Conditions: Anemia Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 84
Healthy volunteers: no

Brief summary:
This study is a nonrandomized, single arm, open-label study stratified by iron-deficiency status.

Detailed description:
The study aims to investigate the effect of FCM (without ESAs) on anemic cancer patients undergoing chemotherapy (with or without radiotherapy); stratified by status of iron deficiency (i.e. non-iron deficient vs. iron deficient patients ). The study will also try to find out whether serum level of Hepcidin and C reactive protein can correlate with response

Patients will receive one or two doses of FCM, based on the body weight and Hb level. Patients will be followed-up for a total of twelve weeks. The study is divided into a screening, treatment and follow-up phases and is expected to be completed in 12 months.

Arms:
arm 1: Patients will receive one or two doses of Ferric carboxymaltose (ferrinject), based on the body weight and Hb level.

* Ferric carboxymaltose will be administered as a single infusion if the needed dose is 1000 mg as a short IV infusion
* If the needed Ferric carboxymaltose dose is \> 1000 mg, an initial dose of 1000 mg will be given as a short IV infusion and the remaining dose will be given the week after in a similar fashion

Interventions: intervention 1: Ferric carboxymaltose (FCM)
Intervention descriptions: intervention 1: intravenous iron formulation

Protocol document:
Prot_000.pdf: 
The Study Will Be Conducted According To The Ethical Principles That Have Their Origin In The Declaration Of 
Helsinki, The Best Practices Described In The ICH E6 Guidance On Good Clinical Practice And The Local Laws 
Of Jordan 
 
Official title: 
The use of intravenous ferric carboxymaltose (FCM) without erythropoiesis-stimulating agents (ESA)  in the 
treatment of anemia in cancer patients undergoing chemotherapy with or without radiotherapy 
NCT number:  
NCT04246021 
 
Document date: 
August 03, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


King Hussein Cancer Center 
Clinical Trial Protocol 
 
PRT-INM-0615/09 V06 
 
Confidential, Do not distribute without approval 
Page 2 of 37 
 
 
 
Title 
 
The use of intravenous ferric carboxymaltose (FCM) without erythropoiesis-
stimulating agents (ESA)  in the treatment of anemia in cancer patients undergoing 
chemotherapy with or without radiotherapy 
Protocol No. 
 
PRT-INM-0615/09 
Release Date 
 
August 3, 2016 
Protocol Type 
 
Original Document (V06) 
Coordinating Center 
and Sponsor 
 
King Hussein Cancer Center 
Queen Rania Al-Abdullah street 
P.O.Box 1269 Al-Jubaiha 
Amman 11941 Jordan 
Tel:  +962-6-5300460 Ext:1408 
Principal 
Investigator 
 
Dr. Hikmat Abdel-Razeq 
King Hussein Cancer Center 
Co-Investigator 
 
Dr. Sameer Yasser 
King Hussein Cancer Center 
 
Dr. Hazem Abdulelah 
King Hussein Cancer Center 
 
Dr. Salwa Saadeh 
King Hussein Cancer Center 
 
Dr. Razan Malhas               
King Hussein Cancer Center 
 
Dr. Ghaida Khalaf 
King Hussein Cancer Center 
 
Dr. Rana AlJaber 
King Hussein Cancer Center 
 
Funding 
 
Contact Name 
Hikma Pharmaceuticals 
 
Study Centers 
 
King Hussein Cancer Center 


King Hussein Cancer Center 
Clinical Trial Protocol 
 
PRT-INM-0615/09 V06 
 
Confidential, Do not distribute without approval 
Page 3 of 37 
 
Medical Tests 
 
King Hussein Cancer Center’s Medical Laboratory 
Study Support 
 
Protocol Development and template production: Raja’ Sammour 
KHCC Office of Scientific Affairs and Research/Center of Research Shared 
Resources: 
Clinical Trials Unit: Ahmad Qawas, Rouba Ismaeil (CRCs) 
Data Management Unit: Hadeel Abdelhaq 
Biostatistics Unit: Dalia Rimawi, Ayat Taqash 
 
 


King Hussein Cancer Center 
Clinical Trial Protocol 
 
PRT-INM-0615/09 V06 
 
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Protocol Content 
 
1. Investigator Statement.................................................................................................. 5 
2. Clinical Trials Unit Role & Responsibility ........................................................................ 6 
3. List of Abbreviations ..................................................................................................... 7 
4. Summary ...................................................................................................................... 8 
5. Introduction ................................................................................................................ 11 
5.1 Background .............................................................................................................................................. 11 
5.1.1 Transfusions ...................................................................................................................................................... 11 
5.1.2 Erythropoiesis-stimulating agents (ESAs).......................................................................................................... 11 
5.1.3 Parenteral Iron ...................................................................................................... Error! Bookmark not defined. 
5.2 Aim of Study ................................................................................................ Error! Bookmark not defined. 
6. Study Objectives ......................................................................................................... 15 
6.1 Primary objectives: ...................................................................................... Error! Bookmark not defined. 
6.2 Secondary Objectives: ................................................................................. Error! Bookmark not defined. 
6.3 Study Endpoints ....................................................................................................................................... 14 
6.3.1 Primary Endpoint: ............................................................................................................................................. 14 
6.3.2 Secondary Endpoints: ............................................................................................ Error! Bookmark not defined. 
7. Rationale .................................................................................................................... 16 
7.1 Dose Rationale ............................................................................................. Error! Bookmark not defined. 
8. Patient Selection ......................................................................................................... 17 
8.1 Source Population and Sample size ............................................................. Error! Bookmark not defined. 
8.2 Eligibility Criteria .......................................................................................... Error! Bookmark not defined. 
8.2.1 Inclusion Criteria ................................................................................................... Error! Bookmark not defined. 
8.2.2 Exclusion Criteria ................................................................................................... Error! Bookmark not defined. 
8.3 Subject Withdrawal ..................................................................................... Error! Bookmark not defined. 
9. Investigational Product ............................................................................................... 19 
9.1 About Ferinject ® (FCM) .............................................................................. Error! Bookmark not defined. 
9.2 Storage, Dispensing and Accountability ...................................................... Error! Bookmark not defined. 
9.3 Dose and Administration ......................................................................................................................... 20 
9.4 Stopping Rules ......................................................................................................................................... 20 
10. Procedures and Assessments..................................................................................... 21 


King Hussein Cancer Center 
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10.1 Screening and Baseline .......................................................................................................................... 21 
10.2 Treatment phase ................................................................................................................................... 21 
10.3 Follow-up ................................................................................................... Error! Bookmark not defined. 
11. Adverse events .......................................................................................................... 26 
11.1 Definitions ................................................................................................. Error! Bookmark not defined. 
11.2 Management of Adverse Events ............................................................... Error! Bookmark not defined. 
11.3 Reporting Methodology ............................................................................ Error! Bookmark not defined. 
11.4 Follow-up of Adverse Events ..................................................................... Error! Bookmark not defined. 
12. Data management ............................................................ Error! Bookmark not defined. 
12.1 Case Report Forms .................................................................................... Error! Bookmark not defined. 
12.2 Data Entry and the study database ........................................................... Error! Bookmark not defined. 
12.3 Data Cleaning ............................................................................................. Error! Bookmark not defined. 
13. Statistical Considerations ................................................. Error! Bookmark not defined. 
13.1 Sample Size Calculation ............................................................................. Error! Bookmark not defined. 
13.2 Statistical Analysis for data presentation .................................................. Error! Bookmark not defined. 
13.3 Safety Analysis ........................................................................................... Error! Bookmark not defined. 
14. Quality Assurance and Compliance ............................................................................ 30 
14.1 Quality Assurance of Conduct ............................................................................................................... 30 
14.2 Quality Control of Data .......................................................................................................................... 30 
14.3 Deviations and Violations ...................................................................................................................... 30 
14.4 Retention of Documents ....................................................................................................................... 30 
15. Reporting and Publication ......................................................................................... 31 
15.1 Progress and Final Reports .................................................................................................................... 31 
15.2 Publication of Results ............................................................................................................................ 31 
16. Ethical Considerations ............................................................................................... 32 
16.1 Risk to Benefit Analysis .......................................................................................................................... 32 
16.2 Institutional Review Board .................................................................................................................... 32 
16.3 Ethical Conduct of the Study ................................................................................................................. 32 
16.4 Informed Consent .................................................................................................................................. 33 
16.5 Confidentiality and Privacy .................................................................................................................... 33 
16.6 Rights and Liabilities .............................................................................................................................. 33 
16.7 Premature Termination of the Study .................................................................................................... 34 
17. References ................................................................................................................ 36 
 


