Laso-Morales et al. Trials (2019) 20:23 https://doi.org/10.1186/s13063-018-3125-2 STUDY PROTOCOL Open Access Single dose of intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of postoperative anaemia in colorectal cancer patients: study protocol for a randomised controlled trial María Jesús Laso-Morales1, Roser Vives2,3* , Andrea Vallejo-Tarrat1, Novella Caló1, Anna Valle-Beltran1 and Caridad Pontes2,3 Abstract Background: Patients with colorectal cancer (CRC) often present with associated anaemia which is usually present at the time of diagnosis and is aggravated during the postoperative period due to blood loss during the surgery process. Several guidelines advocate for the treatment of postoperative anaemia in these patients in order to prevent complications and allogeneic blood transfusions. However, there are no publications to shed light on the effectiveness of intravenous iron (IVI) administration after CRC surgery and the optimal dose and regimen. We have started a clinical trial with the objective of comparing the effectiveness of 1000 mg of ferric carboxymaltose with fractionated iron sucrose 200 g/48 h for the treatment of postoperative anaemia, by measuring the change of haemoglobin (Hb) levels from postoperative day (POD) 1 to POD 30. Methods: We designed an open label randomised controlled trial to compare two postoperative IVI treatment regimens. Patients aged > 18 years undergoing CRC surgery, with Hb < 11 g/dL on POD 1 are randomly assigned to receive either 1000 mg of ferric carboxymaltose (single dose) or 200 g/48 h of iron sucrose. The main study endpoint will be the change from POD 1 to POD 30 in Hb levels and the key secondary endpoint the percentage of patients with Hb levels ≥ 13 g/dL at POD 30. Other secondary endpoints include: changes in iron metabolism parameters (Fe, ferritin, transferrin, % saturated trasferrin) at POD 30; total doses of iron received; number of postoperative transfusions; compliance with oral iron treatment; number of medical and surgical complications; adverse reactions reported by the patient; use of health resources after surgery; and changes in quality of life (QoL). It has been estimated that a sample of 48 patients per group will allow detecting a difference of 0.75 g/dL in Hb in the change in Hb levels from POD 1 to POD 30. (Continued on next page) * Correspondence: Roser.vives@uab.cat 2 Clinical Pharmacology Unit, Department of Pharmacy. Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208 Sabadell, Spain 3 Departament de Farmacologia, de Terapèutica i de Toxicologia, Unitat Docent Parc Taulí, Universitat Autònoma de Barcelona, C/Parc Taulí, 1, 08208 Sabadell, Spain Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Laso-Morales et al. Trials (2019) 20:23 Page 2 of 7 (Continued from previous page) Discussion: The results of this study will confirm if the single dose of 1000 mg ferric carboxymaltose should be preferred in front of the fractionated doses and in which type of patients this regimen should be used preferably. Trial registration: European Union Clinical Trials Register, EudraCT 2015-001005-13. Registered on 6 January 2015. Keywords: Colorectal cancer, Postoperative anaemia, Intravenous iron Background received could have been insufficient to induce a signifi- Patients with colorectal cancer (CRC) often present with cant increase in Hb levels. associated anaemia which can be attributed mainly to iron Currently, the trend in CRC surgery is to initiate food deficiency due to blood loss and to the inflammation in- intake and mobilisation as soon as possible to achieve a herent to neoplastic processes [1]. Anaemia is usually prompt functional recovery of the patient and eventually present at the time of diagnosis and is aggravated during shorten hospital stay. In this situation, the treatment of the postoperative period due to blood loss during the sur- postoperative anaemia in patients with CRC should be gery process. On the other hand, it has been well estab- done early and preferably by IV route, as the patient is lished that preoperative anaemia increases the risk of discharged very soon after surgery. allogeneic blood transfusions during the perioperative In our hospital, there is an established protocol for the period and that transfusions are associated with an in- treatment of postoperative anaemia when it is detected in crease in postoperative infections, a higher rate of tumour these patients, aiming at the normalization of Hb levels. recurrences and an increase in five-year mortality [1–3]. This protocol establishes that all patients intervened for This is why alternative strategies to optimise patients with CRC, independent of the Hb