to four times daily. However, as the duodenum can maximally absorb only 10‐20 mg of 
iron a day, greater than 90% of ingested iron is not absorbed, leading to symptomatic adverse 
events including potential erosions and enteric siderosis (Zhu, 2010).  Common adverse effects 
of oral iron supplements include nausea, epigastric discomfort, and constipation, all of which 
are dose‐related. Adverse effects can occur in up to 20% of subjects, impairing compliance 
(Zhu, 2010).  
In  an  effort  to  overcome  the  significant  challenges  of  iron  substitution  with  oral  ferrous 
products (OFP), ferric maltol (also known as ST10‐021 or ST10), 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  gastrointestinal  tract,  providing  the  iron  in  a 
biologically labile form for uptake onto transferrin and ferritin and ultimate haematopoiesis 
and storage on ferritin.  
Unlike OFPs which are often given with food in order to reduce side effects, ferric maltol can, 
and  should,  be  given  on  an  empty  stomach  to  maximise  bioavailability.    Oral  ferric  iron 
chelated  with  maltol  can  be  administered  with  improved  tolerability  and  the  total  dose 
exposure  of  unabsorbed  iron  within  the  gastrointestinal  tract  is  significantly  reduced.  In 
addition, the iron is retained in its chelated form if not absorbed and this may reduce the risk 
of irritation within the gastrointestinal tract that is often seen with OFP.  
Pharmacokinetic (PK) data from the pivotal GCP PK studies conducted in both IBD patients and 
patients with IDA of any cause demonstrated that uptake of maltol and iron into the plasma 
after  administration  of  ST10  display  completely  independent  absorption  profiles  (studies 
ST10‐01‐101 and ST10‐01‐102).  In study ST10‐01‐101, the PK and iron uptake of ST10 was 
investigated in blood and urine after single and repeated bid oral doses of 30 mg, 60 mg and 
90 mg  for  8 days  in  subjects  with  iron  deficiency  (with  or  without  anaemia)  through 
measurement of total serum iron, transferrin saturation (TSAT), as well as plasma and urine 
concentrations of maltol and maltol glucuronide.  In study ST10‐01‐102 the PK of ST10 after a 
30 mg single dose administered at steady‐state were investigated in patients already being 
treated in the open label phase of studies ST10‐01‐301 or ST10‐01‐302 through measurement 
of serum iron parameters (transferrin, transferrin saturation [TSAT], total iron binding capacity 
[TIBC],  ferritin,  soluble  transferrin  receptor,  total  serum  iron),  plus  plasma  and  urine 
concentrations of maltol and maltol glucuronide. 
5.3 
RESULTS FROM PREVIOUS CLINICAL STUDIES 
Data for ferric maltol in healthy volunteers at a high iron dose of 180 mg and at the expected 
therapeutic daily dose of 60 mg (as iron) in ferrous intolerant subjects, suggests that the lack 
of toxicity to the gastrointestinal tract, as demonstrated in these and nonclinical studies, may 
translate to a better tolerated and efficacious iron product (Shield TX, data on file; Harvey, 
1998).   
An  open  label,  uncontrolled  study  of  23  IDA  subjects  with  documented  ferrous  sulphate 
intolerance and GI conditions, was conducted with the same ferric maltol dose as intended 
for this Phase 3 protocol (30 mg bid for 12 weeks) (Harvey, 1998). Anaemia was fully corrected 
in 74% of subjects who completed the study (14 out of 19 subjects). Mean Hb increased from 
10.6 ± 1.5 to 12.6 ± 1.6 g/dl. Similarly, there was a significant increase in ferritin from pre‐
treatment levels (8.1 ± 3.5 to 17.4 ± 11.4 µg/l (p < 0.001).  


 
 
 
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The majority (74%) of subjects who completed the study reported no significant change in 
overall mean daily symptom score during the treatment period. Based on these findings, the 
publication concluded that ferric maltol could correct iron deficiency and resulted in a low 
incidence of side effects in subjects with a history of ferrous sulphate intolerance.  
A recent, randomised Phase III study of ST10 in subjects with IDA and IBD, who were intolerant 
of oral iron products or unsuitable for treatment with them has been completed (ST10‐01‐301 
and ST10‐01‐302).  One hundred and twenty eight (128) subjects were randomised to 12 
weeks of blinded medication (30mg bid ST10 or matched placebo capsule) followed by a 52 
week open‐label extension period; during which all available subjects received ST10 at the 
same dose.  87% and 82% of ST10 and Placebo treated subjects, respectively, completed the 
12 week double blind period.  The difference between the treatment groups in mean Hb from 
baseline to week 12 was 2.25g/dL (ANCOVA p<0.0001).  Hb increased to normal values at week 
12 in 65% of ST10 group and 10% of Placebo subjects (see ST10 Investigator’s Brochure).  
When the Placebo subjects were transferred to ST10 treatment in the open‐label phase, there 
was a sharp rise in Hb levels that mirrored the response in the ST10 group in the double‐blind 
phase.  There were further increase in Hb up to 48 weeks of treatment and no indication of 
any reduction in efficacy over the full 64 week treatment period. Patients who were dosed on 
ST10 for up to 64 weeks demonstrated no evidence of elevated haemoglobin or iron overload. 
In the double‐blind phase, adverse events (AEs) were recorded in 58% of ST10 and 72% of the 
Placebo subjects. Gastrointestinal AEs were observed in 38% and 40%, respectively. In the 
ST10 group the most common AEs were abdominal pain (10%), diarrhoea (7%), constipation 
(6%) and nasopharyngitis (4%).  Study medication was discontinued due to adverse events 
(AEs) in 8 ST10 and 5 Placebo subjects.  There was 1 serious AE in the ST10 and 2 in the Placebo 
group. AE data and IBD activity scores (SCCAI, CDAI and IBDQ) suggested that ST10 did not 
increase IBD symptoms over the 12 week period (see ST10 Investigator’s Brochure). 
The profile of adverse events in the open‐label phase was comparable to that of ST10‐treated 
subjects in the double‐blind phase.   The most common (>5%) events in the cumulative data 
set  were  abdominal  pain  (16.2%)),  abdominal  pain  upper  (5.4%),  colitis  ulcerative  (9.9%), 
constipation  (6.3%),  Crohn’s  disease  (7.2%),  diarrhoea  (14.4%)  flatulence  (8.1%), 
nasopharyngitis  (18.0%)  and  arthralgia  (8.1%).  Overall,  events  of  the  Gastrointestinal 
Disorders SOC were recorded for 63 (56.8%) ST10‐treated subjects. 
During the double‐blind phase, the most common study drug‐related TEAE, occurring in 7.8% 
ST10 and 6.3% Placebo subjects, was abdominal pain. Other more common treatment‐related 
events were constipation (6.3% versus 1.6%) and flatulence (6.3% versus 0). All other study 
drug‐related AEs occurred in 1.6% or 3.1% subjects in either treatment group. 
The results of this randomized study showed that 30mg bid ST10 effectively increased Hb in 
IDA with good levels of tolerability and without worsening IBD symptoms (Gasche, 2015). 
Pharmacokinetic Studies 
The pharmacokinetics and iron uptake of 30mg bid ST10 has also been recently investigated 
in a cohort of 15 IBD patients participating in the open‐label phase of studies ST10‐01‐301 and 
ST10‐01‐302 (Shield TX, data on file).  Plasma concentrations of maltol above the limit of assay 
detection  were  transiently  observed  between  15min  and  4h  after  dosing  (mean  Cmax 
67.3ng/mL;  median  Tmax  1.0h;  mean  AUC  136h*ng/mL;  mean  t1/2term  0.8h).    However, 
consistent with earlier studies of ST10, maltol glucuronide predominated in plasma (mean 
Cmax  4677ng/mL;  median  Tmax  1.0h;  mean  AUC  9651h*ng/mL  and  mean  t1/2term  1.1h).  


 
 
 
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Maximal change in serum iron and TSAT was observed 2h after dosing.  The inter‐subject 
variability  for  AUC  of  both  maltol  and  maltol‐glucuronide  in  this  cohort  was  low 
(approximately 27%). 
5.4 
RATIONALE FOR THE STUDY 
Ferric maltol has been shown to be effective and have an acceptable safety profile in a study 
of IBD/IDA subjects who were not tolerant of traditional oral iron preparations (Gasche, 2015).  
This study was placebo‐controlled because of the ethical issue of re‐randomising patients to 
other oral iron products and the feasibility of using masked placebo IV study medications.  
Now  that  the  safety  and  efficacy  profile  of  ferric  maltol  has  been  established  a  direct 
randomised  comparison  with  IV  iron  in  IBD/IDA  is  desirable  to  show  what  differences  in 
efficacy, safety and burden upon the patient there may be between the two treatments.  This 
will  allow  better  choice  of  IV  versus  ferric  maltol  in  treating  IDA  in  subjects  both  from  a 
patient/physician perspective but also wider healthcare decision making.  
 
5.4.1 
Medical and regulatory background 
For all patients with IDA, and for IBD patients in particular, there is an ongoing need for well 
tolerated  oral  iron  therapies  that  effectively  normalize  haemoglobin  without  adversely 
affecting IBD activity (Weiss, 2005; Zimmerman, 2007). Current guidelines for treating IDA in 
patients with clinically active IBD address well‐known drawbacks of oral therapy with ferrous 
iron salts, including poor gastrointestinal tolerability, slow treatment effects and a potential 
for  disease  worsening  (Gasche,  2007).  While  intravenous  iron  is  undoubtedly  effective  in 
correcting  anaemia,  it  is  associated  with  higher  healthcare  costs,  the  inconvenience  of 
intravenous infusion (Stein, 2010; Gasche,2007; Evstatiev, 2011) and a risk of anaphylactic 
reactions  that  require  immediate  emergency  intervention  (EMA,  2013;  Auerbach,  2007; 
Gomollon, 2014) such that these therapies must be given only when resucitation equipment 
is at hand. 
 
5.4.2 
Population 
As no curative treatment is presently available for IBD, treatment options are restricted to 
controlling symptoms, maintaining remission and preventing relapse.  As such, treatment of 
IDA,  a  key  symptom  of  the  disease,  is  integral  to  the  medical  management  of  IBD.    Iron 
deficiency  anaemia  in  UC  for  example  is  a  chronically  debilitating  disorder  which  has  a 
significant impact on the QOL of affected subjects.  Up to one third of patients with UC suffer 
from recurrent anaemia, with hospitalisation required in severe cases (Gasche, 2007).   
The current protocol will include subjects with IDA in the presence of IBD, diagnosed by either 
endoscopy or biopsy (see Van Assche, 2010; Dignass, 2012). 
 
5.4.3 
Study Design 
The study will be performed using a prospective, multicentre, randomised, open‐label design. 
Subjects will be randomised to receive either ferric maltol 30mg bid or Intravenous (IV) iron 
(ferric carboxymaltose, FCM), dosed according to the local SPC/PI. Efficacy and safety of ferric 
maltol compared with IV iron (FCM) will be evaluated during the study.  


 
 
 
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Subjects who entered the study under the previous protocol for the 52 weeks open‐label 
design and completed their study beyond the 12 weeks treatment period, the next scheduled 
visit will be their End of Study Visit. Otherwise, subjects after the eligibility screening period 
will enter a 12 weeks treatment period.  
  
The primary endpoint of this study is:  
 Proportion of subjects achieving either a 2g/dL increase in Hb OR normalization of 
Hb (>12g/dL women, >13g/dL men) at Week 12 
 
Secondary efficacy endpoints will include the following 
 Change in Hb concentration from baseline to Week 12 
 Change in Hb concentration from baseline to Week 12 in subjects with a baseline 
Hb <9.5 g/dL 
 Proportion of subjects who experience a change from baseline in Hb concentration 
≥1.0 g/dL at Week 12 
 Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase in Hb 
concentration of ≥1 g/dL at Week 12  
 Proportion of subjects with Hb concentration within normal limits at Week 12 
 Proportion  of  subjects  with  baseline  Hb  concentration  <9.5  g/dL  that  is  within 
normal limits at Week 12 
 Change in Hb concentration from baseline to Week 4 
 Change in Hb concentration from baseline to Week 4 in subjects with a baseline Hb 
<9.5 g/dL  
 Proportion of subjects who experience a change from baseline in Hb concentration  
≥2.0 g/dL at Week 12 
 Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase in Hb 
concentration of ≥2 g/dL at Week 12  
 Proportion of subjects who experience a change from baseline in Hb concentration 
≥1.0 g/dL at Week 4 
 Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase in Hb 
concentration of ≥1 g/dL at Week 4  
 Proportion of subjects with Hb concentration within normal limits at Week 4  
 Proportion  of  subjects  with  baseline  Hb  concentration  <9.5  g/dL  that  is  within 
normal limits at Week 4 
 Proportion of subjects who experience a change from baseline in Hb concentration 
≥2.0 g/dL at Week 4 
 Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase in Hb 
concentration of ≥2 g/dL at Week 4 


 
 
 
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 Long term efficacy endpoints i.e. proportion of subjects who are non‐anaemic at 6 
and 12 months; normalization of ferritin levels at 6 and 12 months 
 
Secondary safety endpoints 
 Treatment‐emergent Adverse Events (AEs)  
 Treatment‐emergent Serious Adverse Events (SAEs) 
 Adverse Events leading to premature discontinuation of study drug 
 Adherence to study medication 
 
Pharmacoeconomic (PE) Endpoints 
 Number of hospital or clinic visits for administration of IV iron 
 Proportion of subjects who restart FCM during the study 
 Other pharmacoeconomic endpoints 
 
5.4.4 
Comparator Drugs 
Intravenous iron as ferric carboxymaltose (FCM) 
 
5.5 
DOSE SELECTION AND TREATMENT DURATION 
The dose of ferric maltol will mirror the dose evaluated in the pivotal phase 3 trials (ST10‐01‐
301 and ST10‐01‐302) of 30mg BID.  The comparator product is IV ferric carboxymaltose of 
which the dose is determined by the local summary of product characteristics (SPC/PI). 
Ferric Maltol 
Subjects will remain on therapy for the whole duration of the study treatment period (12 
weeks). If the subjects went beyond the 12 weeks the next scheduled visit will be their End of 
Study Visit. 
The date of Visit 2 will be the date of initial dosing with ferric maltol. 
 