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1. Investigator Statement 
1. The INVESTIGATOR shall be responsible for all the acts of the sub-investigator(s) and any party 
designated by the Investigator to fulfill the Investigator’s obligations under this PROTOCOL.  
2. The INVESTIGATOR shall procure that sub-investigator(s) and any party designated by the 
Investigator complies with all regulatory requirements and mandates for the conduct of clinical trials.  
3. The INVESTIGATOR will assure that sub-investigator(s) and any party designated by the Investigator 
to support the conduct of this trial will be qualified and have attended the required training planned for 
this trial. 
4. The INVESTIGATOR shall protect the rights and welfare of patients participating in the CLINICAL 
TRIAL in accordance with the PROTOCOL. 
5. The INVESTIGATOR shall obtain and maintain any and all licenses, permits, approvals, and patient 
informed consent documents required by the Protocol and Regulations for conducting of the relevant 
part of the Clinical Trial from the INSTITUTION, IRB/EC and/or any other authorized body. Specifically, 
INVESTIGATOR shall obtain a signed and legally valid written Informed Consent Form from each 
potential participant in the Clinical Trial (or his/her legal guardian, as appropriate) before initiating any 
procedures specified in the Protocol. 
 
I have revised this version of the protocol and agree to conduct the trial in accordance with all the 
requirement set in the protocol, the applicable laws and regulations and in accordance with the ethical 
principles outlined in the declaration of Helsinki. 
__________________________________________ 
Principal Investigator Name, Signature & Date 
 
 


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2. Clinical Trials Unit Role & Responsibility 
The clinical trials unit primary job is to support the execution and conduct of clinical trials at KHCC. Such 
support includes but is not limited to the development of trial related documents. Such documents used 
include the source template for this clinical trial protocol which may not necessarily be fully completed by 
the unit in response to a request from the investigator. The investigator may have elected to complete his 
protocol by himself. 
The involvement of the clinical trial unit is generally arranged with the Principal Investigator and defined for 
any of its employees in the delegation sheet set for the trial. Such arrangements are finalized during an 
initiation meeting planned for the trial before the first patient is recruited. Tasks that will be carried for this 
protocol: 
1. 
Assistance with protocol development 
2. 
Assistance with the development of the study CRFS and ICFs 
3. 
Training the trial team on the study protocol 
4. 
Development of the trial master file 
5. 
Coordination with the biostatistics unit and data management unit support 
6. 
Following –up on the study conduct with the investigator. 
7. 
Assist investigator in completing the trial master file and archiving of the trial for the 
planned period of retention. 
8. 
Registration of the Trial to a public registry if required (clinicaltrial.gov) 
 
 
_________________________ 
Clinical Trial Unit Head Signature 
 
 


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3. List of Abbreviations 
AE 
Adverse Event 
AID 
Absolute Iron Deficiency 
CAA  
Cancer Associated Anemia 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case report form 
CRP 
C-Reactive Protein 
ECOG 
Eastern Cooperative Oncology Group 
ESA 
Erythropoiesis-Stimulating Agents 
FCM 
Ferric Carboxymaltose 
FID 
Functional Iron Deficiency 
Hb 
Hemoglobin 
ICH 
International Conference on Harmonization 
IDA 
Iron Deficiency Anemia 
IRB 
Institutional Review Board 
JFDA 
Jordan Food and Drug Administration 
KHCC 
King Hussein Cancer Center 
QOL 
Quality of Life 
Rx History 
Drug History 
SAE 
Serious Adverse Event 
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
US FDA 
the United States Food and Drug Administration 
WMA 
World Medical Association 
 
 


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4. Summary: 
PROTOCOL TITLE 
 
The use of intravenous ferric carboxymaltose (FCM) without erythropoiesis-
stimulating agents (ESA)  in the treatment of anemia in cancer patients 
undergoing chemotherapy  with or without radiotherapy 
STUDY OBJECTIVES 
 
The study aims to investigate the effect of FCM (without ESAs) on anemic cancer 
patients undergoing chemotherapy (with or without radiotherapy); stratified by 
status of iron deficiency (i.e. non-iron deficient vs. iron deficient patients ). The 
study will also try to find out whether serum level of Hepcidin and CRP can 
correlate with response.  
 
STUDY ENDPOINTS 
 
Primary Endpoint: 
 
Response Rate: Percentage of patients with Hb increment of at least 1.0 
gm/dL. 
 
Proportion of patients achieving correction of anemia (Hb >11.0 gm/dL) 
 
The mean Hb change from baseline to week 12 
Secondary Endpoints: 
 
Response in relation to Hepcidin level.  
 
Response in relation to CRP level. 
 
Response in relation to base line iron deficiency status; iron-deficient or 
not. 
 
Parentage of  patients who will  require blood transfusion or ESA 
treatment  
STUDY DESIGN 
 
This study is a nonrandomized, single arm, open-label study stratified by iron-
deficiency status.  
Patients will receive one or two doses of FCM, based on the body weight and Hb 
level. Patients will be followed-up for a total of twelve weeks. The study is 
divided into a screening, treatment and follow-up phases and is expected to be 
completed in 12 months. 
INVESTIGATIONAL 
PRODUCT 
 
Ferrous Carboxymaltose (Ferrinject®) 1000 mg/20 ml 
The dose will be based on the following regimen: 
 
Baseline Hb (g/dL) 
Body Weight (Kg) 
<70 
>70 
<10 
1500 mg 
2000 mg 
>10 
1000 mg 
1500 mg 
 
STUDY POPULATION 
 
One hundred (100) anemic cancer patients undergoing chemotherapy (with or 
without radiotherapy) identified as eligible per selection criteria of the study will 
be enrolled. 
A patient is considered eligible if he meets all the inclusion criteria and none of 
the exclusion criteria. 


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INCLUSION CRITERIA 
 
 
Patient is an adult ≥ 18 years old at the time of informed consent. 
 
Patient has pathologic diagnosis of solid tumor (breast cancer, 
colorectal, lung, sarcoma, head & neck, sarcoma, genitourinary  or 
gynecological cancer).  
 
Patients who started chemotherapy (with or without radiotherapy) or  
planned to receive chemotherapy for at least 12 weeks. 
 
Patient has an Eastern Cooperative Oncology Group (ECOG) 
performance status  
between 0 and 2. 
 
Patient with Hb ≤11 g/dL. 
 
Patient has a Life expectancy  at least 6 months.  
 
