Received: 28 October 2016
|
Revised: 19 December 2016
|
Accepted: 21 December 2016
DOI 10.1002/ajh.24633
A JH
RESEARCH ARTICLE
A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia Richard Derman1 | Eloy Roman2 | Manuel R. Modiano3 | Maureen M. Achebe4 | Lars L. Thomsen5 | Michael Auerbach6 1 Thomas Jefferson University, Philadelphia, Pennysylvania, USA; 2Lakes Research, Miami Lakes, Florida, USA; 3ACRC Arizona Clinical Research, Tucson, Arizona, USA; 4Division of Hematology, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Boston, Massachusetts, USA; 5Department of Clinical and Non-clinical Research, Pharmacosmos A/S, Holbaek, Denmark; 6 Georgetown University School of Medicine, Washington, District of Columbia, USA
Abstract Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open-label, comparative, multi-center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as
Correspondence Richard Derman, MD, MPH, FACOG, Associate Provost, Global Affairs, Director, Global Health Research, Professor, Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Email: [email protected]
repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase 2 g/dL from baseline at any time between weeks 1-5. Both non-inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase 2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.
1 | INTRODUCTION
with better adherence, fewer visits to the medical practitioner, and greater convenience. Iron isomaltoside is one of the newer IV iron for-
Iron deficiency anemia (IDA) is a common problem associated with many
mulations available. It was initially launched in Europe in 2010 and con-
chronic diseases which include chronic kidney disease (CKD),1 cancer,2
sists of iron and a carbohydrate moiety where the iron is tightly bound
3
4
infections, chronic heart failure (CHF), inflammatory bowel disease
in a matrix structure. It is the matrix structure that enables a controlled
(IBD),5 and bariatric procedures.6 It is also common in women who have
and slow release of iron to iron-binding proteins, avoiding potential tox-
recently given birth7 or suffer from heavy menstrual bleeding.8
icity from release of labile iron.12 Previous published data demonstrate
International guidelines9–11 recommend IV iron as the preferred
good safety and efficacy of iron isomaltoside in different populations
option when oral iron was either ineffective or not tolerated, either
with different comparators.13–22 A previous trial compared efficacy of
because of limited absorption, lack of adherence, intolerance, or when
ferric carboxymaltose versus iron sucrose in IBD patients,23 and iron
the iron need is high. IV iron is considered more effective, better toler-
isomaltoside has been compared with iron sucrose in CKD.13 This trial
ated, and improves quality of life (QoL) to a greater extent than oral
is the first head to head trial of iron isomaltoside against iron sucrose
iron. Thus, the use of IV iron may result in improved iron correction
outside the realm of CKD. The objective of the present trial was to
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. C 2017 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc. V
286
|
wileyonlinelibrary.com/journal/ajh
Am J Hematol. 2017;92:286–291
DERMAN
A JH
ET AL.
compare the efficacy and safety of iron isomaltoside with iron sucrose
|
287
The primary efficacy endpoint was the proportion of patients with a Hb increase of 2 g/dL from baseline at any time from weeks 1 to 5.
in patients with IDA over a wide range of different clinical diagnoses.
The secondary efficacy endpoints included time to Hb increase 2 g/
2 | PATIENTS AND METHODS
dL, and change in Hb, s-ferritin, TSAT, and s-iron, and total quality of life (QoL) score (Short Form 36 (SF-36) questionnaire). Safety end-
2.1 | Trial design
points included the number of patients who experienced any adverse
This was a prospective, comparative, open-label, randomized, non-inferiority
drug reaction (ADR) and safety laboratory assessments (complete
multicenter trial incorporating 7–12 visits during a 5-week period.
hematology, s- sodium, s-potassium, s-calcium, s-phosphate, s-urea, s-
The protocol and amendments were approved by the relevant
creatinine, s-albumin, s-globulin, s- bilirubin, aspartate aminotransferase,
Institutional Review Boards and conducted in accordance with good
alanine aminotransferase, and C-reactive protein). The primary end-
clinical practice and the Declaration of Helsinki of 1975, as revised in
point was tested for non-inferiority. Additionally, if the 95% confidence
2008. The trial was registered with ClinicalTrials.gov (NCT02130063).
interval (CI) was entirely above 0, this was evidence of statistically sig-
Written informed consent was obtained from all participants.
nificant superiority at the 5% level. The p-value associated with a test of superiority was to be calculated. The remaining endpoints were
2.2 | Participants
tested for superiority.