IV Iron (FCM) 
Initial dosing and post randomization dosing will be as per the local SPC/PI with the dose 
administered being calculated based on a subject’s screening visit Hb and weight. Initial dosing 
should be timed to occur on the same day as randomization wherever possible and within 5 
days of randomization if not possible. The date of Visit 2 will be the date of initial dosing of 
FCM. Hb levels will be used for ongoing treatment decisions at subsequent visits, as required 
per the local SPC/PI.  Subjects who remain anaemic will receive additional FCM IV iron doses 
according to the local SPC/PI. 
This study will continue until the last randomized subject completes the study safety follow 
up visit  or prematurely discontinues from the study. 
 


 
 
 
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5.6 
RISK‐BENEFIT EVALUATION 
A positive benefit‐risk for treatment with ferric maltol has been established in a randomized 
clinical study and the data published in a peer‐reviewed journal (Gasche, 2015).  The safety 
profile of ferric maltol in IBD is considered to be acceptable, with few discontinuations and no 
evidence of IBD flare or disease worsening.  The Hb rise seen in this group of subjects was also 
comparable  to  earlier  reports  of  IDA  treatment  with  intravenous  iron.    The  comparator 
product, FCM, is approved throughout Europe for the treatment of IDA including in subjects 
with IBD.  There is considered to be a good balance of risks and potential benefits in either 
treatment arm, justifying randomization of subjects within this open‐label clinical study. 
The  current  study  design  does  not  pose  additional  risk  for  the  subjects  as  no  additional 
interventional procedures are planned during the study period, except for blood sampling 
similar  to  clinical  routine.    Total  blood  loss  as  a  result  of  monthly  phlebotomy  will  be 
approximately 65 millilitres; substantially below the volume of routine blood donation. 
Subjects that develop Hb concentrations ≤7.5 g/dL (4.7 mmol/l) will be withdrawn from the 
study to receive best standard medical care. 
The current protocol contains all information to perform the study according to the legal 
requirements, and to the current revisions of the recommendations of the Declaration of 
Helsinki, Good Clinical Practice (GCP) and International Conference on Harmonization (ICH) 
guidelines. 


 
 
 
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6 
STUDY OBJECTIVES 
6.1 
PRIMARY OBJECTIVE 
To compare the efficacy of ferric maltol and intravenous iron (FCM) in the treatment and 
maintenance of iron deficiency anaemia in subjects with IBD. 
6.2 
SECONDARY OBJECTIVE 
To evaluate the safety and tolerability of ferric maltol and IVI in subjects over a treatment 
duration of up to 52 weeks. 
To evaluate long‐term healthcare resources utilized in the management of IDA in IBD. 
7 
INVESTIGATIONAL PLAN 
7.1 
STUDY DESCRIPTION 
A phase 3b, randomized, controlled, multicentre study with oral ferric maltol or intravenous 
iron (FCM), for the treatment of iron deficiency anaemia in subjects with inflammatory bowel 
disease. 
Primary efficacy and safety of ferric maltol and intravenous iron (ferric carboxymaltose) will 
be evaluated after 12 weeks.  
In the FCM arm, IV iron treatment will be repeated if the subject is anaemic (see section 5.5) 
per the local SPC/PI. 
The  protocol  will  include  subjects  with  IDA  in  the  presence  of  IBD,  diagnosed  by  either 
endoscopy or biopsy (see Van Assche, 2010; Dignass, 2012). 
Anaemia entry criteria in this study is defined by an Hb concentration 8.0 g/dl and ≤11.0 g/dl 
(4.96 ‐ 6.83 mmol/l) in females and  8.0 g/dl and ≤12 g/dl (4.96 ‐ 7.45 mmol/l) in men. 
The study will consist of 3 periods:  
 Screening: Up to 14 days  
 
Randomised Treatment:  
 12 weeks treatment period  
 subjects entered in the 52 weeks treatment period will finish their randomized 
treatment at week 12, unless they went beyond this visit. If so, the next 
scheduled visit will be their last treatment visit.  
 
 End  of  study  evaluations  will  occur  Week  12/premature  discontinuation  or  next 
scheduled visit if subjects went beyond Week 12. 
 Post‐treatment  safety  follow‐up:  14  days  after  last  treatment  visit  or  premature 
discontinuation of ferric maltol or FCM 
Subjects that develop Hb concentrations ≤7.5 g/dl (4.7 mmol/l) will be withdrawn from the 
protocol to receive best standard medical care. 
Effectiveness will be analysed by determining whether the Test group (ferric maltol) shows a 
statistically significant non inferiority of responder rate (≥ 2g/dL Hb rise at Week 12 compared 
to  baseline  OR  normal  Hb  at  Week  12)  as  compared  to  IV  iron  (ferric  carboxy  maltose). 


 
 
 
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Approximately 242 subjects in this study will be randomised at a ratio of 1:1, ferric maltol or 
IV iron (ferric carboxy maltose, FCM). 
For the purposes of this protocol, the following conventions are used: 
 1 week equals 7 days 
 4 weeks equal 28 days 
 12 weeks equal 84 days 
 52 weeks equal 364 days 
 
7.2 
INVESTIGATIONAL SITES 
The study will involve approximately 37 EU sites and 18 US sites. 
To ensure the successful completion of the study, the Sponsor may wish to replace sites that 
have very low subject enrolment.  Sites not able to recruit any subjects within 2 months of 
study initiation or sites with subjects exhibiting major protocol deviations will be considered 
for closure. 
7.3 
STUDY VARIABLES 
7.3.1 
Primary Efficacy variables 
 Haemoglobin 
7.3.2 
Primary Safety variables 
General safety and tolerability will be assessed by: 
 Adverse events  
 Standard laboratory evaluation 
Additional exploratory endpoints and variables will also be defined. For details, please refer 
to the Statistical Analysis Plan.  
7.4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
No deviations to the inclusion or exclusion criteria are allowed.   
7.4.1 
Inclusion criteria 
All of the following criteria must be met to randomize a subject in the study: 
1. Subjects must be competent to understand the information given in the Independent 
Ethics Committee (IEC) or Institutional Review Board (IRB) approved informed consent 
form  and  must  sign  and  date  the  informed  consent  prior  to  any  study  mandated 
procedure  
2. Subjects must be willing and able to comply with study requirements  
3. Age ≥ 18 years 
4. Subjects must have a confirmed diagnosis of IBD (endoscopic and/or biopsy) 
5. Subjects  must  be  considered  suitable  for  intravenous  iron  treatment  by  the 
Investigator 
6. Subjects must have iron deficiency anaemia defined by the following criteria: 


 
 
 
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a.  Hb 8.0 g/dL and ≤11.0 g/dL for women OR a Hb 8.0 g/dL and ≤12.0 g/dL for 
men 
b. AND Ferritin <30ng/ml OR Ferritin <100 ng/ml WITH Transferrin saturation 
(TSAT) <20% 
7. 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 they have completed the study and for at least 
4 weeks following their final study visit.  Reliable contraception is defined as a method 
which results in a low failure rate, i.e., less than 1% per year when used consistently 
and correctly, such as implants, injectables, some intrauterine contraceptive devices 
(IUDs), complete sexual abstinence, or a vasectomized partner.  Oral contraceptive 
medications  are  allowed  in  this  study.    Female  subjects  who  are  surgically  sterile 
(bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or postmenopausal 
(defined  as  no  menstrual  period  within  1  year  of  screening)  are  also  allowed  to 
participate. 
7.4.2 
Exclusion criteria 
A subject who meets any of the following criteria is not eligible for participation in the 
study. 
1. Subject with anaemia due to any cause other than iron deficiency, including, but not 
limited to: 
a. Untreated or untreatable severe malabsorption syndrome 
b. Immunosuppressant use.  Immunosuppressants are permitted so long as there 
is no clinical evidence or suspicion of the immunosuppressant contributing to 
the subject’s anaemia or affecting erythropoiesis.  
Variations to dosing are permitted at the discretion of the investigator so long 
as  there  is  no  clinical  evidence  or  suspicion  of  the  immunosuppressant 
contributing to the subject’s anaemia or affecting erythropoiesis 
2. Subject who has received prior to screening: 
a. Within  8  weeks  intramuscular  or  intravenous  (IV)  iron  or  administration  of 
depot iron preparation 
b. Within 2 weeks a blood transfusion 
c. Oral  iron  supplementation,  taken  specifically  to  treat  anaemia,  within  the 
previous 4 weeks (Over the Counter (OTC) multivitamins containing iron are 
permitted)  
3. Subjects with active inflammatory bowel disease as defined by a SCCAI score greater 
than  5  at  Screening  or  a  CDAI  score  greater  than  300  in  the  Screening  period  (as 
assessed using the Screening haematocrit (HCT) and CDAI diary card completed by the 
subject for 7 days prior to planned randomization). 
4. Subjects  with  known  hypersensitivity  or  allergy  to  either  the  active  substance  or 
excipients  of  ferric  maltol  capsules  or  ferric  carboxymaltose  solution  for  IV 
administration 
5. Subjects  who  have  had  serious  adverse  reactions  to  previous  doses  of  ferric 
carboxymaltose or any other intravenous iron. 


 
 
 
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6. Subjects  with  contraindication  for  treatment  with  iron  preparations,  e.g. 
hemochromatosis, chronic hemolytic disease, sideroblastic anaemia, thalassemia, or 
lead intoxication induced anaemia. 
7. Subjects  with  vitamin  B12  or  folic  acid  deficiency  as  determined  by  the  central 
laboratory screening results. Subjects may start vitamin B12 or folate replacement and 
rescreen after at least 2 weeks. 
8. Subjects who are pregnant or breast feeding.  
9. Concomitant medical conditions with significant active bleeding likely to initiate or 
prolong anaemia. 
10. Participation  in  any  other  interventional  clinical  study  within  30  days  prior  to 
screening. 
11. Subject with cardiovascular, liver, renal, haematologic, gastrointestinal, immunologic, 
endocrine, metabolic, or central nervous system disease that, in the opinion of the 
Investigator, may adversely affect the safety of the subject or severely limit the lifespan 
of the subject (i.e. unlikely to complete the full duration of the study). 
12. Subject with significant neurologic or psychiatric symptoms resulting in disorientation, 
memory  impairment,  or  inability  to  report  accurately  that  might  interfere  with 
treatment compliance, study conduct or interpretation of the results (e.g., Alzheimer’s 
disease, schizophrenia or other psychosis, active or current alcohol or drug abuse) 
13. Subject who is an inmate of a psychiatric ward, prison, or other state institution. 
14. Subject who is an Investigator or any other team member involved directly or indirectly 
in the conduct of the clinical study. 
15. Subjects with severe renal impairment: creatinine clearance < 30 mL/min. (Applicable 
to US sites Only) 
 
7.4.3 
Concomitant medication at baseline and during the study 
 Iron preparations other than ferric maltol or FCM are prohibited at baseline and during 
study; with the exception of: 
 Over  the  Counter  (OTC)  oral  supplements/multivitamin  type  preparations 
which may be taken, however Subjects are encouraged to keep to the same 
dose during the course of this study 
 Blood transfusions or donations prohibited 
 Erythropoiesis‐stimulating  agents  (ESAs)  are  permitted  during  the  study,  but  the 
subject  must  have  been  on  a  stable  dose  for  the  preceeding  3  months  before 
randomization 
 Vitamin B12 and folic acid supplements/replacement are allowed during the study 
 Immunosuppressants are permitted so long as there is no clinical evidence or suspicion 
of  the  immunosuppressant  contributing  to  the  subject’s  anaemia  or  affecting 
erythropoiesis. Variations to dosing are permitted at the discretion of the investigator 
so  long  as  there  is  no  clinical  evidence  or  suspicion  of  the  immunosuppressant 
contributing to the subjects anaemia or affecting erythropoiesis. 