levels and iron status, must preoperative anaemia have been implemented to avoid receive during the early postoperative period 200 mg of transfusions. Intravenous iron (IVI) has been shown as an IVI to substitute the intraoperative loss of blood. On post- efficacious alternative to transfusion [4–7] and is now operative day (POD) 1, patients must have blood tests recognised as more effective than the oral route in this with a haemogram. If Hb is < 11 g/dL patients will receive setting. The main reasons why oral iron has been super- one dose of 1000 mg of ferric carboxymaltose. If Hb is be- seded by IVI are malabsorption due to the inflammation tween 11 and 13 g/dL, patients receive 200 mg/48 h of associated to the neoplastic process and the poor compli- iron sucrose during hospital stay until iron deficit is solved ance due to gastric intolerance [8–10]. (calculated according to Ganzoni Formula) and after hos- The optimisation of CRC cancer patients with anaemia pital discharge, they will be prescribed oral iron in case before undergoing surgery was well established in our the target doses have not been completed. To implement centre a decade ago, after a multidisciplinary team imple- this protocol, two formulations are available at our institu- mented a diagnostic track for this type of patients [11]. tion: ferric carboxymaltose 500 mg strength and iron su- According to the diagnostic track, all patients presenting crose 100 mg strength. with anaemia at the time of diagnosis should be treated Despite the advantages of the single 1000-mg doses before surgery with IVI. An expert consensus of different of ferric carboxymaltose administration, that would Spanish scientific societies addresses the management of guarantee that patients receive the iron load needed anaemia in surgical procedures with medium-high bleed- before hospital discharge. In a recent retrospective ing, such as CRC surgery, and advises that it would be de- study, we observed an underuse of the 1000-mg sin- sirable to reach haemoglobin (Hb) levels > 13 g/dL before gle dose even in patients with low Hb levels [14]. On surgery in order to minimise the risk of transfusion and the one hand, the difference in cost compared to quickly correct the anaemia [10, 12]. However, although fractionated formulations of iron sucrose may account this document also recommends treatment of postopera- for this. However, the lack of acceptance of such pro- tive anaemia with IVI with the aim of minimising transfu- tocols may also be related to the limited evidence sions and complications, there is no robust evidence to perceived by surgeons of the benefit of the 1000-mg endorse this recommendation. doses over the fractionated doses. In fact, there is a Titos et al. describe a retrospective study [13] where lack of information of which is the clinical impact of treatment with IVI after CRC surgery did not affect the the two different approaches. Thus, we have consid- needs of transfusion nor did it significantly increase Hb ered that comparing both schemes would give an an- levels. However, it has to be taken into account that the swer to a relevant clinical question that may impact sample size was small and that patients were only stud- clinical practice in the future. Our hypothesis is that ied up to the moment they were discharged; thus, doses treatments with a single dose of ferric carboxymaltose Laso-Morales et al. Trials (2019) 20:23 Page 3 of 7 in patients who present with Hb levels < 11 g/dL at Randomisation POD 1 will be more effective in achieving normal Hb A computer-generated block randomisation (block size 8) levels at POD 30. has been created with WinPepi etcetera module version 3.26. Randomisation has been stratified by Hb level on day 1 (Hb < 10 g/dL or Hb ≥ 10 g/dL). Sealed envelopes Participants and methods have been created for each individual patient. Pre- Study design and interventions screened patients are randomly assigned to one of the two This is a single-centre, open-label randomised controlled study treatments on POD 1 and after knowing the results trial to compare the effectiveness of two different IVI regi- of the blood tests for Hb levels. mens to treat postoperative anaemia in patients undergo- ing CRC surgery. During the visit before surgery with the Study procedures anaesthesiologist, patients meeting the eligibility criteria During the preoperative anaesthesiology visit, patients will be informed and those willing to participate will sign meeting eligibility criteria will be informed and those will- the informed consent form. On POD 1, Hb levels will be ing to participate in the study will sign the ICF. During determined and those patients