Adequate hepatic & renal function defined as a serum aspartate 
aminotransferase or alanine aminotransferase level that are no more 
than 3 times the upper limit of the normal range, a serum bilirubin level 
that is no more than 2 times the upper limit of the normal range and a 
serum Creatinine level of less than 2 mg per deciliter. 
 
Patient is able to understand and provide informed consent to 
participate in the study. 
 
EXCLUSION CRITERIA 
 
 
Patient has Hb < 8.0 g/dL  
 
Patient presenting with hematologic malignancy including any of the 
following: Acute Leukemia, MDS (Myelodysplastic Syndromes), CML, CLL, 
Multiple Myeloma, Myelodysplastic syndrome and lymphoma with bone 
marrow involvement 
 
Prior gastric surgery. 
 
Patients on definitive radiotherapy alone. 
 
Patients with relevant history (within six weeks) or clinical evidence of 
hemolysis or active bleeding that could, in the investigator's judgment, be 
a potential cause for the anemia (no gross hematuria, hemoptysis, 
hematochezia or melena and negative stool for hemoccult-at least one 
reading) 
 
Presence of other nutritional anemia; deficiency of vitamin B12<187pg/ml 
and deficiency of Folate<3.1ng/ml according to the local laboratory 
normal ranges. 
 
Patient has Iron overload (Serum Ferritin > 800 ng/ml or Transferrin 
saturation (TSAT) > 40%) 
 
Patient is pregnant or lactating. 
 
Patient has a personal or family history of hemochromatosis. 
 
Patient has hypersensitivity to any form of IV iron. 
 
Patient has received red blood cells (RBCs) transfusion or used 
erythropoietin within 2 weeks of enrollment into the study. 
 
Patient has received any form of IV iron within the last 12 weeks 
 
Patient has received oral iron supplements within 1 month of enrollment 
to the study, except for multivitamin supplements containing less than 
30mg iron. 
 
EFFICACY ASSESSMENTS 
 
 
Hb at baseline and at 3,6,9 and 12 weeks 


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SAFETY ASSESSMENTS 
 
 
Serum ferritin level (baseline and at 12 weeks) 
 
Liver Enzymes (ALT, AST), Alk Phosphatase, GGT, LDH and serum 
phosphate levels at base line and at week-3 
 
Record all adverse events 
OTHER ASSESSMENTS 
 
 
CRP levels at baseline 
 
Hepcidin at baseline 
STUDY SITE 
 
King Hussein Cancer Center (KHCC) 
ETHICAL 
CONSIDERATIONS 
 
 
The study will be submitted for ethical review and approval before 
execution. 
 
Informed consent will be obtained from study patients before 
implementing any study procedure. 
STATISTICAL PLAN 
 
Descriptive statistics will be used to present the two groups baseline 
characteristics and disease information.  
Analysis will be done for the two groups separately:  
o 
Group I: Patient Iron-deficiency anemia based on iron studies at 
base line 
o 
Group II: Patient with non-iron deficiency anemia  
 
Hb test results will be presented as mean, median and range through all 
twelve weeks.  
 
Average percent change from baseline will be used to show the changes 
of Hb level. Comparison between means of Hb level will be made 
between the baseline Hb and Hb levels in the following weeks using 
Paired T-test.   
 
Response to IV iron therapy will be assessed in relation to Hepcidin and 
CRP levels. 
 
Univariate analysis will be used to assess the effect of patient 
characteristics and disease variables on the response using Chi square 
test or fisher’s exact test. 
 
Adjusting for all significant factors that may affect the response will be 
done using Logistic regression. 
 
Odds ratio out of the Logistic regression will be reported with their 
corresponding 95% CI. 
 
A significance criterion of p< 0.05 will be used in the analysis.  
All analyses will be performed using SAS version 9.4 (SAS Institute Inc, Cary, NC). 
 
 


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5. Introduction 
5.1 Background 
Anemia, defined as an inadequate circulating level of hemoglobin, is a common complication of cancer and 
its treatment; especially in patients undergoing chemotherapy and/or radiotherapy. It may arise from the 
underlying disease, bleeding, poor nutrition, chemotherapy, or radiation therapy. Prevalence of anemia 
varies between 30 and 60 %. Preliminary studies suggest that survival and loco-regional control after 
radiation therapy, especially in head and neck and cervical cancers, may be compromised by anemia.1,2 
Anemia often worsens symptoms such as fatigue, weakness, and dyspnea, and thus may have a negative 
impact on the quality of life (QOL) and performance status of patients with cancer. Thus, to improve physical 
functioning, QOL, and prognosis in patients with cancer, it would be reasonable to take a proactive approach 
in identifying populations who need treatment for cancer-associated anemia (CAA) and provide a timely 
management.3,4,5,6 
5.1.1 Transfusions 
Blood transfusion is an effective way to replace depleted Hb within a short period, but the effect is, 
unfortunately, temporary and can cause serious adverse risks and increase mortality7.  
5.1.2 Erythropoiesis-stimulating agents (ESAs) 
ESAs were proposed as an effective treatment for anemia for several years. Randomized clinical 
trials in patients with CAA has demonstrated that ESAs produced significant increases in Hb level, 
decreased transfusion requirements, and improved QOL8,9,10,11,12,13. However, 30%-50% of patients 
do not respond to such agents. Lack of response to erythropoietin stimulation in patients with 
cancer is partly attributed to the functional iron deficiency state, in which the high rate of 
erythropoiesis exceeds the delivery of usable iron, despite adequate iron stores. Many randomized 
trials were conducted to examine the role of IV iron in addition to ESAs in the treatment of anemia in 
patients with cancer14,15,16,17. Many of these studies showed improvement in ESA response, time to 
maximal response, reduction in ESA dose, and improvement in QOL parameters, when measured, in 
favor of the combination over ESAs alone. The observed benefit was independent of baseline iron 
parameters. 
Several recent studies had raised serious concerns related to shortened overall survival, or time to 
tumor progression in patients treated with ESAs especially among patients whose Hb reached levels 


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beyond 12 g/dL. These concerns, in addition to higher incidence of thromboembolism, resulted in a 
significant decline in the use of these agents especially among potentially curable cancers18,19,20,21. In 
2008, Centers for Medicare and Medicaid Services recommended through new guidelines that ESAs 
are not to be used in patients with long life expectancy. 
5.1.3 Parenteral Iron 
Iron plays an important role in hemoglobin synthesis and an inadequate supply is a major element in 
the pathogenesis of anemia. Intravenous iron therapy is routinely used to treat iron-deficiency 
anemia especially so in patients with severe anemia and in those who failed or could not tolerate 
oral formulations.  Absolute iron deficiency (AID) occurs when iron delivery is impaired because iron 
stores are depleted (serum ferritin < 100 ng/mL; transferrin saturation (TSAT) < 20%).  
Functional iron deficiency (FID), on the other hand, occurs when access to iron stores is restricted or 
too slow to keep-up with the process of erythropoiesis22. In cancer, tumor cells interact with the 
immune system leading to a chronic state of inflammation. Pro-inflammatory cytokines are released 
leading also to the release of Hepcidin; a small (25 amino acids) peptide produced by the liver. 
Hepcidin is a regulator in iron homeostasis. It binds to ferroportin-expressing cells, inhibiting iron 
transport across cell membranes and decreasing accessibility to the iron stores. At high enough 
circulating levels, it impairs gastrointestinal absorption of dietary iron. This state of blocked release 
from stores and inhibited absorption leads to an increased frequency of iron-restricted 
erythropoiesis. Hence, it was proposed that patients identified with FID may benefit from the extra 
doses of iron to overcome the negative effect of Hepcidin23,24,25,26. 
5.2 Aim of Study 
In a previous pilot study conducted by our group, we investigated the use of IV iron without ESAs in a group 
of non-iron deficient anemic cancer patients undergoing chemotherapy.  Patients were given 12 weekly 
short infusions of ferric sucrose while on chemotherapy. The mean increment in hemoglobin level for the 15 
patients who completed at least 9 treatments was 1.7 g/dL (median, 1.1 g/dL; range, -1.9 g/dL to 3.2 g/dL).  
Five (20.0%) patients were transfused and considered as treatment failures. No treatment-related adverse 
events were reported.  
With such results and to move forward with the investigation, we have considered using a new intravenous  
iron formulation. Ferric carboxymaltose (FCM), is widely used to treat iron deficiency anemia in different 
clinical settings including pregnancy-related and in chronic renal failure patients.27. 