 
 
 
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7.4.4 
Advice regarding potential ferric maltol drug interactions 
Iron‐drug interactions of clinical significance have been reported to occur with a large number 
of concomitant therapies. Concurrent ingestion of oral iron causes marked decrease in the 
bioavailability of a number of drugs due to the formation of iron‐drug complexes (chelation or 
binding of iron by the second drug). Examples of affected drugs are: quinolone or tetracycline 
antibiotics,  bisphosphonates,  angiotensin‐converting  enzyme  inhibitors,  folic  acid, 
methyldopa, levodopa, carbidopa, levothyroxine, and mycophenolate.  
To minimize the potential for drug interactions, ferric maltol should be taken orally first thing 
in the morning at least 1 hour before food and concomitant medications and last thing at night 
before bed at least 2 hours after food and concomitant medications. Capsules must be taken 
on an empty stomach with water only. There should be at least an 8‐hour gap between doses. 
7.4.5 
Rescreening 
A subject who fails initial screening for any reason may be re‐screened one additional time; 
subjects may be screened up to two times total.  All screening visits must be adequately 
documented in the subject’s source documents. Subjects who fail screening due to either 
vitamin B12 or folate deficiency may receive vitamin B12 or folate replacement and then 
rescreen after a minimum of 2 weeks.   
7.4.6 
Individual discontinuation criteria 
Treatment will be stopped for any of the following reasons: 
 
Pregnancy or not using a reliable method of birth control (female subjects of childbearing 
potential) 
 
Withdrawal of informed consent 
 
Hb ≤7.5 g/dL 
 
TSAT above 60% or a ferritin above 800 ng/ml (the subject may remain in the study if the 
rise is confirmed by a laboratory retest to be transient as a result of recent FCM or ferric 
maltol administration. Retests must occur 7‐10 days after the initial TSAT result becomes 
available and should be conducted at least 4 hours post dosing with FCM or ferric maltol) 
 
Serious adverse events that are judged by the Investigator to be related to ferric maltol or 
FCM treatment 
 
Use of prohibited co‐medications during the study treatment period (see Section 7.4.3) 
 
Blood transfusions for any cause during the study treatment period 
 
Any dose changes to dosing of immunosuppressants and/or ESAs that may cause anaemia 
or affect erythropoiesis 
The reason for study drug discontinuation and the date of last dose must be recorded in the 
CRF.  Subjects who prematurely discontinue study drug or withdraw consent must return to 
clinic for an End of Study Visitat the time of discontinuation. Should the End of Study Visit 
occur 14 days or more following the last dose of ferric maltol or FCM then a subsequent safety 
follow‐up phone call is not required.  
7.4.7 
Subject selection 
The subject will receive a copy of the written informed consent form containing a complete 
and comprehensive explanation of the significance, nature, extent and possible risks of the 
study, duties concerning insurance and the statement that the subject is free to withdraw 


 
 
 
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from the study at any time without any negative consequences.  In addition, a physician will 
carry out an oral information session during which the subject will be given sufficient time and 
opportunity to clarify any questions.  After this, the written informed consent will be given to 
the subject for signature.  The original must be filed in the Investigator's Study File and a copy 
will be given to the subject. 
The  Investigator  will  confirm  that  each  individual  subject  has  received  an  explanation  in 
accordance with the study protocol and has signed the appropriate informed consent form. 
If  an  Investigator  chooses  to  advertise  for  subjects,  whether  in  professional  or  consumer 
publications, via public broadcast, or any other means, all advertising must be approved by 
the Sponsor and the IEC/IRB prior to first use.  A copy of the IEC/IRB‐approved advertising and 
approval letter must be provided to the Sponsor. 
7.4.8 
Replacement policy 
While each subject will be expected to complete the full course of the study, a participant may 
withdraw  from  the  study  at  any  time  for  any  reason.    The  reason  for  withdrawal  will  be 
documented on the End of Study Case Report Form (CRF).  
Discontinuations during the screening phase are considered screening failures and will be 
replaced.  Discontinuations after randomization will not be replaced. 
8 
STUDY DRUGS 
8.1 
INVESTIGATIONAL MEDICAL PRODUCT  
Eligible subjects will be randomised to receive one of the following treatments for the duration 
of the study : 
 Oral ferric maltol, 30 mg capsule bid. 
 Intravenous iron (ferric carboxymaltose, FCM), administered as per the local SPC/PI. 
Ferric maltol medication will be capsules to be taken orally first thing in the morning at least 
1 hour before food and concomitant medications. and last thing at night before bed at least 2 
hours after food and concomitant medications. Capsules must be taken on an empty stomach 
with water only. There should be at least an 8‐hour gap between doses. 
For  detailed  information  regarding  the  components  of  ferric  maltol,  please  refer  to  the 
Investigator’s Brochure. 
If a subject forgets to take a morning capsule, this dose may be taken with the evening capsule 
on an empty stomach with water last thing at night before bed.  Missed evening tablets should 
be documented as ‘missed’ and should not be taken the next day.  
Intravenous iron (ferric carboxymaltose) will be administered as per the local SPC/PI. 
8.2 
PACKAGING 
The ferric maltol product 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. 
8.3 
LABELLING  
All  ferric  maltol  bottles  will  be  identified  by  lot  number  and  unique  bottle  number  for 
reconciliation purposes only.   


 
 
 
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Labels of the ferric maltol Investigational Medicinal Product (IMP) will contain information 
according to European Directives 2003/94/EC, 2001/20/EC and Annex 13/ 21CFR312.6. 
8.4 
STORAGE 
Ferric maltol IMP must be stored between the range of ≥5°C to <25°C (min/max = 5 ‐ 24.99°C) 
and must not be refrigerated or frozen.  In the event that the drug is exposed to temperatures 
lower than 5°C or greater than or equal to 25 °C, the Sponsor should be contacted for review 
and further instruction. 
FCM must be stored in accordance with the instructions in the local SPC/PI. 
8.5 
TREATMENT ASSIGNMENT AND BLINDING  
At randomization the eCRF randomization module will assign the subject to either the ferric 
maltol  30mg  bid  or  IV  iron  (ferric  carboxy  maltose,  FCM)  treatment  group.    The  site  will 
dispense the appropriate number of open‐label ferric maltol bottles at each scheduled study 
visit  according  to  the  schedule  of  assessments  (Section  9.1)  or  administer  IV  iron  (ferric 
carboxymaltose) as per the local summary of product characteristics/prescribing information. 
IV iron dosing with FCM should ideally commence on the same day as randomization or no 
later than 5 days after randomization.  The date of Visit 2 is the date of the first dose of IV iron 
or ferric maltol (see Section 9.2.2).  
This is an open label study and treatment assignment is not blinded. 
8.5.1 
Treatment assignment 
Subjects  will  be  randomized  1:1  to  either  treatment.  Randomization  will  be  centrally 
controlled and stratified by screening Hb (< or ≥ 10g/dL Female; < or ≥ 11g/dL Male) and by 
IBD (UC or CD). 
8.5.2 
Subject screening and Randomization number 
Subjects who sign the informed consent will be identified at the Screening Visit by a unique 
number consisting of a 4 digit site number and 3 digit subject number.  If a subject is re‐
screened, they will be identified in the eCRF/database with the same number. The number 
uniquely identifies every subject eligible for the study.   
8.5.3 
Maintenance of the randomization code 
Not applicable as this study is an open label study. 
8.5.4 
Emergency unblinding 
Not applicable as this study is an open label study. 
8.6 
TREATMENT COMPLIANCE 
Subjects will be instructed to take the ferric maltol study drug as described in detail on the 
drug labels and by the study site.  Subjects will be instructed to return all unused supplies and 
all clinical study medication packaging at each visit.  The delivery of medication to the site, its 
use and return, as well as subject‐specific compliance, will be reconciled and documented 
using  a  Drug  Accountability  Form  in  order  to  monitor  compliance  with  the  medication 
schedule.  All opened containers, together with remaining contents, and unopened containers 
will be kept by the Investigator in a secure, locked area until return to the drug supplier by the 
monitor or the Sponsor approves local destruction at the Investigator site, based on prior 
documented review that the appropriate SOPs are in place at site and written confirmation of 
destruction will be provided for the TMF.  The Drug Accountability Forms will be maintained 


 
 
 
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regularly and must be available for inspection at any time.  The Investigator will use the IMP 
only within the framework of this clinical study and in accordance with the existing study 
protocol.  A written explanation must be given for any container/IMP that is missing.  
As discussed in Section 8.1, ferric maltol study drug will be capsules taken orally first thing in 
the morning at least 1 hour before food and concomitant medications and last thing at night 
before bed at least 2 hours after food and concomitant medications. Capsules must be taken 
on an empty stomach with water only. There should be at least an 8‐hour gap between doses. 
If a subject forgets to take a morning capsule, this dose may be taken with the evening capsule 
on an empty stomach with water, last thing at night before bed.  Missed evening tablets 
should be documented as ‘missed’ and should not be taken the next day.  
If a subject is found to be non‐compliant with the study medication (defined as less than 80% 
or more than 120% compliant with the dosage schedule), the subject will be counselled and 
trained on the importance of maintaining adherence to study medication. If the subject is 
repeatedly non‐adherent, a decision will be made by the medical monitor and/or Sponsor as 
to whether the subject should be withdrawn from the study treatment. 
Intravenous iron (ferric carboxymaltose) will be administered according to the local summary 
of product characteristics.  Subjects who do not attend for their intravenous iron treatment 
may be withdrawn from the study.  A copy of the relevant local SPC/PI for FCM will be available 
in the Investigator Site File (ISF).  Special safety information and warnings/precautions relating 
to administration of FCM will be highlighted to the Investigator during the Site Initiation Visit 
(SIV). 
 


 
 
 
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9 
STUDY PROCEDURES 
9.1 
SCHEDULE OF ASSESSMENTS 
   
Screening 
Period 
Treatment 
8Follow‐up 
Duration 
Up to 
14 days  
Week 
14 days after 
drug 
discontinuation 
Week 
 
0 
4 
12 
(24)15 
(36)16 
(52)17 
(54)  
9Visits 
1 
2 
3 
4 
(5) 
(6) 
(7) 
(8) 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
1Vital signs 
X 
 
 
 
 
 
 
 
2Height & weight 
X 
X 
X 
X 
(X) 
(X) 
(X) 
 
3Basic chemistry 
X 
 
 
 
 
 
 
 
4Liver function tests 
X 
 
 
 
 
 
 
 
5Haematology; Iron 
markers 
X 
X 
X 
X 
(X) 
(X) 
(X) 
 
C‐reactive protein  
 
X 
 
 
 
 
 
 
13Retained plasma and 
serum samples 
 
X 
 
X 
 
 
 
 
6Randomization 
 
X 
 
 
 
 
 
 
Collect IV Iron History / 
FCM dosing detail 
X 
X 
X 
X 
(X) 
(X) 
(X) 
 
SCCAI or CDAI12 
X12 
 
 
X 
(X) 
(X) 
(X) 
 
10Collect 
pharmacoeconomic (PE) 
and SF‐36 data 
 
X 
11X 
X 
(X) 
(X) 
(X) 
 
7Pregnancy test 
X 
 
 
X 
 
 
(X) 
 
Dispense/Administer 
study medication 14 
 
X 
 
(X) 
(X) 
(X) 
 
 
Compliance check 
 
 
X 
X 
(X) 
(X) 
(X) 
 
Adverse events 
 
X 
X 
X 
(X) 
(X) 
(X) 
X 
Prior/Concomitant 
medication 
X 
X 
X 
X 
(X) 
(X) 
(X) 
X 
 
1   Vital signs (blood pressure & heart rate) are taken after subject has been sitting for 5 minutes 
2   Height & weight measured during Screening, weight only at other visits 
3  Basic chemistry: bicarbonate, BUN, creatinine, chloride, glucose, potassium, sodium, Vitamin B12 and folate, creatinine clearance (US‐
only) 
4  Liver function tests: ALT, AST and total bilirubin 
5  Haematology  and  Iron  markers  all  visits:  haematocrit,  haemoglobin,  platelets,  RBC  count,  RBC  Hb  concentration;  WBC  count  and 
differential; total serum iron; ferritin, transferrin; TSAT.  
6   Maximum 14 days between screening and randomization. 
7  Urine pregnancy test, kits provided by central laboratory. 


 
 
 
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8 Follow up is conducted by telephone, unless the Subject has an ongoing AE that requires physical examination or investigations for 
assessment/management.  Visit 8 will take place 14 days after Visit 4 (Week 12/Early Termination) unless subject discontinued treatment 
early and end of study/ Week 12 assessments occurred 14 days or more after the last dose.  
9 Visit Windows: Maximum of 14 days between screening and randomization.  Subjects randomised to FCM must complete Visit 2 ideally on 
the day of randomization or within 5 days.  The Subject must visit to complete: 
 
Visits 3 and 4: +/‐ 1 week relative to date of Visit 2/first dose administered 
 
Visits 4 to 7: +/‐ 1 week relative to date of Visit 2/first dose administered  
 
Visit 8: 14 days (+5 days) after Visit 4 (unless subject discontinued treatment early and end of study/ Week 12 assessments occurred 14 
days or more after the last dose 
10 SF36 to be administered at Week 0 (baseline), and Week 12, 24, 36 and 52 
11 SF36 is not collected at this visit 
12 For CD subjects, a CDAI diary card will be provided at Screening, for completion over the 7 days prior to scheduled Visit 2. The screening 
haematocrit value will be used for the screening CDAI calculation to assess eligibility prior to randomization and will also count as the 
baseline CDAI value. For CD subjects, CDAI diary cards will then be provided at Visits 3 and  4. Subjects who went beyond week 12 will 
receive CDAI diary, at  5 & 6 for completion over the 7 days prior to the scheduled dates of Visit 4, 5, 6 & 7. 
13 Retained serum and plasma samples will only be collected from trial subjects at those Investigator sites who have suitable freezer facilities 
for storage of the samples at ‐70°C/‐80°C, prior to subsequent periodic shipping to the central laboratory on dry‐ice.  Detailed instructions 
will be provided in the Laboratory Manual. 
14. Dispense/Administer study drug: based on the randomization stratification subjects will receive FCM/Ferric Maltol on Visit 2. If subjects 
went beyond Visit 4 (Week 12) and their treatment period will be continuing according to previous protocol until the next scheduled visit.  
15. Visit 5 (Week 24) will only occur if subjects went beyond Visit 4 according to previous protocol, otherwise this will be the End of Study 
Visit.    
16. Visit 6 (Week 36) will only occur if subjects went beyond Visit 5 (week 24) according to previous protocol, otherwise this will be the End 
of Study Visit.  
17. Visit 7 (Week 52) will only occur if subjects went beyond Visit 6 (Week 36) according to previous protocol, otherwise this will be the End 
of Study Visit.    
 