presenting with levels < 11 this visit, and after signing the ICF, patients will complete g/dL will be randomly assigned to one of the following a quality-of-life questionnaire (QL-C30). On POD 1, and study treatments: (1) single dose of 1000 mg of ferric car- after checking eligibility (Hb levels < 11 g/dL), treatment boxymaltose (Ferinject®, Vifor, France) intravenously in a will be randomly assigned to one of the two treatment 15-min infusion; or (2) repeated doses of 200 mg of iron arms. After hospital discharge, patients will come for a sucrose (different brand names) every 48 h from POD1 up visit on POD 30 when blood tests assessing iron metabol- to hospital discharge or up to the total dose equivalent to ism and Hb will be performed and patients will be asked iron deficit calculated according to the Ganzoni formula, to complete the QL-C30 questionnaire. Any additional whichever occurs first. Patients who are discharged before blood tests assessing Hb levels and iron metabolism achieving the calculated doses will be prescribed oral iron performed from patient diagnosis to end of trial (i.e. up to POD 30. Patients with Hb levels ≥ 11 g/dL on POD at diagnosis, immediately before surgery and on POD 1 will not be included in the study and will follow the 4 or hospital discharge) will be recorded. When pa- treatment according to hospital protocols. After discharge, tients are hospitalised, regular checks for adverse patients will be followed up to POD 30 (Fig. 1). events or any complication are performed. Iron treat- ment will be discontinued in patients admitted in the Study population intensive care unit on POD 1 due to organic fail or Patients aged > 18 years undergoing programmed CRC presenting Claviens grade 4 complications. Whenever surgery, with Hb levels < 11 g/dL on POD 1 and who possible, these patients will be followed up to POD have signed the informed consent form (ICF) are in- 30 (Fig. 2). cluded in the study. Patients who present with Hb levels ≥ 11 g/dL on POD 1, with anaesthetic risk ASA 4, with Study endpoints Claviens classification of surgical complications grade 4, The main study endpoint will be the change in Hb levels pregnant or lactating women, and patients with previous from POD 1 to POD 30. The percentage of patients with known intolerance/adverse reactions or with contraindi- Hb levels ≥ 13 g/dL at POD 30 will be considered as a cations to IVI are excluded. key secondary endpoint. Other secondary endpoints Fig. 1 Study design. Ganzoni Formula: Total iron dose (mg iron) = body weight (kg) × (target – actual Hb) (g/dL) × 2.4 + iron for iron stores (mg iron)*. *Iron stores: body weight < 35 kg = 15 mg/kg body weight; body weight > 35 kg = 500 mg Laso-Morales et al. Trials (2019) 20:23 Page 4 of 7 Fig. 2 Schedule of enrolment, interventions and assessments include: changes in iron metabolism parameters (Fe, Statistical methods ferritin, transferrin, % saturated trasferrin) at POD 30; Sample size total doses of iron received up to POD 30; number of Our hypothesis is that the difference in change in Hb postoperative transfusions; percentage of patients not levels (primary endpoint) between the two studied regi- compliant with oral iron treatment; number of med- mens will be 0.75 g/dL. With a two-sided risk of 5% and ical and surgical complications; adverse reactions a power of 80%, and assuming a common standard devi- reported by the patient; and use of health resources ation of 1.3, a total of 48 evaluable patients per group after surgery: number of admissions, length of are to be included. hospital stay; changes in quality of life (QoL). Poten- tial adverse reactions of IVI are headache, dizziness, nausea, abdominal pain, constipation, diarrhoea, Populations of analysis exanthema, hypophosphatemia and increases in ala- For safety analysis, all patients who have received at least nine-aminotransferase. Hypersensitivity and injection one dose of IVI will be considered, in the group of treat- site reactions are rare. Oral iron treatment is associ- ment they actually received. ated with gastric intolerance and constipation. The intention to treat (ITT) population will consist of all randomised patients with at least one Hb measure- ment after POD 1. Patients with missing POD 30 assess- Data collection and management ments (main endpoint) will be assigned the last value Study data will be collected in paper case report available after POD1 (if any assessment is available). A forms (CRF) designed for the study. Risk adjusted modified intention to treat population (mITT) will con- monitoring will be performed by personnel independ- sider all randomised patients with Hb assessments avail- ent from the