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Therefore, the study aims to investigate the effect of FCM without ESAs on anemic cancer patients 
undergoing chemotherapy or radiotherapy; stratified by status of iron deficiency (i.e. non-iron deficient vs. 
iron deficient patients). 
Furthermore, we aim to investigate the value of Hepcidin and also CRP (which is closely associated with 
inflammatory cytokines, as well) as predictors of response. 
 
 
 
 
 


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6. Study Objectives 
6.1 Primary objectives: 
 
Assess the response to FCM in each strata 
6.2 Secondary Objectives: 
 
Assess the utility of hepcidin and CRP in predicting response to FCM 
 
Assess the effect of FCM on the need for blood transfusions 
 
Assess the effect of FCM on the need for ESAs 
6.3 Study Endpoints 
6.3.1 Primary Endpoint: 
 
Response Rate: Percentage of patients with Hb increment of at least 1.0 gm/dL. 
 
Proportion of patients achieving correction of anemia (Hb >11.0 gm/dL) 
 
The mean Hb change from baseline to week 12 
6.3.2 Secondary Endpoints: 
 
Response in relation to Hepcidin level.  
 
Response in relation to CRP level. 
 
Response in relation to base line iron deficiency status; iron-deficient or not. 
 
Parentage of  patients who will  require blood transfusion or ESA treatment 


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7. Rationale 
Unresolved anemia is a problem in cancer patients. If it remains uncorrected, it will negatively impact 
patient response to treatment and QOL. With the limitations set on use of ESAs in cancer and absence of 
alternatives that lower the need for transfusion, iron loading is a tempting choice to explore. Trials on the 
use of iron as a lone treatment are generally few. This study is important in that it allows assessing FCM in 
both AID and FID. It will shed light on a different dosing regimen and help build understanding on the use of 
Hepcidin and CRP as predictors of response. 
7.1 Dose Rationale 
Ferric carboxymaltose in a single dose, or two, is assumed sufficient to produce a clinically observable 
change in the status of hemoglobin in 12 weeks’ time comparable to what has been achieved with small 
frequent doses. This has been demonstrated before using FCM in FID and lymphoid malignancies patients. 
FCM iron complex allows rapid increase in iron levels peaking within approximately an hour. Total serum 
iron levels then rapidly decline reaching normal levels within 24 to 72 hr after infusion. This allows sufficient 
amount of time for the body to engage the circulating iron in erythropoiesis and hence induce the proposed 
response. Though single high FCM dose is expected to be safe and tolerable, dosing of patients will be based 
on body weight to lower any chances of unwanted risks. 
 


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8. Patient Selection 
8.1 Source Population and Sample size 
The study aims to enroll anemic cancer patients planned to receive chemotherapy or radiotherapy. The 
study sample will be selected to fulfill the selection criteria. The patient is eligible if he meets all the inclusion 
criteria and none of the exclusion criteria. The estimated sample size necessary in each strata is 50 which can 
be easily recruited in 10 months. 
8.2 Eligibility Criteria 
Evaluation of eligibility is the sole responsibility of the PI and will be documented in the patient CRF. If 
deviations from selection criteria occur, the PI will provide the proper justifications for continued inclusion of 
the patient in the study which will be documented in the CRF. 
8.2.1 Inclusion Criteria 
 
Patient is an adult ≥ 18 years old at the time of informed consent. 
 
Patient has pathologic diagnosis of solid tumor (breast cancer, colorectal, lung, sarcoma, head & 
neck, sarcoma, genitourinary  or gynecological cancer).  
 
Patients who started chemotherapy (with or without radiotherapy) or  planned to receive 
chemotherapy for at least 12 weeks. 
 
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status  
between 0 and 2. 
 
Patient with Hb ≤11 g/dL. 
 
Patient has a Life expectancy  at least 6 months.  
 
Adequate hepatic & renal function defined as a serum aspartate aminotransferase or alanine 
aminotransferase level that are no more than 3 times the upper limit of the normal range, a serum 
bilirubin level that is no more than 2 times the upper limit of the normal range and a serum 
Creatinine level of less than 2 mg per deciliter. 
 
Patient is able to understand and provide informed consent to participate in the study. 
8.2.2 Exclusion Criteria 
 
Patient has Hb < 8.0 g/dL  


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 
Patient presenting with hematologic malignancy including any of the following: Acute Leukemia, 
MDS, CML, CLL, Multiple Myeloma, Myelodysplastic syndrome and lymphoma with bone marrow 
involvement 
 
Prior gastric surgery. 
 
Patients on definitive radiotherapy alone. 
 
Patients with relevant history (within six weeks) or clinical evidence of hemolysis or active bleeding 
that could, in the investigator's judgment, be a potential cause for the anemia (no gross 
hematuria, hemoptysis, hematochezia or melena and negative stool for hemoccult-at least one 
reading) 
 
 Presence of other nutritional anemia; deficiency of vitamin B12 <187 pg/ml  and deficiency of 
Folate < 3.1 ng/ml  according to the local laboratory normal ranges 
 
Patient has Iron overload (Serum Ferritin > 800 ng/ml or Transferrin saturation (TSAT) > 40%) 
 
Patient is pregnant or lactating. 
 
Patient has a personal or family history of hemochromatosis. 
 
Patient has hypersensitivity to any form of IV iron. 
 
Patient has received red blood cells (RBCs) transfusion or used erythropoietin within 2 weeks of 
enrollment into the study. 
 
Patient has received any form of IV iron within the last 12 weeks 
 
Patient has received oral iron supplements within 1 month of enrollment to the study, except for 
multivitamin supplements containing less than 30mg iron. 
8.3 Subject Withdrawal 
Patients are free to withdraw from the study at any time without prejudice or loss of benefits to which they 
are otherwise entitled. The investigator may remove a patient from the study if, at his discretion, the 
participation is seen to jeopardize the patient safety or for administrative or behavioral reasons. Neither the 
investigator nor the study supporting staff will try to coerce patients to continue participating in the study 
against their will. The withdrawal case with reasons will be documented. Withdrawn subjects will be 
replaced to have a complete set of 50 analyzable subjects in each strata. 
Additionally, patient will be dropped out and will be considered treatment failure if  
1 .Receive ESA or blood transfusion for medical reasons not related to the study 
2. if they Develop a grade IV toxicity of any kind in the week between the initial and the remaining   
dose that is possibly related to study drug. 
 