 
 
 


 
 
 
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9.2 
TREATMENT PROCEDURES BY VISIT 
9.2.1 
Screening visit (Visit 1/between Day ‐14 and Day ‐1) 
The following screening procedures will be performed at the Screening visit: 
1. Fully inform subject regarding study and obtain written informed consent 
2. Assign subject number 
3. Document demographic information 
4. Document medical history including all ongoing conditions and relevant medical history 
from  the  past  5  years  (including  all  major  hospitalisations  and  surgeries).    Symptoms 
related to IBD need not be listed on the medical history form; however, worsening of any 
symptoms and flares during the course of this study must be captured as AEs.  
5. Conduct a brief physical exam including vital signs (BP and HR), body weight, height, and 
review of the following systems: General appearance; skin; head, eyes, ears, nose and 
throat; cardiovascular; respiratory; abdominal and gastrointestinal; and musculoskeletal. 
6. Collect basic chemistry, liver function, iron markers and haematology samples 
7. Document concomitant medications including all ongoing medications and those taken 
within the last 12 weeks, plus 
a. Document all prescription iron replacement therapies taken in the last 12 months, 
all prior oral ferrous treatment history (with associated IBD disease severity score, 
see Section 10.4.1) and all prior IV iron treatment history where applicable. 
b. Verify that subject has not received any prohibited concomitant medications as 
described in the inclusion/exclusion criteria and Section 7.4.3 
8. For UC subjects, record the SCCAI score. For CD subjects dispense CDAI diary and instruct 
the subject to complete for 7 days prior to randomization. Use the central laboratory 
screening haematocrit value to calculate the CDAI score for eligibility assessment, which 
will also count as the baseline value. 
9. For female subjects of childbearing potential, perform urine pregnancy test and document 
method of contraception   
10. Complete the Visit Specific eCRFs 
Subjects  who  appear  to  meet  all  inclusion  and  exclusion  criteria  will  be  scheduled  for 
randomization within 14 days of Screening.  CD subjects will be reminded to complete their 
CDAI diary for the 7 days prior to scheduled randomization date.  
9.2.2 
Randomization visit (Visit 2/ Day 0) 
Subjects who meet all Inclusion/Exclusion criteria are eligible to be randomised during this 
visit.  Subjects will be randomized into one of two dose groups; 30 mg ferric maltol bid or 
Intravenous iron (ferric carboxymaltose, FCM).  Randomization must occur no more than 14 
days after the Screening Visit (Visit 1). 
Initial dosing with ferric maltol must occur on the same day of randomization at Visit 2. Dosing 
with IV iron (FCM) should occur on the same day of randomization wherever possible and 
within 5 days from randomization if not. The date of Visit 2 is the date of first dose with ferric 
maltol or FCM. 


 
 
 
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The following procedures will be completed.  Procedures 1‐8 must be completed prior to 
randomising the subject and first dosing with ferric maltol or FCM. 
1. Collect haematology, iron markers, C‐reactive protein and retained samples (see Section 
10.2.12 for additional information regarding retained samples collection) 
2. Review and record all concomitant medications.  Subjects who have received an excluded 
medication since Screening (Visit 1) will be ineligible for randomization 
3. Collect IV Iron History 
4. Measure subject’s body weight 
5. For CD subjects, use the screening period CDAI diary data and screening haematocrit (HCT) 
value from the central laboratory to calculate the CDAI score for eligibility assessment, 
which will also count as the baseline value 
6. Collect pharmacoeconomic (PE) and SF‐36 data 
7. Review all Inclusion/Exclusion criteria 
8. Record all AEs since last visit 
9. If subject qualifies, complete the eCRF Randomization module to treatment assignment 
10. If the subject has been assigned to receive ferric maltol, dispense 3 bottles from study drug 
kit which will be sufficient for 12 weeks of treatment. Remind the subject to take the study 
medication  first  thing  in  the  morning  at  least  1  hour  before  food  and  concomitant 
medications. and last thing at night before bed at least 2 hours after food and concomitant 
medications. Capsules must be taken on an empty stomach with water only. There should 
be at least an 8‐hour gap between doses. 
11. If the subject has been assigned to receive IV ferric carboxymaltose follow the dosing 
instructions as per the local summary of product characteristics/prescribing information 
and record the FCM dosing information in the eCRF. 
12. Instruct the subject to call the clinic or return promptly should an AE occur 
13. Schedule the Week 4 visit 
14. Complete the Visit Specific eCRFs 
9.2.3 
Visit 3 (Week 4) 
The following procedures will be completed during the visit:  
1. Collect haematology and iron markers samples 
2. Collect FCM dosing history information 
3. Collect PE data 
4. Measure subject’s body weight 
5. Check Hb, TSAT and ferritin levels (when central laboratory results available).  
6. FCM subjects may be administered IV iron as per the local summary of product 
characteristics/Prescribing Information, if clinically required.  
7. Review and record all concomitant medications 
8. Record all AEs since last visit 
9. For subjects assigned to ferric maltol, remind the subject to take the study medication first 


 
 
 
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thing in the morning at least 1 hour before food and concomitant medications, and last 
thing  at  night  before  bed  at  least  2  hours  after  food  and  concomitant  medications. 
Capsules must be taken on an empty stomach with water only. There should be at least an 
8‐hour gap between doses. 
10. For subjects assigned to ferric maltol, check bottles dispensed at prior visit, perform drug 
accountability and a compliance check and return bottles to subject. 
11. Schedule Visit 4 at Week 12 
12. For CD subjects, dispense CDAI diary and instruct subject on completion for 7 days prior to 
planned Visit 4 
13. Complete the Visit Specific eCRFs 
9.2.4 
Visit 4 (Week 12) or End of Study 
The following procedures will be completed at Visit 4 (Week 12): 
1. Collect  haematology,  iron  markers  and  retained  samples  (see  Section  10.2.12  for 
additional information regarding retained samples collection) 
2. Collect FCM dosing history information 
3. Measure subject’s body weight 
4. For UC subjects, record the SCCAI score; for CD subjects, collect CDAI diary dispensed at 
Visit 3 and calculate the current CDAI score using the Visit 4 HCT result from the central 
laboratory (when available) 
5. Collect PE and SF‐36 data 
6. For female subjects of childbearing potential, perform urine pregnancy test 
7. Check Hb, TSAT and ferritin levels (when central laboratory results available) 
8. For ferric maltol study drug continuation, dispense 3 bottles from study drug kit which 
will be sufficient for 12 weeks of treatment. Check compliance and remind the subject to 
take the study medication first thing in the morning at least 1 hour before food and 
concomitant medications. and last thing at night before bed at least 2 hours after food 
and concomitant medications. Capsules must be taken on an empty stomach with water 
only. There should be at least an 8‐hour gap between doses. 
9. FCM subjects who have low Hb (see section 5.5) should be administered IV iron as per the 
local summary of product characteristics/ prescribing information. 
10. Review and record all concomitant medications   
11. Record all AEs since last visit 
12. Collect bottles dispensed at prior visit and perform drug accountability and a compliance 
check 
13. Instruct the subject to call the clinic or return promptly should an AE occur 
14. For CD subjects, dispense CDAI diary and instruct subject on completion for 7 days prior to 
planned Visit 5, if subjects went beyond Visit 4. 
15. Schedule a telephone follow up visit at least 14 days after Visit 4.   
16. Complete the Visit Specific eCRFs 


 
 
 
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9.2.5 
Visit 5 (Week 24) or End of Study 
The following procedures will ONLY BE COMPLETED if subjects went beyond week 12 
according to previous protocol. In that case this visit will be the End of Study Visit.  
1. Collect haematology and iron markers samples 
2. Collect FCM dosing history information 
3. Measure subject’s body weight 
4. For UC subjects, record the SCCAI score; for CD subjects, collect CDAI diary dispensed at 
Visit 4 and calculate current CDAI score using the Visit 5 HCT result from the central 
laboratory (when available) 
5. Collect PE and SF‐36 data 
6. Check Hb, TSAT and ferritin levels (when central laboratory results available) 
 
7. Review and record all concomitant medications   
8. Record all AEs since last visit 
9. Collect bottles dispensed at prior visit and perform drug accountability and a compliance 
check 
10. Instruct the subject to call the clinic or return promptly should an AE occur 
17. Schedule a telephone follow up visit at least 14 days after Visit 5.   
11. Complete the Visit Specific eCRFs 
9.2.6 
Visit 6 (Week 36) or End of Study 
The following procedures will ONLY BE COMPLETED if subjects went beyond week 12 
according to previous protocol. In that case this visit will be the End of Study Visit 
1. Collect haematology and iron markers samples  
2. Collect FCM dosing history information 
3. Measure subject’s body weight 
4. For UC subjects, record the SCCAI score; for CD subjects, collect CDAI diary dispensed at 
Visit  5  and  calculate  current  CDAI  score  using  the  Visit  6  HCT  result  from  the  central 
laboratory (when available) 
5. Collect PE and SF‐36 data 
6. Check Hb, TSAT and ferritin levels (when central laboratory results available) 
7. Review and record all concomitant medications   
8. Record all AEs since last visit 
9. Collect bottles dispensed at prior visit and perform drug accountability and a compliance 
check 
10. Instruct the subject to call the clinic or return promptly should an AE occur 
11. Schedule a telephone follow‐up visit at least 14 days after Visit 6.  Complete the Visit 
Specific eCRFs 


 
 
 
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9.2.7 
Visit 7 (Week 52) or End of study visit  
ONLY BE COMPLETED if subjects went beyond Visit 6 according to previous protocol. The 
following procedures will be completed during the visit:  
1. Collect haematology and iron markers samples  
2. Collect FCM dosing history information 
3. Measure subject’s body weight 
4. For UC subjects, record the SCCAI score; for CD subjects, collect CDAI diary dispensed at 
Visit  6  and  calculate  current  CDAI  score  using  the  Visit  7  HCT  result  from  the  central 
laboratory (when available) 
5. Collect PE and SF‐36 data 
6. For female subjects of childbearing potential, perform urine pregnancy test 
7. Review and record all concomitant medications   
8. Record all AEs since last visit 
9. For ferric maltol subjects, collect bottles dispensed at prior visit, perform drug 
accountability and calculate compliance. 
10. Instruct the subject to call the clinic or return promptly should an AE occur 
11. Schedule Visit 8 at Week 54 telephone follow up 
12. Complete the Visit Specific eCRFs 
9.2.8 
Telephone follow up 
1. Review and record all concomitant medications   
2. Record all AEs since last visit 
3. Complete the Visit Specific eCRFs 
Note: this follow‐up call does not need to occur if End of Study Assessments have occurred 14 
days or more from the date of last dose of ferric maltol or FCM. 
If an AE is reported or is ongoing at the time of this visit, or if a significant lab abnormality is 
identified  at  the  last  visit  prior  to  this  visit,  the  Investigator  must  follow  the  event  until 
resolution or until there is a satisfactory explanation of the changes observed.  
9.2.9 
Premature Discontinuation 
All subjects have the right to withdraw formal consent without prejudice at any time during 
the study.  If a subject withdraws formal consent, the Investigator should make a reasonable 
effort to determine the cause for withdrawal of consent and completed and end of study visit. 
Subjects who prematurely discontinue the study, but do not withdraw consent, must return 
to clinic for visit end of study visit, according to the schedule of assessments (Section 9.1). 
10 
ASSESSMENTS  
10.1 
EFFICACY 
10.1.1 
Haemoglobin 
Haemoglobin concentration measurement is among the most commonly performed blood 
tests, usually as part of a complete blood count.  Results are reported in g/L, g/dL or mmol/L.  


 
 
 
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One g/dL equals approximately 0.6206 mmol/L.  In this study, Hb will be evaluated using a 
central laboratory at every clinic visit, according to the schedule of assessments (Section 9.1).  
10.2 
SAFETY  
10.2.1 
Definitions 
10.2.2 
Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and does not necessarily have a causal relationship with this treatment.  An AE can therefore 
be  any  unfavourable  or  unintended  sign  or  symptom,  intercurrent  illness,  injury,  or  any 
concomitant  impairment  of  the  subject’s  health,  temporally  associated  with  the  use  of  a 
medicinal product, whether or not considered related to the medicinal product.   
A  treatment‐emergent  AE  is  any  AE  temporally  associated  with  the  use  of  a  study  drug, 
whether or not considered related to the study drug.  
Adverse events include: 
 Exacerbation  of  a  chronic  or  intermittent  pre‐existing  condition/disease  including 
either an increase in frequency and/or intensity of the condition/disease. 
 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. 
 Continuous persistent disease or symptoms present at baseline that worsen within the 
study. 
 Events considered by the Investigator to be related to study‐mandated procedures.  
 Abnormal  safety  assessments,  e.g.  laboratory  test  abnormalities,  physical  exam 
findings  or  vital  sign  measurements  must  be  reported  as  AEs  if  they  represent  a 
clinically significant finding in the medical and scientific judgment of the Investigator, 
symptomatic  or  not,  which  was  not  present  at  baseline  or  if  present  at  baseline, 
worsened during the course of the study or led to dose reduction, interruption or 
permanent  discontinuation  of  study  drug.    However,  if  an  abnormal  laboratory  or 
other safety‐related test result is associated with clinical signs or symptoms, the signs 
or  symptoms  should  be  recorded  as  an  AE.    If  signs  and  symptoms  are  part  of  a 
diagnosis, then the diagnosis should be recorded as AE. 
 Signs, symptoms of a suspected drug interaction. 
 Signs, symptoms of a suspected overdose of either the study drug or a concomitant 
medication (overdose per se will not be reported as AE/SAE). 
 