investigator team, consisting on check- able at POD 30 irrespective of whether they have ing all informed consent forms and completeness of adhered to the study protocol procedures. all CRFs and source data verification for a random The per-protocol (PP) population will consist of pa- sample of patients. Data will be entered in the study tients in the mITT populations who have received treat- database by members of the study team. Patients will ment according to the study protocol and for whom an be identified by a numerical code and no personal in- 80% adherence to oral iron is reported and with no rele- formation will be included in the paper CRF and the vant protocol deviation that may affect main efficacy as- database. sessments (i.e. transfusion). Laso-Morales et al. Trials (2019) 20:23 Page 5 of 7 Although the main efficacy analysis will be Discussion performed on the PP population, the other two popu- We have designed a randomised controlled study to lations will be used for a sensitivity analysis for the compare two IVI regimens to treat CRC postoperative main endpoint. anaemia in terms of change in Hb levels from POD 1 to POD 30. Other variables, such as percentage of patients Descriptive statistics presenting with normal Hb levels at POD 30, changes in Patient characteristics will be described by treatment iron metabolism parameters, safety of both IVI regimens group and for the entire sample of patients. Quantitative and complications and QoL, have been considered. variables will be presented as means with standard devi- According to our procedures, patients with preopera- ations or in cases of skewed distribution as medians and tive anaemia follow an optimisation treatment with the interquartile ranges. Qualitative data will be presented as aim of reaching adequate levels before surgery and thus absolute and relative frequencies. minimising postoperative anaemia and the need for transfusions. In addition, in our hospital, all patients Inferential statistics receive 200 mg of iron sucrose right after surgery to Differences in the main variable (change in Hb levels from account for surgical blood loses. There are no clear rec- POD 1 to POD 30) between the treatment groups will be ommendations on the use and efficacy of postoperative tested by means of an analysis of covariance (ANCOVA) iron treatment, especially in patients who have already using Hb at POD 1 as covariable. Chi-square test will be received IVI before surgery. In these cases, the risk of used for the key secondary variable, percentage of patients iron overload has not been demonstrated. However, with Hb levels at POD 30 ≥ 13 g/dL, as well as for other there are a large number of patients who arrive at the categorical variables. For categorical ordinal variables the postoperative period with Hb levels lower than desired ANOVA or Kruskall–Wallis test will be used. Continuous [16, 17]. This may lead to complications, a longer hos- variables will be analysed by means of T-test or the corre- pital stay and eventually to a slower recovery. sponding non-parametric tests. A subgroup analysis for Currently, CRC patients without surgical complica- the stratification variable (Hb < 10 g/dL and Hb ≥ 10 g/dL) tions are discharged after 3–4 days. This implies that, for is planned. some patients, the treatment with fractionated IVI can- An exploratory multivariate analysis will be performed not be completed to the calculated doses and thus they to identify characteristics of patients associated to larger are prescribed oral iron after discharge. However, the ab- changes in Hb levels and to identify subgroups of sorption of oral iron in this context is known to be min- patients that may benefit most of the single IVI dose. imal [1, 8–10, 12] and, together with the low compliance expected due to mild but unpleasant side effects, pa- Feasibility tients end up receiving doses lower than required. To Despite the large number of elective CRC surgeries per- overcome these problems, a single dose of 1000 mg is an formed in our hospital (200 CRC surgeries are per- option for patients with lower Hb levels. However, the formed each year on average), recruitment is limited by high cost of this formulation from a commercially avail- the fact that only patients with Hb levels < 11 g/dL can able brand results in an underuse of this regimen in this be included. Recruitment started in September 2015 and setting as evidenced in a previous study [14]. Thus, it is is planned to finish in September 2018. of importance to assess whether, in patients with Hb levels < 11 g/dL, treatment with single doses of IVI may Ethics lead to larger increases in Hb levels and if this benefit Written