The trial was conducted at 48 sites in the United States. Patients 18 years of age with moderate-to-severe IDA caused by different etiolo-
2.5 | Sample size and randomization
gies, and with a documented history of intolerance of, or unresponsive-
A stratified block randomization methodology was used to assign
ness to, oral iron, a Hb
|
Revised: 19 December 2016
|
Accepted: 21 December 2016
DOI 10.1002/ajh.24633
A JH
RESEARCH ARTICLE
A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia Richard Derman1 | Eloy Roman2 | Manuel R. Modiano3 | Maureen M. Achebe4 | Lars L. Thomsen5 | Michael Auerbach6 1 Thomas Jefferson University, Philadelphia, Pennysylvania, USA; 2Lakes Research, Miami Lakes, Florida, USA; 3ACRC Arizona Clinical Research, Tucson, Arizona, USA; 4Division of Hematology, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Boston, Massachusetts, USA; 5Department of Clinical and Non-clinical Research, Pharmacosmos A/S, Holbaek, Denmark; 6 Georgetown University School of Medicine, Washington, District of Columbia, USA
Abstract Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open-label, comparative, multi-center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as
Correspondence Richard Derman, MD, MPH, FACOG, Associate Provost, Global Affairs, Director, Global Health Research, Professor, Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Email: [email protected]
repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase 2 g/dL from baseline at any time between weeks 1-5. Both non-inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase 2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.
1 | INTRODUCTION
with better adherence, fewer visits to the medical practitioner, and greater convenience. Iron isomaltoside is one of the newer IV iron for-
Iron deficiency anemia (IDA) is a common problem associated with many
mulations available. It was initially launched in Europe in 2010 and con-
chronic diseases which include chronic kidney disease (CKD),1 cancer,2
sists of iron and a carbohydrate moiety where the iron is tightly bound
3
4
infections, chronic heart failure (CHF), inflammatory bowel disease
in a matrix structure. It is the matrix structure that enables a controlled
(IBD),5 and bariatric procedures.6 It is also common in women who have
and slow release of iron to iron-binding proteins, avoiding potential tox-
recently given birth7 or suffer from heavy menstrual bleeding.8
icity from release of labile iron.12 Previous published data demonstrate
International guidelines9–11 recommend IV iron as the preferred
good safety and efficacy of iron isomaltoside in different populations
option when oral iron was either ineffective or not tolerated, either
with different comparators.13–22 A previous trial compared efficacy of
because of limited absorption, lack of adherence, intolerance, or when
ferric carboxymaltose versus iron sucrose in IBD patients,23 and iron
the iron need is high. IV iron is considered more effective, better toler-
isomaltoside has been compared with iron sucrose in CKD.13 This trial
ated, and improves quality of life (QoL) to a greater extent than oral
is the first head to head trial of iron isomaltoside against iron sucrose
iron. Thus, the use of IV iron may result in improved iron correction
outside the realm of CKD. The objective of the present trial was to
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. C 2017 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc. V
286
|
wileyonlinelibrary.com/journal/ajh
Am J Hematol. 2017;92:286–291
DERMAN
A JH
ET AL.
compare the efficacy and safety of iron isomaltoside with iron sucrose
|
287
The primary efficacy endpoint was the proportion of patients with a Hb increase of 2 g/dL from baseline at any time from weeks 1 to 5.
in patients with IDA over a wide range of different clinical diagnoses.
The secondary efficacy endpoints included time to Hb increase 2 g/
2 | PATIENTS AND METHODS
dL, and change in Hb, s-ferritin, TSAT, and s-iron, and total quality of life (QoL) score (Short Form 36 (SF-36) questionnaire). Safety end-
2.1 | Trial design
points included the number of patients who experienced any adverse
This was a prospective, comparative, open-label, randomized, non-inferiority
drug reaction (ADR) and safety laboratory assessments (complete
multicenter trial incorporating 7–12 visits during a 5-week period.
hematology, s- sodium, s-potassium, s-calcium, s-phosphate, s-urea, s-
The protocol and amendments were approved by the relevant
creatinine, s-albumin, s-globulin, s- bilirubin, aspartate aminotransferase,
Institutional Review Boards and conducted in accordance with good
alanine aminotransferase, and C-reactive protein). The primary end-
clinical practice and the Declaration of Helsinki of 1975, as revised in
point was tested for non-inferiority. Additionally, if the 95% confidence
2008. The trial was registered with ClinicalTrials.gov (NCT02130063).
interval (CI) was entirely above 0, this was evidence of statistically sig-
Written informed consent was obtained from all participants.
nificant superiority at the 5% level. The p-value associated with a test of superiority was to be calculated. The remaining endpoints were
2.2 | Participants
tested for superiority.
The trial was conducted at 48 sites in the United States. Patients 18 years of age with moderate-to-severe IDA caused by different etiolo-
2.5 | Sample size and randomization
gies, and with a documented history of intolerance of, or unresponsive-
A stratified block randomization methodology was used to assign
ness to, oral iron, a Hb