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9. Investigational Product 
9.1 About Ferinject ® (FCM)28 
FCM is a polynuclear iron (III)-hydroxide carbohydrate complex. FCM has been designed to enable 
controlled, systemic release of iron within cells of the reticuloendothelial system, minimizing the risk of 
releasing large amounts of iron into the serum.  
The structure of polynuclear iron (III) hydroxide core resembles that of ferritin: the iron is trapped in the core 
in a non-redox active form and, therefore, toxic effects from weakly-bound iron are limited. The complex has 
an average molecular weight of 150,000 Da. 
Following IV administration, FCM is metabolized by the RES in the spleen and the liver and the iron is 
delivered to the bone marrow. 
Adverse drug reactions observed during clinical trials and post-marketing experience: 
System Organ Class 
Common (≥1/100 to 
<1/10) 
Uncommon (≥1/1000 to 
<1/100) 
Rare (≥1/10000 to 
<1/1000) 
Immune system disorders  
Hypersensitivity 
Anaphylactoid reactions 
Nervous system disorders Headache, dizziness 
Paraesthesia, dysgeusia 
Loss of consciousness(3) 
Psychiatric disorders 
 
 
Anxiety(4) 
Cardiac disorders 
 
Tachycardia 
 
Vascular disorders 
Hypertension 
Hypotension, flushing 
Phlebitis, syncope(4), 
presyncope(4) 
Respiratory, thoracic and 
mediastinal disorders 
 
Dyspnoea 
Bronchospasm(4) 
Gastrointestinal disorders Nausea 
Vomiting, dyspepsia, 
abdominal pain, 
constipation, diahorrea 
Flatulence 
Skin and subcutaneous 
tissue disorders 
 
Pruritus, urticaria, 
erythema, rash(1) 
Angioedema(4), pallor(3), 
and face oedema(3) 
Musculoskeletal and 
connective tissue 
disorders 
 
Myalgia, back pain, 
arthralgia, muscle spasms 
 
General disorders and 
administration site 
conditions 
Injection site reactions(2) 
Pyrexia, fatigue, chest 
pain, oedema peripheral, 
chills 
Rigors, malaise 


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System Organ Class 
Common (≥1/100 to 
<1/10) 
Uncommon (≥1/1000 to 
<1/100) 
Rare (≥1/10000 to 
<1/1000) 
Investigations 
Alanine aminotransferase 
increased 
Aspartate 
aminotransferase 
increased, gamma-
glutamyltransferase 
increased, blood lactate 
dehydrogenase increased, 
blood alkaline phosphatase 
increased 
 
Metabolism and 
nutritional disorders 
Hypophosphataemia 
 
 
 
1 Includes the following preferred terms: rash (individual ADR frequency determined as uncommon) and 
rash erythematous, -generalised, -macular, -maculo-papular, -pruritic (all individual ADRs are frequency 
determined as rare). 
2 Includes the following preferred terms: infusion site burning, -pain, -bruising, -discolouration, -
extravasation, -irritation, reaction, (all individual ADRs are frequency determined as uncommon) and -
paraesthesia (individual ADR frequency determined as rare). 
3 ADRs exclusively reported in the post-marketing setting. 
4 ADRs reported in the post-marketing setting which were also observed in the clinical setting. 
Note: ADR = Adverse drug reaction. 
 
9.2 Storage, Dispensing and Accountability 
The study product will be stored in a secure drug cabinet at KHCC outpatient pharmacy at less than 30 C. 
The storage area is separate from the rest of products within the pharmacy. It is access limited to a 
dedicated Investigational Drug Pharmacist (IDP) who will be responsible to dispense the product for use in 
the study. Storage conditions will be monitored throughout the study and if there are aberrant conditions 
they will be reported, justified and corrected as seen appropriate. 
Dispensing will be based on paper prescriptions signed by the investigator. The IDP will dispense the 
required vials to the clinical research coordinator (CRC). The IDP will track product dispensing through the 
accountability logs. Product documentation for shipment, storage and allocation will be maintained in the 
pharmacy files until end of study. Documents will then be transferred to the trial master file (TMF). 
 
 


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9.3 Dose and Administration 
FCM will be administered based on the following: 
Baseline Hb (g/dL) 
Body Weight (Kg) 
<70 
>70 
<10 
1500 mg 
2000 mg 
>10 
1000 mg 
1500 mg 
 
9.4 Stopping Rules 
There are no formal stopping rules for the study but should the patient develop anaphylaxis or para-venous 
leak is observed, the infusion will be interrupted and patient treatment will be left to the attending 
physician. 
 
 
 


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10. Procedures and Assessments 
All study procedures will be conducted at KHCC. The investigator and supporting study team will be 
responsible to document all related procedures and assessments done in the appropriate source document 
and the patient CRFs. All procedures and assessments will support the safety and validity of conclusions 
drawn from the study protocol. 
10.1 Screening and Baseline 
Patients will be invited to participate in the study once they are diagnosed as anemic and are planned to 
receive chemotherapy or radiotherapy within seven days. The Investigator will discuss the study with the 
patient and acquire a written informed consent before starting any study related procedure. If the patient 
agrees to participate the following will be carried out: 
1. Obtaining medical and oncologic history 
2. Physical Examination 
3. Vital Signs 
4. Laboratory assessments will include:  
 
Hemoglobin, reticulocyte count 
 
Serum iron, ferritin, total iron binding capacity, TSAT 
 
Vitamin B12, folate 
 
Creatinine 
 
Phosphorous 
 
Liver function test including: total bilirubin, ALT, AST, LDH, GGT 
 
Serum Hepcidin 
 
CRP  
 
Pregnancy test 
 
5. Evaluation of ECOG performance status 
10.2 Treatment phase 
 
Patients will receive their prescribed FCM infusion in the KHCC  infusion areas or in the inpatients 
units.  
 
FCM will be administered as a single infusion if the needed dose is 1000 mg as a short IV infusion, 
diluted in 250mL  of 0.9 saline over 15-30 minutes. 


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 
If the needed FCM dose is  > 1000 mg, an initial dose of 1000 mg will be given as above and the 
remaining dose will be given the week after in a similar fashion if the remaining dose is 1000mg; if 
the remaining dose is 500mg, then it will be given as a short IV infusion, diluted in 100mL  of 0.9 
saline over a minimum period of 6 minutes. 
 
 During the infusion, the patient will be monitored for adverse events. 
10.3 Follow-up 
 
Hemoglobin assessments will be carried out every 3 weeks in line with the chemotherapy protocol 
visits and at week 12.  
 
Laboratory monitoring of ALT, AST, LDH, Alk-phosphatase, GGT and  phosphorous will be done at 
week-3 
 
Ferritin level will be repeated at week-12 
 
A total of four follow-up visits are required for the study: weeks 3, 6, 9 and 12. 
 