Adverse events do not include: 
 Medical  or  surgical  procedure,  e.g.,  surgery,  appendectomy,  endoscopy,  tooth 
extraction,  transfusion  (as  these  are  treatments  for  an  AE).    However,  the  event 
resulting in the procedure is an AE (e.g. appendicitis, abdominal pain).  
 Pre‐existing disease or medical condition that does not worsen. 
 Situations in which an adverse change did not occur, e.g., hospitalisations for cosmetic 
elective surgery or for social and/or convenience reasons. 


 
 
 
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 Anticipated day‐to‐day fluctuations or seasonal fluctuations (e.g. allergic rhinitis) of 
pre‐existing disease(s) or condition(s) present or detected at the start of the study and 
recorded on the Medical History CRF. 
 The disease/disorder being studied, or the expected progression, signs or symptoms 
(including laboratory values) of the disease/disorder being studied, unless it is more 
severe than expected for the subject’s condition. 
 Overdose  of  either  study  drug  or  concomitant  medication  without  any  signs  or 
symptoms.  
10.2.3 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose 
‐ 
is fatal, 
‐ 
is life‐threatening, 
‐ 
requires inpatient hospitalisation or prolongation of existing hospitalisation, 
‐ 
results in persistent or significant disability/incapacity, 
‐ 
results in a congenital anomaly/birth defect or 
‐ 
is otherwise judged as medically significant (may jeopardise the subject). 
Besides the explanations already included in the definition, the following guidelines should 
be used: 
Life‐threatening: Refers to an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were 
more severe. 
Inpatient hospitalisation: Subject has to stay in hospital at least overnight 
The following reasons for hospitalisations are not considered AEs, and therefore not SAEs:  
 Hospitalisations for cosmetic elective surgery, social and/or convenience reasons. 
 Standard  monitoring  of  a  pre‐existing  disease  or  medical  condition  that  did  not 
worsen, e.g., hospitalisation for coronary angiography in a subject with stable angina 
pectoris. 
 Elective treatment of a pre‐existing disease or medical condition that did not worsen, 
e.g.,  hospitalisation  for  chemotherapy  for  cancer,  elective  hip  replacement  for 
arthritis, vein stripping for preventive and/or cosmetic purpose. 
Prolongation  of  hospitalisation:  Complications  that  occur  during  hospitalisation  are  AEs.  
However, if a complication prolongs hospitalisation or would have required hospitalisation or 
fulfils any other serious criteria, that complication is considered an SAE.  In any case, admission 
to an intensive care unit is considered a prolongation of hospitalisation.  When in doubt as to 
whether  “prolongation  of  hospitalisation”  was  necessary,  the  AE  should  be  considered 
serious. 
Significant disability: The term significant disability means that there is a substantial disruption 
of a person’s ability to conduct normal life functions.  This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, accidental trauma (e.g. sprained ankle) or uncomplicated chronic diseases which 
may interfere or prevent everyday life functions but do not constitute a substantial disruption. 


 
 
 
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Medically  significant:    Medical  and  scientific  judgement  should  be  exercised  in  deciding 
whether other situations should be considered serious such as important medical events that 
might not be immediately life‐threatening or result in death or hospitalisation but might/may 
jeopardize  the  subject  or  might/may  require  intervention  to  prevent  one  of  the  other 
outcomes listed in the definition above.  Examples of such events are invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse. 
Serious adverse event 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. 
All other AEs not fulfilling any of the criteria above are considered as “non‐serious.” 
10.2.4 
Reporting and Documentation 
Adverse events 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 not related to IDA or IBD present in a 
subject prior to the start of the study should be recorded on the Medical History CRF.  
All AEs that occur after informed consent is obtained through study completion or premature 
discontinuation must be reported on the AE form in the eCRF.  All AEs must be reported 
REGARDLESS OF WHETHER OR NOT THEY ARE CONSIDERED DRUG RELATED. 
Any SAE that occurs during the clinical study or within four weeks of receiving the last dose of 
study drug, whether or not related to the study drug, must be reported by the Investigator to 
the Study Safety officer at Clinipace Worldwide via the eCRF or by FAX or telephone within 24 
hours of awareness.   
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.  Adverse events not previously documented in the study will 
be recorded on the AE CRF.  The nature of each event, date and time (where appropriate) of 
onset, outcome, course (i.e., intermittent or constant), maximum intensity, actions taken with 
respect  to  dosage,  and  relationship  to  study  treatment  should  be  established.    Details  of 
changes  to  study  drug  dosing  or  any  subsequent  treatment  should  be  recorded  on  the 
appropriate pages of the CRF. 
Adverse events 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. 


 
 
 
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10.2.5 
Immediate reporting 
The following AEs must be reported within 24 hours: 
• Serious Adverse Events 
• Pregnancies 
Pregnancy is not considered as an AE, but must be reported immediately  
For immediate reporting, the Investigator must notify the Study Safety Officer at Clinipace 
Worldwide within 24 hours after awareness via the eCRF or FAX (also for pregnancies). 
If the site obtains relevant follow‐up information, this information needs to be forwarded to 
the Study Safety Officer within 24 h of awareness.  
Other documents must be submitted upon request.  All documents must be blinded with 
respect to the subject’s personal identification to meet data protection requirements, e.g., on 
the discharge summary this data must be blinded and the subject number added.  
As soon as the Study Safety Officer is informed about an SAE, they will organise evaluation 
and  potential  reporting  to  the  IRB/IEC,  Regulatory  (Competent)  authorities  and  other 
concerned parties. 
10.2.6 
Non‐immediate reporting 
Adverse events that do not qualify for immediate reporting will be documented in the CRF and 
reported with the Integrated Study Report. 
10.2.7 
Evaluation 
Adverse events and the corresponding entries in the CRF will be reviewed by the Investigator 
or qualified member of the study staff. 
10.2.8 
Intensity 
The intensity will be rated by the Investigator as “mild”, “moderate” or “severe”: 
Mild: transient or mild discomfort (< 48 hours); medical intervention/therapy may not be 
required. 
Moderate:  discomfort  enough  to  cause  interference  with  usual  activity  and  may  warrant 
intervention. 
Severe: incapacitating with inability to do usual activities or significantly affects clinical status, 
and warrants intervention. 
A mild, moderate or severe AE may or may not be serious.  These terms are used to describe 
the  intensity  of  a  specific  event  (as  in  mild,  moderate,  or  severe  myocardial  infarction).  
However,  a  severe  event  may  be  of  relatively  minor  medical  significance  (such  as  severe 
headache) and is not necessarily serious.  For example, nausea lasting several hours may be 
rated as severe, but may not meet the definition of seriousness.  Fever of 39 °C that is not 
considered severe may become serious if it prolongs hospitalisation. 
10.2.9 
Causality 
In addition, the Investigator is expected to discern the relationship of the AE to the IMP by 
answering the following question with “yes” or “no”:  
"According to your clinical experience is there a reasonable possibility that the event may have 
been caused by the study drug?" 


 
 
 
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If  there  is  any  valid  reason  (e.g.,  temporal  relationship,  de‐challenge  (diminishing)  or  re‐
challenge behaviour) even if undetermined or untested, for suspecting a possible cause‐and 
effect relationship between the study drug and the occurrence of the AE, the answer should 
be “yes”.  
If no valid reasons exist for suggesting a possible relationship, then the answer should be “no”. 
10.2.10 
Outcome 
The outcome of each AE has to be assessed as follows: 
Fatal:  The AE resulted in death (“Death” is recorded as an outcome, not as the AE) 
Ongoing/Not resolved: The AE has not resolved 
Recovered with sequelae:  Resolution of the AE has occurred, but the subject retains some 
sequelae 
Recovered: The AE fully resolved with no observable residual effects 
Unknown:  The outcome of the AE is not known as the subject did not return for follow‐up 
and attempts to locate the subject and/or to obtain follow‐up information were unsuccessful 
(lost to follow‐up). 
10.2.11 
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 discontinuation 
of IMP and is judged by the Investigator to be unrelated to investigational products, the IMP 
may be restarted at the discretion of the Investigator.  Discontinuation of the IMP (unless 
protocol  specified)  on  more  than  one  occasion,  or  for  longer  than  4  weeks  continuously 
(unless protocol specified) will require the subject to withdraw from the study. The decision 
to re‐introduce the medication requires prior approval of the Sponsor or designee. 
10.2.12 
Clinical laboratory 
Haematology and iron markers samples will be collected at screening and Visits 2‐4, as well as 
at premature discontinuation and unscheduled visits for FCM administration, if applicable. 
Basic  safety  chemistry,  liver  function  and  Vitamin  B12/folate  samples  will  be  collected  at 
screening only. Serum CRP will be measured at Visit 2 only.  A central laboratory will analyse 
all  protocol‐specified  clinical  laboratory  tests.    In  addition,  a  urine  pregnancy  test  will  be 
performed at screening and Visit 4/early discontinuation for female subjects of childbearing 
potential.  
Processing,  labelling,  and  shipping  of  the  samples  will  be  completed  following  central 
laboratory guidelines as provided in a Laboratory Manual.  Additional laboratory tests may be 
performed if clinically relevant abnormal values are obtained at any time during the course of 
the study.  
Haematology  (all  visits):  haematocrit,  haemoglobin,  platelets,  RBC  count,  RBC  Hb 
concentration; WBC count and differential. 
Iron markers (all visits): total serum iron, ferritin and transferrin. TSAT will be calculated and 
reported from the values obtain in these analysis at each visit. 
Basic safety chemistry, liver function and vitamins (Visit 1 only):  Serum ALT, Serum AST, total 
bilirubin, creatinine, blood urea nitrogen (BUN), sodium, potassium, chloride, bicarbonate, 
glucose, vitamin B12, folate.  


 
 
 
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C‐reactive protein will be measured at Visit 2 only. 
Retained Samples: Additional serum and plasma samples will be collected at Visit 2 and Week 
12 (Visit 4) for possible future analysis related to IBD, anaemia and/or iron deficiency.  No 
genetic testing will be  completed on any samples obtained during this study without the 
further  consent  of  the  subject.    Only  Investigator  sites  with  access  to  secure  ‐70°C/‐80°C 
freezer storage facilities will be required to collect and process blood for retained serum and 
plasma samples at Visit 2 and Visit 4.   
Retained samples will stored at site (‐70°C/‐80°C) for subsequent periodic dry‐ice shipping to 
the Central Laboratory.  Full details will be provided in the Laboratory Manual. 
Urine Pregnancy Test: For female subjects of childbearing potential, a urine pregnancy test 
will be performed as per visit schedule at the investigative site.  Sites will be provided with 
urine pregnancy test kits by the Central Laboratory. 
Up‐to‐date  reference ranges will be provided during the study in the Laboratory Manual.  
Laboratory results will be compared to these reference ranges and flagged if they are outside 
the normal range or the protocol‐specified range for randomization and/or continued study 
participation. 
Investigators  will  review,  sign  and  date  all  lab  results  upon  receipt  from  the  Central 
Laboratory.  If a value is flagged as abnormal, the Investigator must document the abnormality 
as ‘clinically significant’ (CS) or ‘non‐clinically significant’ (NCS).  Any lab abnormality assessed 
as ‘CS’ must be recorded as an AE if not explained by a coexisting condition (documented in 
the medical history).  
The signed paper copy of the laboratory result is retained at the investigational site.  The 
electronic  file  transferred  from  the  Central  Laboratory  to  the  Sponsor  will  be  considered 
source data for laboratory analysis.  
10.3 
PHARMACOECONOMICS COLLECTION 
10.3.1 
Medical outcomes study 36‐item short form  
A 36‐item short‐form (SF‐36) QOL questionnaire will be administered at Randomization and 
other study visits as indicated in the schedule of assessments (Section 9.1).  The SF‐36 was 
constructed to survey health status in the Medical Outcomes Study and was designed for use 
in clinical practice and research, health policy evaluations, and general population surveys 
(www.SF‐36.org).  The SF‐36 includes one multi‐item scale that assesses eight health concepts:  
 
limitations in physical activities because of health problems;  
 
limitations in social activities because of physical or emotional problems;  
 
limitations in usual role activities because of physical health problems;  
 
bodily pain;  
 
general mental health (psychological distress and well‐being);  
 
limitations in usual role activities because of emotional problems;  
 
vitality (energy and fatigue); and  
 
General health perceptions. 
The survey was constructed for self‐administration by persons 14 years of age and older, and 
for administration by a trained interviewer in person or by telephone.  The survey will be 
completed by the subjects in their native language. 