informed consent will be obtained from each par- depends on POD 1 Hb levels or other characteristics of ticipant before any trial-related procedures are carried patients, in order to make evidence-based decisions. out. This trial is being conducted in accordance with the One of the main limitations of the study is the lack of Declaration of Helsinki and good clinical practice princi- blinding. Masking of the different administration sched- ples. The study protocol (Version 2, April 2015) was ap- ules would need a double dummy strategy which would proved by the Research Ethics Committee of Corporació modify the pragmatic approach of the study. Addition- Parc Taulí in April 2015 and by the Spanish Medicines ally, the manufacturing of placebo and the masking pro- Agency (Agencia Española de Medicamentos y Productos cedures are a hurdle for an investigator-initiated study, Sanitarios) in July 2015. The study is registered in the EU needing the logistic and economic support, in most Clinical Trials Register (EudraCT: 2015–001005-13). The cases, of the marketing authorisation holder, a situation present study protocol has been written according to the which is not desirable for an independent trial. On the Recommendations for Interventional Trials (SPIRIT) 2013 other hand, the main endpoint is based on an analytical statement for reporting a clinical trial protocol [15]. The parameter and thus it is less prone to be affected by ob- SPIRIT checklist is provided in Additional file 1. servation bias. Laso-Morales et al. Trials (2019) 20:23 Page 6 of 7 In addition, while we consider that studying the QoL AVB reviewed the protocol and the manuscript and is a member of the is a relevant endpoint, we foresee that changes in QoL clinical study team. CP wrote the study protocol and reviewed the manuscript. All authors read and approved the final manuscript. will be difficult to interpret due to the health condition of patients before surgery. Ethics approval and consent to participate In a previous observational study [14], we observed The study has been approved by the Research Ethics Committee of our centre (Comité Ético de Investigación Clínica de la Corporació Sanitària Parc that patients treated with postoperative IVI, increased Taulí) on April 2015. All participants are informed and asked for informed Hb levels in about 2 points at POD 30. Despite these in- consent before any study procedure. creases, a considerable number of patients do not reach Consent for publication normal levels. Thus, we expect changes of this magni- Not applicable. tude and expect them to be larger with the single dose of ferric carboxymaltose than with the fractionated doses Competing interests The authors declare that they have no competing interests. regimen with iron sucrose. We also hypothesise that pa- tients with lower Hb levels will benefit more from the Publisher’s Note single-dose regimen. Springer Nature remains neutral with regard to jurisdictional claims in The study is being performed in only one centre and, published maps and institutional affiliations. in most cases, the principal investigator, an anaesthetist, Author details is responsible for the inclusion, randomisation and treat- 1 Department of Anaesthesiology. Parc Taulí Hospital Universitari, Institut ment of the patient, ensuring uniformity of procedures. d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Additionally, adapted risk monitoring has been imple- Parc Taulí 1, 08208 Sabadell, Spain. 2Clinical Pharmacology Unit, Department of Pharmacy. Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació mented to ensure that the protocol is performed accord- Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208 ing to GCP criteria and to ensure the quality of data. Sabadell, Spain. 3Departament de Farmacologia, de Terapèutica i de The results of this study will confirm whether the sin- Toxicologia, Unitat Docent Parc Taulí, Universitat Autònoma de Barcelona, C/ Parc Taulí, 1, 08208 Sabadell, Spain. gle dose of 1000 mg of ferric carboxymaltose should be preferred ahead of the fractionated doses and in which Received: 16 April 2018 Accepted: 11 December 2018 type of patients this regimen should preferably be used. References Trial status 1. Muñoz M, Gómez-Ramírez S, Martín-Montañez E, Auerbach M. Perioperative anemia management in colorectal cancer patients: a pragmatic approach. The trial is ongoing. At the time of finishing this manu- World J Gastroenterol. 2014;20(8):1972–85. script, 122 patients have been screened and signed in- 2. Acheson AG, Brookes MJ, Spahn DR. Effects of allogeneic red blood cell formed consent. 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