 
 


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Figure 1 Study Scheme 
 
 
 
Enrolment and stratifying  
Functional Iron Deficiency (FID) 
Absolute  Iron Deficiency (AID) 
Weight: 
< 70 Kg 
Dose of FCM:  
Hb < 10 gm/dl : 1500mg 
Hb ≥ 10 gm/dl: 1000mg 
Weight: 
≥70 Kg 
Dose of FCM:  
Hb < 10 gm/dl : 2000mg 
Hb ≥ 10 gm/dl: 1500mg 
Weight: 
< 70 Kg 
Dose of FCM:  
Hb < 10 gm/dl : 1500mg 
Hb ≥ 10 gm/dl: 1000mg 
Weight: 
≥70 Kg 
Dose of FCM:  
Hb < 10 gm/dl : 2000mg 
Hb ≥ 10 gm/dl: 1500mg 
Follow-up: 3, 6, 9 and 12 weeks 
Screening of patients  


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Table 1 Study Procedures Schedule 
 
Procedure 
Screening 
Phase 
 
 
Treatment Phase  
Follow up Phase 
Week 3  
± 3 days 
Week 6 
± 3 days 
Week 9 
± 3 days 
Week 12 
± 3 days 
Week-0 
Week-1 
Week-2 
Medical and oncologic 
history 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
X 
X 
X 
X 
ECOG performance status 
X 
 
 
X 
X 
X 
X 
Vital Signs 
X 
 
 
X 
X 
X 
X 
Hb  
X 
 
 
X 
X 
X 
X 
Reticulocyte count 
X 
 
 
 
 
 
 
Serum iron  
X 
 
 
 
 
 
 
Serum ferritin  
X 
 
 
 
 
 
X 
Total Iron Binding Capacity 
(TIBC) 
X 
 
 
 
 
 
 
TSAT 
X 
 
 
 
 
 
 
Hepcidin levels 
X 
 
 
 
 
 
 
CRP 
X 
 
 
 
 
 
 
vitamin B12  
X 
 
 
 
 
 
 
Folate 
X 
 
 
 
 
 
 
Creatinine 
X 
 
 
 
 
 
 
Bilirubin total 
X 
 
 
 
 
 
 
AST  
X 
 
 
X 
 
 
 
ALT 
X 
 
 
X 
 
 
 
Alkaline phosphatase 
X 
 
 
X 
 
 
 
Gamma-
glutamyltransferase (GGT) 
X 
 
 
X 
 
 
 
LDH 
X 
 
 
X 
 
 
 
Phosphorous level 
X 
 
 
X 
 
 
 
B-hCG (pregnancy test)  
X 
 
 
 
 
 
 
Monitoring of adverse 
events 
X 
 
 
X 
X 
X 
X 
FCM infusion 
 
X 
X  
(when needed) 
 
 
 
 
 
 


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11. Adverse events 
The best effort will be done by the investigator or study supporting staff to record all adverse events that 
arise during the study with possible causality and relationship to the study treatment. The proper channels 
to process these events will be as described in this section. All adverse events reporting will be done with 
reference to ICH E6: Guidance on Good Clinical Practice29 and the ICH E2D: Post Approval Safety Data 
Management30, and in-house policies. 
11.1 Definitions 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporarily associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
Adverse Drug Reaction (ADR): all noxious and unintended responses to a medicinal product related to any 
dose should be considered adverse drug reactions.  
The phrase ‘responses to a medicinal product’ means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility i.e. the relationship cannot be ruled out.  
Regarding marketed medicinal products, a response to a drug which is noxious and unintended and which 
occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of 
physiologic function. 
A reaction, in contrast to an event, is characterized by the fact that a causal relationship between the drug 
and the occurrence is suspected. For regulatory reporting purposes, if an event is spontaneously reported, 
even if the relationship is unknown or unstated, it meets the definition of an adverse drug reaction.  
Serious Adverse Events (SAE) or Serious Adverse Drug Reaction (Serious ADR): any untoward medical 
occurrence that at any dose: 
 
Results in death, 
 
Is life-threatening, 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
 
Results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
 
is a medically important event or reaction 


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Unexpected ADR: An ADR whose nature, severity, specificity, or outcome is not consistent with the term or 
description used in local/regional product labeling (e.g. package insert or summary of product 
characteristics) should be considered unexpected. If it is uncertain whether the ADR is expected or 
unexpected, the ADR should be treated as unexpected. 
An expected ADR with a fatal outcome should be considered unexpected unless the local/regional product 
labeling specifically states that the ADR might be associated with a fatal or life threatening outcome. 
11.2 Management of Adverse Events 
Standard medical care will be followed in managing adverse events reported during the study in compliance 
with in house policies and procedures. The PI may ask for additional tests to be done if the adverse event 
warrants an investigation. The patient will be treated free of charge for all study related events. If the 
patient is to be discontinued from the study because of the AE he/she will be followed up until the AE abates 
or returns to baseline. 
11.3 Reporting Methodology 
All study support staff that are in contact with the patients during the study are responsible to note down 
any adverse events or complaints reported by patients and report them back to the PI. During their hospital 
stay, patients will be questioned for adverse events. The team will avoid leading the patient in their adverse 
event interview. The patient will be asked to describe the severity of their complaint and specify an onset 
date. Open-ended question will be considered by the study team. The seriousness of the event will be 
assessed by the investigator and he will determine whether it is expected or unexpected based on the 
definitions described. Clinical judgment will be used with consideration to the product labeling and known 
literature. 
All AE that are both serious and unexpected will be subject to expedited reporting. For serious unexpected 
AE with fatal or life threatening consequences, the investigator will notify the JFDA and the institutional 
review board (IRB) as soon as possible but no later than 7 calendar days from the first time the AE comes to 
his/her attention. A complete report will be submitted as soon as possible within 8 additional calendar days. 
Those serious and unexpected ADE/ADR that are not fatal or life threatening will be reported to the JFDA 
and IRB as soon as possible but no later than 15 calendar days from the first time the AE comes to the 
knowledge of the investigator with a reasonable suspected causal relationship: A full report will be written 
to describe the events using the CIOMS I form. The investigator will contact the marketing authorization 
holder (MAH) of the suspected product with the report in the same manner as would he/she do with the 
JFDA and IRB if required.  


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For AE that is not serious whether expected or unexpected do not follow expedited reporting. Within the 
scope of definitions described above, recording of AE will include description, intensity onset, duration, end 
and outcome. An evaluation of relationship to the study product will be done according to the following 
terms: Presence or absence of reasonable possibility that the AE is related to the study drug. AEs will be 
captured in the case report form. The MAH will not be informed about these AE. 
11.4 Follow-up of Adverse Events 
All patients will be followed up until recovery or resolution of the AE. The priority for follow-up will be for 
cases which are 1) serious and unexpected, 2) serious and expected, and 3) non-serious and unexpected. 
Follow-up information can be through a telephone call and/or site visits (not necessarily related to the 
predefined study visits or calls). If the patient refuses to provide the information or to come for a follow-up 
visit it will be indicated in the AE follow-up report. Written confirmation of details given verbally will be 
obtained whenever possible. 
 
 
 


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12. Data management 
12.1 Case Report Forms 
Data for each patient will be compiled in a case report. The case report form used is sufficiently detailed to 
capture the required information to meet the objectives of the study. Case report form will be retained as 
part of the TMF and will not have identifiable patient information such as name or medical records number. 
Case reports forms will be identified with the study ID of the patient. 
12.2 Data Entry and the study database 
All data from this study that will be used in analysis of primary and secondary endpoints including possible 
analysis in subgroups of the study population will be transcribed from the subject CRF into an Access 
database. The transcription of data will be double checked by a member of the support staff that is different 
from the one entering the data. The database will be designed in house to reflect the subject CRF and the 
necessary analysis elements. The database will only be used as a reservoir for all the collected data before it 
is exported into SAS for statistical treatment. Access 2003 or 2007 (2003 compatible mode) database will be 
used. 
12.3 Data Cleaning 
Two stages of data cleaning are identified for the study. The first stage is the review of CRFs for missing  or 
misplaced or invalid data before entry into the study database. The second stage is the verification of data 
entry at the closure of database and before analysis. Queries will be issued by data management to be 
resolved by the investigator and his team. 
Documentation of all queries and corrections made will be maintained in the study masterfile. 
 