 
 
 
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10.3.2 
Pharmacoeconomics 
The  pharmacoeconomic  data  collected  will  contain  but  not  be  limited  to  the  number  of 
hospital or clinical visits for administration of IV iron, or unscheduled visits for repeat testing 
of Hb/Iron.  Also the nature of the subjects’ transport (own or hospital/clinic) will be recorded.  
These two items will be included in a pharmacoeconomic analysis of the two treatment arms. 
10.4 
BASELINE PARAMETERS AND CONCOMITANT MEDICATIONS 
10.4.1 
Baseline demographics and disease characteristics 
The following baseline demographics and disease characteristics are to be recorded in the 
CRF:  
 Year of birth, age 
 Race and ethnicity 
 Weight 
 Height 
 Gender 
 Relevant and significant medical history of the last 5 years preceding randomization 
 Month and Year of diagnosis of IBD 
 Month and Year of the last 3 flares of IBD preceding randomization 
 IBD sub group 
 Whether the subject has received IV iron previously or not 
 Prior oral ferrous product(s) and IV iron use history. Severity of IBD at the time of prior 
OFP failure will also be recorded in the CRF if applicable (from documented historical 
SCCAI/CDAI,  Mayo  and/or  Montreal  classification  score  (see  Van  Assche,  2010; 
Dignass, 2012), or any other guideline used to confirm disease severity at the time of 
OFP failure) 
 The  most  recently  prescribed  oral iron  medication  including  dose  and  time  of  last 
administration 
 Method of contraception for female subjects of childbearing potential  
10.4.2 
Concomitant medications 
All concomitant medications are to be reported on the CRF 
 Iron preparations other than study medications are prohibited at baseline and during 
study; with the exception of: 
 Over  the  Counter  (OTC)  oral  supplements/multivitamin  type  preparations 
which may be taken, however Subjects are encouraged to keep to the same 
dose during the course of this study 
 Blood transfusions or donations are prohibited from screening and throughout the 
study period. 
 Erythropoiesis‐stimulating  agents  (ESAs)  are  permitted  during  the  study,  but  the 
subject  must  have  been  on  a  stable  dose  for  the  preceeding  3  months  before 


 
 
 
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randomization 
 Vitamin B12 and folic acid supplements are allowed during the study.  
 Immunosuppressants are permitted so long as there is no clinical evidence or suspicion 
of  the  immunosuppressant  contributing  to  the  subject’s  anaemia  or  affecting 
erythropoiesis. 
Variations to dosing are permitted at the discretion of the investigator so long as there 
is  no  clinical  evidence  or  suspicion  of  the  immunosuppressant  contributing  to  the 
subject’s anaemia or affecting erythropoiesis. 
 
 
All non‐iron concomitant medications ongoing at time of screening or stopped within 1 month 
of screening have to be recorded in the CRF. Prescription iron replacement therapies stopped 
within 12 months of screening have to be recorded in the CRF, along with prior oral ferrous 
product(s) and IV iron use history. 
Concomitant medications initiated, stopped, up‐titrated or down‐titrated after randomization 
will also be recorded. 
11 
ENDPOINTS 
11.1 
PRIMARY EFFICACY ENDPOINT 
Proportion of subjects achieving either a 2g/dL increase in Hb OR normalization of Hb (>12g/dL 
women, >13g/dL men) at Week 12 
11.2 
SECONDARY EFFICACY ENDPOINTS 
 Change in Hb concentration from baseline to Week 12 
 Change in Hb concentration from baseline to Week 12 in subjects with a baseline 
Hb <9.5 g/dL 
 Proportion of subjects who experience a change from baseline in Hb concentration 
≥1.0 g/dL at Week 12 
 Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase in Hb 
concentration of ≥1 g/dL at Week 12  
 Proportion of subjects with Hb concentration within normal limits at Week 12 
 Proportion  of  subjects  with  baseline  Hb  concentration  <9.5  g/dL  that  is  within 
normal limits at Week 12 
 Change in Hb concentration from baseline to Week 4 
 Change in Hb concentration from baseline to Week 4 in subjects with a baseline Hb 
<9.5 g/dL  
 Proportion of subjects who experience a change from baseline in Hb concentration  
≥2.0 g/dL at Week 12 
 Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase in Hb 
concentration of ≥2 g/dL at Week 12  


 
 
 
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 Proportion of subjects who experience a change from baseline in Hb concentration 
≥1.0 g/dL at Week 4 
 Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase in Hb 
concentration of ≥1 g/dL at Week 4  
 Proportion of subjects with Hb concentration within normal limits at Week 4  
 Proportion  of  subjects  with  baseline  Hb  concentration  <9.5  g/dL  that  is  within 
normal limits at Week 4 
 Proportion of subjects who experience a change from baseline in Hb concentration 
≥2.0 g/dL at Week 4 
 Proportion of subjects with baseline Hb <9.5g/dL that achieve an increase in Hb 
concentration of ≥2 g/dL at Week 4 
 Long term efficacy endpoints i.e. proportion of subjects who are non‐anaemic at 6 
and 12 months; normalization of ferritin levels at 6 and 12 months 
Pharmacoeconomic endpoints: 
 Number of hospital or clinic visits for administration of IV iron 
 Proportion of subjects who restart FCM during the study 
11.3 
SECONDARY SAFETY ENDPOINTS 
During the randomised phase of the study, safety endpoints will include:  
 Treatment‐emergent Adverse Events (AEs)  
 Treatment‐emergent Serious Adverse Events (SAEs) 
 Adverse Events leading to premature discontinuation of study drug 
 Adherence to study medication 
 
 
12 
STATISTICAL CONSIDERATIONS 
12.1 
GENERAL CONSIDERATIONS 
The analysis of the study data is the responsibility of the Sponsor or its designee.   
The primary analysis will be a non‐inferiority comparison of ferric maltol to FCM, comparing 
Response Rate from baseline to Week 12 where response is ≥ 2g/dL rise in Hb OR moved from 
anaemic to non‐anaemic at Week 12. 
Randomization  will  be  centrally  controlled  and  stratified  by  screening  Hb  (<  or  ≥  10g/dL 
Female; < or ≥ 11g/dL Male) and by IBD (UC or CD). 
12.2 
SAMPLE SIZE AND POWER CALCULATIONS 
This study is designed with a ‘responder %’ primary endpoint, where response is ≥ 2g/dL rise 
in Hb OR moved from anaemic to non‐anaemic at Week 12. The comparator group responder 
rate (FCM) is assumed to be 75% and the absolute non‐inferiority margin is 20%.  The non‐
inferiority margin is based on clinical opinion, coupled with the fact that in a previous study, 
the response rate in the placebo arm was less than 5% at 12 weeks.   


 
 
 
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The study is powered at 90% when the true response rate in the ferric maltol arm is 75%, i.e. 
the true difference to FCM is 0%.  The primary statistical test is based on the 2‐sided, 95% 
confidence interval for the difference in response rate between the two groups.  This requires 
108  subjects  per  arm.  In  order  to  allow  for  protocol  deviations,  this  number  has  been 
increased by 12% to 121 per arm.  
12.3 
STATISTICAL METHODS 
12.3.1 
Primary endpoint analysis 
The null hypothesis for the study is that the proportion of responders in the ferric maltol arm 
is lower that the proportion of responders in the FCM arm.  The alternative hypothesis is that 
the proportion of responders in the ferric maltol arm is not lower than the proportion of 
responders in the FCM arm (i.e. ferric maltol non‐inferior to FCM for response rate). 
The primary analysis will be conducted using both the ITT and the PP population (See Section 
12.4).  Subjects whose responder status is unknown will be assumed not to have responded 
(a Baseline Observation Carried Forward (BOCF) approach).   
The analysis will be based on the lower confidence limit (LCL) of a 2‐sided, 95% confidence 
interval for the difference between the proportion of responders in the ferric maltol arm and 
the  FCM  arm.    The  confidence  interval  will  be  calculated  based  on  a  logistic  regression, 
adjusting for study treatment, baseline haemoglobin, and UC or CD IBD disease.   
The null hypothesis will be rejected, i.e. ferric maltol will be deemed non‐inferior to FCM, if 
the LCL for the difference in proportions of responders (ferric maltol – FCM) is at least ‐20% 
for both the PP and the ITT analyses. 
12.3.2 
Secondary and Exploratory Analyses 
Details  regarding  methods  for  analysis  of  secondary  endpoints  will  be  provided  in  the 
Statistical Analysis Plan. In addition, pre‐defined exploratory endpoints, as well as long‐term 
endpoints and analyses, will be provided in detail in the Statistical Analysis Plan. 
No formal multiple comparisons procedure will be used to control the type I error rate for the 
analysis of secondary or other exploratory endpoints, including those defined for the long‐
term open‐label phase of the study.  For these analyses, confidence intervals and/or p‐values 
will be displayed for descriptive purposes only. 
12.3.3 
Sensitivity analyses 
Analysis  of  primary  and  key  secondary  parameters  will  be  performed  also  with  the  per 
protocol  (PP)  population  in  the  sense  of  sensitivity  analyses.    Both  data‐sets,  ITT  and  PP 
populations, will be defined prior to the analysis (see Section 12.4). 
Sensitivity analyses will also be performed for the primary endpoint, including an analysis 
using last observation carried forward (LOCF) and complete case analysis using ANCOVA and 
a mixed model repeated measures (MMRM) analysis.  


 
 
 
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12.3.4 
Imputation of Missing Data 
The handling of missing data for the primary endpoint is described in Section 12.3.1. Missing 
values for efficacy variables will be replaced for the secondary endpoint analyses as follows: 
 For the endpoint ‘Hb concentration within normal range’ subjects not returning to a 
follow‐up visit will be assumed to have Hb concentration not within normal range.  
 For the endpoint ‘Increases in Hb concentration of ≥1g/dL’ subjects not returning to a 
follow‐up visit will be assumed to have not reached the desired concentration.  
 For the endpoint ‘Increases in Hb concentration of ≥2g/dL’ subjects not returning to a 
follow‐up visit will be assumed to have not reached the desired concentration.  
Additionally, the key secondary endpoints will also be evaluated using the multiply imputed 
data. 
Safety data will be used according to availability, with no imputation for missing data. 
Imputation of missing values for long‐term and exploratory efficacy analyses will be defined 
in the Statistical Analysis Plan. 
12.3.5 
Safety analyses  
Adverse Events 
Adverse events will be categorized by primary system organ class and MedDRA preferred term 
as coded using the MedDRA dictionary.  The number, intensity, relation to study medication 
and  action  taken  will  be  described  by  incidence  tables.    Serious  adverse  events  will  be 
discussed separately. 
Laboratory variables 
Laboratory measurements will be summarized with descriptive statistics including changes 
from baseline and shift tables.  
12.3.6 
Pharmacoeconomic Analysis 
The Hb response data, plus the QOL and other resource use information collected as part of 
this study, will be used in a pharmacoeconomic analysis.  This will compare the two treatment 
arms for correction and maintenance treatment of IDA over a minimum of 12 weeks period.  
12.3.7 
Statisical Analysis 
A  two  stage  analysis  of  the  safety  and  efficacy  data  will  be  performed:  the  primary  and 
secondary  analyses  will  be  conducted  when  all  subjects  have  completed  12  weeks  of 
treatment. The results will be provided in an interim study report. The final study report will 
be finalised on completion of the remaining visits. The analysis would include the longer term 
endpoints as well for those with longer treatment period.  


 
 
 
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12.4 
DEFINITION OF POPULATIONS  
12.4.1 
Randomised Population 
All subjects who are randomised.  
12.4.2 
Safety population 
All subjects who have had at least one dose of study drug and one subsequent contact with 
the Investigator will be analysed for safety.  
12.4.3 
Intention‐to‐treat population (Full analysis set) 
For efficacy, all randomised subjects will be included in the ITT analysis.  The ITT analysis will 
be used in the primary efficacy analysis.  
12.4.4 
Per protocol population 
The PP population includes all subjects eligible for ITT evaluation and, in addition, who do not 
have  major  protocol  deviations.  Protocol  deviations  occurring  during  the  study  will  be 
classified as major or minor prior to study database lock. 
12.5 
SOFTWARE APPLIED 
The data analysis will be performed in a validated working environment according to the 
requirements of the ICH‐Guidelines E3 [1995]. 
The software to be used for data evaluation will be described in the statistical analysis plan. 
12.6 
QUALITY CONTROL 
The statistical analysis will be performed according to the statistician’s standard operating 
procedures  (SOPs),  the  statistical  analysis  plan,  the  clinical  study  protocol,  and  all  its 
amendments.  All evaluation steps will be completely documented, and the software to be 
used is validated.  In‐process controls will be performed and documented. 
13 
DATA MANAGEMENT   
Data  management,  including  data  quality  assurance,  will  be  performed  according  to 
international guidelines (GCP, ICH), Clinipace Worldwide SOPs and Working Instructions.  Data 
Management procedures for this protocol will be fully documented in the Data Management 
Plan by Clinipace Worldwide. 
14 
ETHICAL CONSIDERATIONS 
14.1 
SUBJECT INFORMATION AND INFORMED CONSENT 
IRB/IEC approval of the written Informed Consent Form must be obtained prior to use.  The 
consent  form  will  contain  a  phrase  by  which  consent  is  given  for  the  access  to  the  non‐
personalised data by the Sponsor / applicant, national and regulatory authorities.  In addition, 
it states that the subject is free to withdraw from the study at any time without any negative 
consequences.  The consent form gives a complete and comprehensive explanation of the 
significance, nature, extent and possible risks of the study.  For details of the informed consent 
procedure please refer to Section 7.4.7 of this protocol.  The procedure complies with all 
applicable regulations governing the protection of human subjects, such as national drug laws 
(German Drug Law: AMG, US‐FDA regulations), ICH‐GCP guidelines, and the Declaration of 
Helsinki. 