 


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13. Statistical Considerations 
13.1 Sample Size Calculation 
Patients will be recruited over a whole year tentatively between February and December, 2016. It is 
estimated that 2-5 % of encountered patients are anemic and eligible for enrollment.  
Assuming at 90 % power, 5 % level of significance, based on previous pilot study: a proportion of responders 
of 0.54 and a standard deviation of 1.21, a response rate of 50 % or more being clinically meaningful, and 
testing for superiority; a minim of 25 subjects are required. To account for a 10 % chance for drop-outs the 
required sample is adjusted to 47.5 and approximated to the nearest tens. A total of fifty subjects will be 
required for the assessment. Since, each strata will be analyzed separately, and assuming both follow the 
same assumptions 50 subjects per strata will be recruited to make a total study sample of one hundred.31,32. 
Recruitment of 100 patients in 10 months is doable. 
East 6.3 software was used in the estimation of sample size. 
13.2 Statistical Analysis for data presentation 
Descriptive statistics will be used to present the two groups baseline characteristics and disease information. 
in addition to the patient’s responses after the whole follow up period. 
 
Analysis will be done for the two groups separately:  
o 
Group I: Patient with iron-deficiency anemia based on iron studies at base line 
o 
Group II: Patient with non-iron deficiency anemia  
 
Hb test results will be presented as mean, median and range through all twelve weeks.  
 
Average percent change from baseline will be used to show the changes of Hb levels. Comparison 
between means of Hb level will be made between the baseline Hb and Hb levels in the following 
weeks using Paired T-test.   
 
Response to IV iron therapy will be assessed in relation to Hepcidin and CRP levels. 
 
Univariate analysis will be used to assess the effect of patient characteristics and disease 
information on the response using Chi square test or fisher’s exact test. 
 
Adjusting for all significant factors that may affect the response will be done using Logistic 
regression. 
 
Odds ratio out of the Logistic regression will be reported with their corresponding 95% CI. 
 
A significance criterion of p< 0.05 will be used in the analysis.  
All analyses will be performed using SAS version 9.4 (SAS Institute Inc, Cary, NC). 
13.3 Safety Analysis 
Rate and incidence of adverse events will be analyzed and reported. Number of patients requiring ESA or 
transfusions will be reported using percentages and counts. 


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14. Quality Assurance and Compliance 
14.1 Quality Assurance of Conduct 
All study procedures and assessments will be carried following standard policies and operating procedures 
that are approved by the Quality Assurance Unit of KHCC. The investigator will be responsible to delegate 
any of the protocol tasks through appropriate channels and documentation through a delegation list. The 
investigator will be responsible to assure that the study team understand and is properly trained to the 
requirements and details of the study protocol. The investigator is responsible to show evidence of this 
training.  
14.2 Quality Control of Data 
Through-out the study conduct study data will be subject to review by members of the study team that have 
no direct relation to the obtained data. Data cleaning measures will be considered at the point of data entry. 
Transcript of data from the CRF or source document to the study database will be checked. Discrepancies 
found will be collected on data correction forms and appropriate actions taken for them will be documented 
and those who are found nonredeemable will be justified as appropriate. 
14.3 Deviations and Violations 
No intentional deviations or violations of the study will be made by the investigator or the study team 
without going to the appropriate channels for approval (i.e. IRB). Those deviations and violations that occur 
beyond the control of the investigator or the study team will be documented and reported. Any corrective or 
preventive actions made will also be described. If the violation or the deviation concerns the study patients 
the investigator will inform the IRB in writing about the incident as detailed as possible. The investigator 
judgment will be exercised to whether or not the deviations or violations have adverse effect on the safety 
of patients or the outcome of the study and hence if there is a need to terminate the patient participation or 
the study as a whole. 
14.4 Retention of Documents 
After the study ends, all study documents will be retained at the clinical trial unit office archives for a 
minimum period of five years post issue of publication. The investigator will then consider if the period of 
retention needs to be extended any further beyond the retention end date. If the study documents are to be 
destroyed the destruction will be documented for future reference. 


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15. Reporting and Publication 
15.1 Progress and Final Reports 
Progress reports about the study conduct will be prepared at the clinical trials unit. The reports will include 
breakdown of screening, enrolment and withdrawal status of subjects, as well as, a summary of safety issues 
and deviations. These reports will be sent to the IRB in each quarter. 
A final report of the study conduct and study results will be prepared at the end of the study at the clinical 
trials unit. The report will be submitted to the IRB after publication of results. 
15.2 Publication of Results 
KHCC is the sole proprietor of the study data. The Principal Investigator has the right to publish the outcome 
of the study in any medical journal he sees befitting. The investigator will follow the rules and regulations on 
authorship defined by KHCC. The principal investigator will be the first and corresponding author. The 
investigator will follow the CONSORT statement format for reporting clinical trials33. Once the publication is 
made the investigator will provide notice to the IRB about it. 
 
 


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16. Ethical Considerations 
16.1 Risk to Benefit Analysis 
FCM has been reported to be well tolerated with no significant adverse side effects The most common 
(≥1/100 to <1/10)  adverse effects reported from trials and marketing experience are headache, nausea, 
hypertension, injection site reactions (pain, bruising, discolorations), mild increase in alanine aminotransferase 
and Hypophosphataemia. A single dose between 500 mg and 1000 mg is only expected to last 72  hours 
(terminal half-life between 7 to 12 hours). Adverse reactions, if happened, are transient and can be 
managed. 
On the other hand, if a  short course of FCM (one or two treatments) proves to be effective and hepcidin 
and/or CRP are proved as effective predictors of response; we will  then have an effective treatment for 
anemia and we will be able to find methods to make the distinction between patients who are likely to 
respond and those who are not. 
16.2 Institutional Review Board 
The IRB of KHCC will review the study protocol and provide their favorable opinion on the study conduct. 
The study will not start without gaining the IRB approval first. The PI is responsible to assure that all 
documents necessary for the IRB review and issue of judgment will be supplied without delay. The 
investigator will not do changes to an already approved protocol without discussing it first with the IRB 
through a written amendment request unless it was necessary to remove an immediate hazard to the study 
patients or the change was of a logistical ground such as the change of phone numbers. 
The investigator will also be responsible to report all AE to the IRB according to KHCC policies and 
procedures. The final outcome of the study will be provided in a written summary report within a reasonable 
time span. 
16.3 Ethical Conduct of the Study 
The study will be conducted in accordance with ethical principles that have their origins enunciated in the 
Declaration of Helsinki, adopted by the General Assembly of the World Medical Association (WMA), Helsinki, 
Finland (1964) and amended by the 59th WMA General Assembly, Seoul, 200834. The study will be conducted 
in accordance with the protocol and the ICH guideline on Good Clinical Practice26 topic E6. 
 