 
 
 
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14.2 
INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE 
The Clinical Study Protocol and Amendments, the Informed Consent, advertisements, and any 
other written information to be provided to the subjects have to be approved by the local 
IRB/IEC. 
The Sponsor or designee is responsible for submitting the documents to the IRB/IEC. 
During the study the following documents will be sent to the IRB/IEC for their review: 
‐ Investigator Brochure updates, both periodic and annual 
‐ Reports of AEs that are serious, unlisted and associated with the IMP (SUSARS), 
‐ Protocol amendments and revised informed consent forms (if any). 
The Sponsor or designee will provide a safety update of the specific study site to the local 
IEC/IRB, including line listings, individual reports of SUSARs, if applicable, and a discussion of 
AEs annually, or more frequently if requested. 
At  the  end  of  the  study,  the  Sponsor  or  designee  will  notify  the  IEC/IRB  of  the  study 
completion.  Furthermore, the Sponsor or designee will provide the synopsis of the final report 
to the IEC/IRB within one year after end of the clinical study.  
14.3 
SUBJECT INSURANCE 
Every subject participating in the study is insured in accordance with local law against injuries 
to health which may occur during the study. 
Excluded from this, however, are injuries to health and deterioration of illnesses already in 
existence which would have continued to exist even if the subject had not taken part in the 
study. 
Insurance  coverage  will  be  jeopardised  if  the  subject  fails  to  immediately  report  to  the 
Investigator or responsible physician any injury to health which might have resulted from the 
participation in the study, or if he/she undergoes any other medical treatment (except for 
emergency treatment) without the Investigator’s knowledge before his/her participation in 
the study has officially ended.  In case of emergency treatment, the subject is obliged to inform 
the Investigator as soon as possible after the treatment. 
Any injury to health which might have occurred as a result of participating in the study must 
be reported by the subject to the insurer without delay.  The subject may also inform the 
Investigator, who is obliged to make a report to the insurer. 
Subject insurance will be arranged by the Sponsor.  
15 
STUDY MANAGEMENT 
15.1 
LEGAL REQUIREMENTS 
The planning and execution of the clinical study are subject to the local legal regulations (e.g. 
§  40,  §  41,  §  42  and  §  67  of  the  German  Drug  Law),  and  the  recommendations  of  the 
Declaration of Helsinki (current revision).  Furthermore, the current ICH‐GCP guidelines will be 
observed. 
15.2 
DATA COLLECTION 
The Investigator must ensure that all source documents (i.e., study and/or medical records) 
are completed and maintained according to the study protocol, and are available at the site. 


 
 
 
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15.2.1 
Case Report Forms 
It  is  the  responsibility  of  the  Investigator  to  maintain  and  submit  accurate  eCRFs  to  the 
Sponsor as soon as possible. 
If  a  subject  does  not  complete  the  study,  all  data  collected  on  the  subject  prior  to  the 
discontinuation will be made available to the Sponsor.  The End of Study CRF should be filled 
out accordingly. 
Instructions for completing the CRFs and any corrections necessary will be provided in the 
Case Report Form Completion Guidelines Manual and in the CRF. 
15.2.2 
Source documents 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to Sponsor in the CRFs and in all required reports, and as such will be asked to 
sign  and  date  the  appropriate  CRFs,  as  verifying  and  taking  responsibility  for  the  data 
collected.  This  also  applies  to  records  for  those  subjects  who  fail  to  complete  the  study 
(including screen failures). If a subject withdraws from the study, the reason must be noted 
on the CRF. 
All data reported on CRFs will be verified against source documents.  The CRF will not act as 
source except in the instance of a subject self‐completion of a questionnaire.   
15.2.3 
Confidential subject identification list and screening log 
In order to permit easy identification of the individual subject during and after the clinical 
study,  the  Investigator  is  responsible  for  keeping  an  up‐dated  Confidential  Subject 
Identification  List.    This  document  will  be  reviewed  by  the  monitor  for  completeness.  
However, in order to ensure subject confidentiality, no copy will be made. 
A Screening Log documenting all subjects who sign Informed Consent and who are evaluated 
for inclusion in the clinical study must be completed by the Investigator.  The Screening Log 
will include the following data: subject number, date of screening, date of informed consent 
and randomization or reason for screen failure, as applicable. 
15.3 
ACCESS TO DATA 
Upon  request  by  the  clinical  monitor,  auditor,  IRB/IEC,  or  any  regulatory  authority,  the 
Investigator/study  site  must  provide  access  to  all  requested  study‐related  records.  The 
anonymity of participating subjects must be maintained. All subject data will be identified only 
by  a  subject  identification  number.  Documents  that  identify  the  subject  (e.g.,  the  signed 
Subject Information Sheet and ICF) must be maintained in confidence by the Investigator. 
However, in compliance with federal guidelines regarding the monitoring of clinical studies 
and in fulfilment of his/her obligations to the Sponsor, the investigator must permit the study 
monitor, Sponsor representative or auditor, and/or FDA representative or other regulatory 
authority to review the portion of the subject’s medical record that is directly related to the 
study. This shall include all study‐relevant documentation including medical history to verify 
eligibility, admission/discharge summaries for hospital stays occurring while the subject is 
enrolled in the study and autopsy reports if a death occurs during the study.  
15.4 
MONITORING 
To ensure accurate, complete, consistent, and reliable data, the Investigative sites and study 
procedures will be monitored by a representative of the Sponsor.  The Sponsor representative 
will  visit  the  site  to  review  the  source  documents  and  CRFs  for  protocol  compliance  and 
accuracy, and to assess facilities and equipment, recruiting, protocol adherence, AE reporting, 


 
 
 
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and other factors.  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 required.  
15.5 
AMENDMENTS 
Any change to a protocol must be considered an amendment.  A proposed amendment should 
be reviewed by the Principal Investigator(s) or Steering Committee, as appropriate. 
Revisions to the Informed Consent requested by IRB/IEC are not considered amendments, so 
long as they do not affect the protocol. 
Non‐substantial amendment 
Minor  administrative  or  logistical  changes  require  a  non‐substantial  amendment.    Such 
changes include, but are not limited to changes, in study staff or contact details (e.g., Sponsor 
instead of CRO monitors) or minor changes in the packaging or labelling of study drug.  
The  implementation  of  a non‐substantial  amendment  could  be  done  with  or  without 
(according  to  national  regulations)  notification  to  the  appropriate  IRB/IEC  and  Regulatory 
(Competent) Authorities.  A non‐substantial amendment does not require the approval or 
acceptance by the Investigators.  
Substantial amendment 
Significant changes to the protocol require a substantial amendment.  Significant changes 
include,  but  are  not  limited  to:  new  data  affecting  the  safety  of  subjects,  change  of  the 
objectives/endpoints 
of 
the 
study, 
eligibility 
criteria, 
dose 
regimen, 
study 
assessments/procedures, treatment or study duration, with or without the need to modify 
the Informed Consent. 
Substantial amendments are to be approved by the appropriate IRB/IEC and in some countries 
by the Regulatory (Competent) Authorities.  The implementation of a substantial amendment 
can  only  occur  after  formal  approval  by  the  appropriate  IRB/IEC  and/or  Regulatory 
(Competent) Authorities and must be accepted by the Investigators. 
15.6 
AUDITS 
An independent quality control unit may audit the study protocol, the documentation and, if 
applicable, the performance of the study and the clinical study report to ensure that the study 
is performed in accordance with ICH‐GCP guidelines and regulatory requirements. 
Correspondingly,  the  agreements  to  this  section  are  also  valid  for  possible  visitors  from 
members of the quality control unit (GCP auditing or governmental control unit) in the event 
of  a  check  of  the  performance  of  this  clinical  study  according  to  ICH‐GCP  guidelines  and 
regulatory requirements. 
15.7 
CONFIDENTIALITY AGREEMENT 
Any  information  concerning  data  or  procedures  of  this  clinical  study  must  be  handled 
confidentially by all persons involved. 
15.8 
NOTICE TO THE LOCAL AND NATIONAL AUTHORITIES 
The local and national Regulatory (Competent) Authorities will be notified about the conduct 
of this clinical study according to local law. 
15.9 
RETENTION OF RECORDS 
The Investigator must retain the informed consent documentation, disposition of the IMP, 
CRFs, medical records, and other source data for at least 2 years after the last approval of a 


 
 
 
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marketing  application  in  an  ICH  region  and  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.  It is the responsibility 
of the Sponsor to inform the Investigator/institution as to when these documents no longer 
need to be retained. 
If  the  Investigator  retires,  or  for  any  other  reason  withdraws  from  the  responsibility  for 
maintaining records for the period of time required, custody of the records may be transferred 
to another person who will accept responsibility for the records.  Notice of such a transfer 
must be given in writing to the Sponsor. 
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  and  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. 
15.10 
INVESTIGATOR MEETING 
An Investigator Meeting may be organised to give study specific information and to support a 
homogenous execution of the study procedures at all participating study sites.  The same 
information will be provided during the Site Initiation Visit prior to study start at each site. 
15.11 
SECURITY AND PUBLICATIONS 
This study protocol remains the Sponsor property until the final fulfilment of the contract and 
may only be passed on to registration authorities and license partners with the Sponsor / 
Applicant’s approval.  The study site will treat all knowledge about the study product and/or 
its manufacturer with strictest confidentiality. 
The  Sponsor/Applicant  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.  Furthermore, the Sponsor 
ensures that the manufacture of the IMP was carried out in accordance with the guidelines of 
European Directives 2003/94/EC, 2001/20/EC and Annex 13/ 21CFR 312.23. 
The  study  results,  including  the  report  and  documentation,  become  the  property  of  the 
Sponsor as soon as the final report has been signed and the final payment to the study site 
has been made.  Publication rights will be described in the Investigator contract.  The study 
site’s agreement is not required for using the study results at registration authorities or for 
negotiations with companies interested in purchasing the product.  Information for specialist 
circles can likewise be compiled without the study site’s specific written consent. 
If information about this study is published, the subject’s personal information will not be 
identified. 
 


 
 
 
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Auerbach M, Rodgers GM. Intravenous iron. N Engl J Med. 2007;357:93‐94. 
Bergamaschi G, Di Sabatino A, Albertini R, Ardizzone S, Biancheri P, Bonetti E, Cassinotti A, 
Cazzola P, Markopoulos K, Massari A, Rosti V, Bianchi Porro G, Corazza GR. Prevalence and 
pathogenesis of anaemia in inflammatory bowel disease. Haematologica 2010; 95: 199‐205. 
Biancone  L,  Michetti  P,  Travis  S,  Escher  JC,  Moser  G,  Forbes  A,  Hoffmann  JC,  Dignass  A, 
Gionchetti P, Jantschek G, Kiesslich R, Kolacek S, Mitchell R, Panes J, Soderholm J, Vucelic B, 
Stange E for the European Crohn‘s and Colitis Organisation (ECCO). European evidence‐based 
Consensus on the management of ulcerative colitis: Special situations. J Crohn’s and Colitis 
2008; 2: 63‐92. 
Blanc B, Finch CA, Hallberg Let al. Nutritional anaemias. Report of a WHO Scientific Group. 
WHO Tech Rep Ser 1968; 405: 1‐40. 
Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, Mantzaris G, Reinisch W, 
Colombel JF, Vermeire S, Travis S, Lindsay JO, Van Assche G. Second European evidence‐based 
consensus  on  the  diagnosis  and  management  of  ulcerative  colitis  part  1:  definitions  and 
diagnosis. J Crohns Colitis. 2012, 6(10):965‐990. 
Dignass AU, Gasche C, Bettenworth D, Birgegård G, Danese S, Gisbert JP, Gomollon F, Iqbal T, 
Katsanos K, Koutroubakis I, Magro F, Savoye G, Stein J, Vavricka S; European Crohn’s and Colitis 
Organisation  [ECCO].    European  consensus  on  the  diagnosis  and  management  of  iron 
deficiency and anaemia in inflammatory bowel diseases. J Crohns Colitis 2015; 9(3): 211‐222. 
EMA  (European  Medicines  Agency).  New  recommendations  to  manage  risk  of  allergic 
reactions  with  intravenous  iron‐containing  medicines.  13  September  2013.  Available  at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/IV_iron_3
1/WC500151308.pdf. 
Evstatiev  R,  Marteau  P,  Iqbal  T,  et  al.  FERGIcor,  a  randomized  controlled  trial  on  ferric 
carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology. 
2011;141:846‐853 e841‐842. 
Gasche C (2008). Anaemia in Inflammatory Bowel Diseases. Bremen; UNI‐Med. 
Gasche C, Kulnigg S. Intravenous iron in inflammatory bowel disease. Semin Hematol 2006; 43 
(suppl 6): S18‐S22. 
Gasche C, Berstad A, Befrits R, Beglinger C, Dignass A, Erichsen K, Gomollón F Hjortswang H, 
Koutroubakis I, Kulnigg S, Oldenburg B, Rampton D, Schroeder O, Stein J, Travis S, Van Assche 
G.  Guidelines  on  the  Diagnosis  and  Management  of  Iron  Deficiency  and  Anaemia  in 
Inflammatory Bowel Diseases. Inflamm Bowel Dis 2007;13: 1545–1553. 
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 
Gomollon F, Chowers Y, Danese S, et al. Letter: European Medicines Agency recommendations 
for  allergic  reactions  to  intravenous  iron‐containing  medicines.  Aliment  Pharmacol  Ther. 
2014;39:743‐744. 
Harvey RSJ, Reffitt DM, Doig LA, Meenan J, Ellis RD, Thompson RPH, Powell JJ. Ferric trimaltol 
corrects iron deficiency anaemia in patients intolerant of iron. Aliment Pharmacol Ther 1998; 
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Latest version of the Investigator’s Brochure for Ferric Maltol (ST10‐021, ST10). 
Stein J, Hartmann F, Dignass AU. Diagnosis and management of iron deficiency anemia in 
patients with IBD. Nature Rev Gastroenterol Hepatol. 2010;7:599‐610. 
Study SWIN 189/ IM, Shield, fragments of statistical analysis on file  
Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, Ochsenkühn T, Orchard 
T, Rogler G, Louis E, Kupcinskas L, Mantzaris G, Travis S, Stange E; European Crohn's and Colitis 
Organisation (ECCO). The second European evidence‐based Consensus on the diagnosis and 
management of Crohn's disease: Definitions and diagnosis.  J Crohns Colitis 2010; 4(1): 7‐27 
Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anaemia in inflammatory bowel 
disease: A systematic review of the literature. Am J Med 2004; 116(7A): 44S‐49S. 
Wells CW, Lewis S, Barton JR, Corbett S. Effects of changes in haemoglobin level on quality of 
life and cognitive function in inflammatory bowel disease patients. Inflamm Bowel Dis 2006; 
12: 123‐130. 
Weiss G, Goodnough LT. Anemia of chronic disease. New England J Med. 2005;352:1011‐1023. 
WGO. World Gastroenterology Organisation Global Guideline. Inflammatory bowel disease: 
a global perspective. 2009. Available at: 
http://www.guideline.gov/content.aspx?id=15231&search=iron+deficiency+anemia. 
www.SF‐36.org. 
Zhu  A,  Kaneshiro  M,  Kaunitz  JD.  Evaluation  and  treatment  of  iron  deficiency  anaemia:  a 
gastroenterological perspective. Dig Dis Sci. 2010;55(3):548‐59. 
Zimmermann MB, Hurrell RF. Nutritional iron deficiency. Lancet. 2007;370:511‐520. 
 