 


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16.4 Informed Consent 
Patients will not be allowed to participate in the study and carry out any of the study procedures before they 
have been properly informed of all aspects of the study, roles and expectation, risks and benefits through a 
thorough consent procedure. The study patients will be required to sign a consent form establishing their 
agreement to participate in the study and that they have understood all implications and attributes of the 
study. If for reasons of illiteracy the patient is unable to sign the consent him/herself, a legally accepted 
representative will be required to attend the consent procedure and sign on behalf of the patient’s guardian. 
The signed consent document will be retained in the study file and another signed copy of the consent will 
be given back to the patient. 
Patients will not be coerced to participate in the study by the investigator or the study team. The patients 
will be given the freedom to review and consider the study before they provide their decision. The decisions 
to participate or not will neither affect the patients in terms of care and treatment nor will it deprive them 
from benefits to which they are entitled. Patients will be free to withdraw at any time without any prejudices 
held against them in any way or to their right to appropriate counseling and management of their case. 
The consent form will be prepared in the Arabic language that is considered the native language in Jordan. 
The level of the text will be prepared at that of an 8th grader. The consent will fulfill the elements of 
informed consent specified in the US FDA code of federal regulation (CFR) on the protection of human 
subjects 21 CFR Part 46.116.  
16.5 Confidentiality and Privacy 
Patients will be introduced to the study during the hospitalization or their out-patient clinic visits. The study 
discussion and consent will be held in a private area such as an office or in the patient bedroom. 
Throughout the study the patients’ identity and data collected for the study will be kept confidential among 
the study team delegated by the investigator to conduct the study. The patient will be addressed with an 
appropriate code and with their initials in all study documentation as appropriate. Access to the patient 
identity and data will be restricted to the study team and the IRB.  
16.6 Rights and Liabilities 
For all study related events regardless of causality, patients have the right for appropriate treatment and 
medication to resolve the event free of charge. Events that are unrelated or are disease related will not be 
covered or considered for coverage. No one from the study team, investigator or the KHCC will be 
responsible for self-inflicted injuries, injuries resulting from violating protocol or the study team instructions 


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that are in the best interest of the patient. Patients coverage for adverse events will be through an arranged 
insurance contract. 
16.7 Premature Termination of the Study 
The study will be terminated if one of the following is met: 
1) The investigator has decided to stop the study due to high incidence of AE to assure the safety of the 
patients.  
2) If the recruitment rate was inefficient or sufficient for the study endpoints to be met. 
3) The IRB has issued a decision to abort the study for any reason. 
The decision to end the patient participation or end the whole study prematurely will be in writing 
regardless of who made that decision and will be conveyed to the other parties. The patients will have the 
appropriate follow-up measures done for them before their files are closed. 
 
 
 


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Page 36 of 37 
 
17. References 
                                                          
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3 Abdel-Razeq HN. Cancer-related anemia. Saudi Med J. 2004; 25 (1): 15-20 
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11 Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck  cancer patients with anaemia 
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12 Hedenus M, Birgegård G, Näsman P, et al. Addition of intravenous iron to epoetin beta increases 
hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative 
malignancies: a randomized multicenter study. Leukemia. 2007;21(4): 627–632 
13 Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients 
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14 Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy 
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15 Auerbach M, Silberstein PT, Webb RT, et al. Darbepoetin alfa 300 or 500 μg once every 3 weeks with or 
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improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving 
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anemia at a single center. Hematol Oncol Stem Cell Ther. 2010;3(2):78-83 
19 Leyland-Jones B; BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated 
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20 Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in 
cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst. 2005;97(7): 489–498. 
21 Wun T, Law L, Harvey D, Sieracki B, Scudder SA, Ryu JK. Increased incidence of symptomatic venous 
thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and 
erythropoietin. Cancer. 2003;98(7):1514–1520. 
22 Hedenus M, Karlsson T, Ludwig H et al. Intravenous iron alone resolves anemia in patients with functional 
iron deficiency and lumphoid malignanciesundergoing chemotherapy Med Oncol 2014:31:302 
23 Andrews NC Anemia of inflammation: the cytokine hepcidin link. J Clin Invest. 2004:113(9):1251-1253 
24 Abdel Razeq H, Abbasi S, Saadi I, Jaber R, Abdelelah H. Intravenous Iron Monotherapy for the Treatment  
of non-iron deficiency anemia in cancer patients undergoing chemotherapy: a pilot study  
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2010; 2010:750643 
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27 Steinmetz T, Tschechne B, Harlin O, et al. Clinical experience with ferric carboxymaltose in the treatment 
of cancer- and chemotherapy-associated anaemia. Ann Oncol. 2013;24(2):475–482. 
28 Vifor Pharma, Ferinject Product Monograph, May 2012. 
29 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals 
for Human Use, ICH Harmonized Tripartite Guideline Topic E6: Guideline For Good Clinical Practice; Note for 
Guidance on Good Clinical Practice (CPMP/ICH/135/95), Step 4:1996. 
30 International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals 
for Human Use, ICH Harmonized Tripartite Guideline Topic E2D: Post Approval Safety Data Management; 
Note for Guidance on Definitions and Standards for Expedited Reporting (CPMP/ICH/3945/03), Step 5: 2003 
31 Shein-Chung Chow, Jun Shao and Hansheng Wand, Sample Size Calculations in clinical research 
32 Abhays Indrayan, Medical Biostatistics, CRC Press Taylor and Francis 2013. 
33 http://www.bmj.com/cgi/content/full/340/mar23_1/c332  
34 http://www.wma.net/en/30publications/10policies/b3/index.html  

SAP_001.pdf: 
Official title: 
The use of intravenous ferric carboxymaltose (FCM) without erythropoiesis-stimulating agents 
(ESA)  in the treatment of anemia in cancer patients undergoing chemotherapy with or without 
radiotherapy 
NCT number:  
NCT04246021 
 
Document date: 
September 26, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Considerations 
Sample Size Calculation 
Patients will be recruited over a whole year tentatively between February and December, 2016. 
It is estimated that 2-5 % of encountered patients are anemic and eligible for enrollment.  
Assuming at 90 % power, 5 % level of significance, based on previous pilot study: a proportion of 
responders of 0.54 and a standard deviation of 1.21, a response rate of 50 % or more being 
clinically meaningful, and testing for superiority; a minim of 25 subjects are required. To account 
for a 10 % chance for drop-outs the required sample is adjusted to 47.5 and approximated to the 
nearest tens. A total of fifty subjects will be required for the assessment. Since, each strata will 
be analyzed separately, and assuming both follow the same assumptions 50 subjects per strata 
will be recruited to make a total study sample of one hundred.i,ii. 
Recruitment of 100 patients in 10 months is doable. 
East 6.3 software was used in the estimation of sample size. 
Statistical Analysis for data presentation 
Descriptive statistics will be used to present the two groups baseline characteristics and disease 
information. in addition to the patient’s responses after the whole follow up period. 
 
Analysis will be done for the two groups separately:  
o 
Group I: Patient with iron-deficiency anemia based on iron studies at base line 
o 
Group II: Patient with non-iron deficiency anemia  
 
Hb test results will be presented as mean, median and range through all twelve weeks.  
 
Average percent change from baseline will be used to show the changes of Hb levels. 
Comparison between means of Hb level will be made between the baseline Hb and Hb 
levels in the following weeks using Paired T-test.   
 
Response to IV iron therapy will be assessed in relation to Hepcidin and CRP levels. 
 
Univariate analysis will be used to assess the effect of patient characteristics and disease 
information on the response using Chi square test or fisher’s exact test. 
 
Adjusting for all significant factors that may affect the response will be done using Logistic 
regression. 
 
Odds ratio out of the Logistic regression will be reported with their corresponding 95% CI. 
 
A significance criterion of p< 0.05 will be used in the analysis.  
All analyses will be performed using SAS version 9.4 (SAS Institute Inc, Cary, NC). 


Safety Analysis 
Rate and incidence of adverse events will be analyzed and reported. Number of patients requiring 
ESA or transfusions will be reported using percentages and counts. 
 
i Shein-Chung Chow, Jun Shao and Hansheng Wand, Sample Size Calculations in clinical research 
ii Abhays Indrayan, Medical Biostatistics, CRC Press Taylor and Francis 2013.