 
 
 
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17 
APPENDICES 
17.1 
SCORING SYSTEM FOR THE SIMPLE CLINICAL COLITIS ACTIVITY INDEX 
Symptom 
Description 
Score 
Bowel frequency (day) 
1‐3 
0 
 
4‐6 
1 
 
7‐9 
2 
 
>9 
3 
Bowel frequency (night) 
0 
0 
 
1‐3 
1 
 
4‐6 
2 
Urgency of defecation 
None 
0 
 
Hurry 
1 
 
Immediately 
2 
 
Incontinence 
3 
Blood in stool 
None 
0 
 
Trace 
1 
 
Occasionally frank 
2 
 
Usually frank 
3 
General well‐being 
Very well 
0 
 
Slightly below par 
1 
 
Poor 
2 
 
Very poor 
3 
 
Terrible 
4 
Extracolonic features 
Per manifestation 
1 
 
 
 


 
 
 
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17.2 
SCORING SYSTEM FOR THE CROHN’S DISEASE ACTIVITY INDEX 
 
Crohn’s Disease Activity Index 
Symptom/characteristic 
Count 
multiplier 
total 
Number of liquid and very soft stools 
(Sum of last 7 days) 
 
x 2 = 
 
Abdominal Pain 
(Sum of last 7 days) 
 
x 5 = 
 
General well‐being 
(Sum of last 7 days) 
 
x 7 = 
 
Other symptoms or findings of Crohn’s Disease 
      Arthritis or arthralgia 
      Iritis or uveitis 
      Skin or mouth lesions 
e.g. erythema nodosum, pyoderma 
gangrenosum, aphthous stomatis 
     Anal fissure, fistula or perirectal abscess 
     Other bowel related fistula 
   Fever above 37.5˚C during past week 
Number of ticked items: 
x 20 = 
 
Symptomatic treatment of diarrhea 
(e.g. loperamide, opiates) during past week 
     No = 0 
 
     Yes = 1 
 
x 30 = 
 
  
 
Abdominal mass 
     None = 0 
     Questionable = 2 
     Definite = 5 
 
x 10 = 
 
  
 
 
*Hematocrit     _ _  % 
f: 42 – HCT 
m: 47 – HCT 
 
=  +/‐   
 
 
x 6 = 
 
+/‐   
_ 
**Body Weight  __ __ . __kg 
Standard Weight  __ __ . __kg 
(1 – body weight/standard weight) 
 
 
= +/ ‐    
 
 
x 100 = 
 
+/‐   
_ 
 
**CDAI Sum: 
 
  
_ 
*HCT value from Visit, use central lab results.  For Screening period CDAI to determine eligibility for study, use 
HCT value from Screening laboratory results. 
**If using a CDAI calculator online tool, please document detail.  For manual calculation, please use Standard 
Weight/Height tables for males and females. 
 
 
 


 
 
 
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17.3 
SF‐36 QUALITY OF LIFE QUESTIONNAIRE 
 
Questionnaire not attached. SF‐36 v2 will be used for this study and provided to trial subjects 
in validated local language, IEC‐approved versions for completion at the required study visits 
(see www.SF‐36.org).  
 
 
 


 
 
 
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17.4 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Patients 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION  
1. The  World  Medical  Association  (WMA)  has  developed  the  Declaration  of 
Helsinki  as  a  statement  of  ethical  principles  for  medical  research  involving 
human patients, including research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant 
paragraphs. 
2. Although  the  Declaration  is  addressed  primarily  to  physicians,  the  WMA 
encourages other participants in medical research involving human patients to 
adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, 
including  those  who  are  involved  in  medical  research.  The  physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International 
Code of Medical Ethics declares that, “A physician shall act in the patient's best 
interest when providing medical care.” 
5. Medical progress is based on research that ultimately must include studies 
involving human patients. Populations that are underrepresented in medical 
research should be provided appropriate access to participation in research. 
6. In medical research involving human patients, the well‐being of the individual 
research patient must take precedence over all other interests. 
7. The  primary  purpose  of  medical  research  involving  human  patients  is  to 
understand  the  causes,  development  and  effects  of  diseases  and  improve 
preventive,  diagnostic  and  therapeutic  interventions  (methods,  procedures 
and  treatments).  Even  the  best  current  interventions  must  be  evaluated 
continually  through  research  for  their  safety,  effectiveness,  efficiency, 
accessibility and quality. 


 
 
 
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8. In medical practice and in medical research, most interventions involve risks 
and burdens. 
9. Medical research is patient to ethical standards that promote respect for all 
human patients and protect their health and rights. Some research populations 
are particularly vulnerable and need special protection. These include those 
who  cannot  give  or  refuse  consent  for  themselves  and  those  who  may  be 
vulnerable to coercion or undue influence. 
10. Physicians  should  consider  the  ethical,  legal  and  regulatory  norms  and 
standards for research involving human patients in their own countries as well 
as applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research patients set forth in this Declaration. 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the 
life,  health,  dignity,  integrity,  right  to  self‐determination,  privacy,  and 
confidentiality of personal information of research patients. 
12. Medical  research  involving  human  patients  must  conform  to  generally 
accepted  scientific  principles,  be  based  on  a  thorough  knowledge  of  the 
scientific  literature,  other  relevant  sources  of  information,  and  adequate 
laboratory  and,  as  appropriate,  animal  experimentation.  The  welfare  of 
animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that 
may harm the environment. 
14. The design and performance of each research study involving human patients 
must be clearly described in a research protocol. The protocol should contain a 
statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include 
information  regarding  funding,  sponsors,  institutional  affiliations,  other 
potential conflicts of interest, incentives for patients and provisions for treating 
and/or  compensating  patients  who  are  harmed  as  a  consequence  of 
participation in the research study. The protocol should describe arrangements 
for post study access by study patients to interventions identified as beneficial 
in the study or access to other appropriate care or benefits. 
15. The  research  protocol  must  be  submitted  for  consideration,  comment, 
guidance and approval to a research ethics committee before the study begins. 
This committee must be independent of the researcher, the sponsor and any 
other undue influence. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research patients set forth in this 
Declaration. The committee must have the right to monitor ongoing studies. 
The  researcher  must  provide  monitoring  information  to  the  committee, 
especially  information  about  any  serious  adverse  events.  No  change  to  the 
protocol may be made without consideration and approval by the committee. 
16. Medical  research  involving  human  patients  must  be  conducted  only  by 
individuals with the appropriate scientific training and qualifications. Research 


 
 
 
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on patients or healthy volunteers requires the supervision of a competent and 
appropriately  qualified  physician  or  other  health  care  professional.  The 
responsibility for the protection of research patients must always rest with the 
physician or other health care professional and never the research patients, 
even though they have given consent. 
17. Medical  research  involving  a  disadvantaged  or  vulnerable  population  or 
community is only justified if the research is responsive to the health needs and 
priorities of this population or community and if there is a reasonable likelihood 
that this population or community stands to benefit from the results of the 
research. 
18. Every medical research study involving human patients must be preceded by 
careful  assessment  of  predictable  risks  and  burdens  to  the  individuals  and 
communities involved in the research in comparison with foreseeable benefits 
to them and to other individuals or communities affected by the condition 
under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first patient. 
20. Physicians may not participate in a research study involving human patients 
unless  they  are  confident  that  the  risks  involved  have  been  adequately 
assessed and can be satisfactorily managed. Physicians must immediately stop 
a study when the risks are found to outweigh the potential benefits or when 
there is conclusive proof of positive and beneficial results. 
21. Medical  research  involving  human  patients  may  only  be  conducted  if  the 
importance of the objective outweighs the inherent risks and burdens to the 
research patients. 
22. Participation by competent individuals as patients in medical research must be 
voluntary.  Although  it  may  be  appropriate  to  consult  family  members  or 
community leaders, no competent individual may be enrolled in a research 
study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research patients and 
the confidentiality of their personal information and to minimize the impact of 
the study on their physical, mental and social integrity. 
24. In  medical  research  involving  competent  human  patients,  each  potential 
patient must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may 
entail, and any other relevant aspects of the study. The potential patient must 
be informed of the right to refuse to participate in the study or to withdraw 
consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential patients as well 
as to the methods used to deliver the information. After ensuring that the 
potential patient has understood the information, the physician or another 
appropriately qualified individual must then seek the potential patient’s freely‐
given  informed  consent,  preferably  in  writing.  If  the  consent  cannot  be 
expressed in writing, the non‐written consent must be formally documented 
and witnessed. 


 
 
 
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25. For  medical  research  using  identifiable  human  material  or  data,  physicians 
must normally seek consent for the collection, analysis, storage and/or reuse. 
There may be situations where consent would be impossible or impractical to 
obtain for such research or would pose a threat to the validity of the research. 
In  such  situations  the  research  may  be  done  only  after  consideration  and 
approval of a research ethics committee. 
26. When  seeking  informed  consent  for  participation  in  a  research  study  the 
physician  should  be  particularly  cautious  if  the  potential  patient  is  in  a 
dependent relationship with the physician or may consent under duress. In 
such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
27. For a potential research patient who is incompetent, the physician must seek 
informed consent from the legally authorized representative. These individuals 
must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the population represented 
by  the  potential  patient,  the  research  cannot  instead  be  performed  with 
competent persons, and the research entails only minimal risk and minimal 
burden. 
28. When a potential research patient who is deemed incompetent is able to give 
assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorized representative. 
The potential patient’s dissent should be respected. 
29. Research involving patients who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical 
or  mental  condition  that  prevents  giving  informed  consent  is  a  necessary 
characteristic of the research population. In such circumstances the physician 
should seek informed consent from the legally authorized representative. If no 
such  representative  is available  and  if  the  research cannot  be  delayed,  the 
study  may  proceed  without  informed  consent  provided  that  the  specific 
reasons for involving patients with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has 
been  approved  by  a  research  ethics  committee.  Consent  to  remain  in  the 
research should be obtained as soon as possible from the patient or a legally 
authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the 
publication of the results of research. Authors have a duty to make publicly 
available the results of their research on human patients and are accountable 
for the completeness and accuracy of their reports. They  should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive  results  should  be  published  or  otherwise  made  publicly  available. 
Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
31. The physician may combine medical research with medical care only to the 
extent that the research is justified by its potential preventive, diagnostic or 


 
 
 
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therapeutic  value  and  if  the  physician  has  good  reason  to  believe  that 
participation in the research study will not adversely affect the health of the 
patients who serve as research patients. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best current proven intervention, except in the 
following circumstances: 
• The use of placebo, or no treatment, is acceptable in studies where no current 
proven intervention exists; or 
• Where for compelling and scientifically sound methodological reasons the 
use  of  placebo  is  necessary  to  determine  the  efficacy  or  safety  of  an 
intervention and the patients who receive placebo or no treatment will not be 
patient to any risk of serious or irreversible harm. Extreme care must be taken 
to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to 
be informed about the outcome of the study and to share any benefits that 
result from it, for example, access to interventions identified as beneficial in 
the study or to other appropriate care or benefits. 
34. The  physician  must  fully  inform  the  patient  which  aspects  of  the  care  are 
related to the research.  The refusal of a patient to participate in a study or the 
patient’s decision to withdraw from the study must never interfere with the 
patient‐physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have 
been  ineffective,  the  physician,  after  seeking  expert  advice,  with  informed 
consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgment it offers hope of saving 
life,  re‐establishing  health  or  alleviating  suffering.  Where  possible,  this 
intervention should be made the object of research, designed to evaluate its 
safety  and  efficacy.  In  all  cases,  new  information  should  be  recorded  and, 
where appropriate, made publicly available.