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Oncology
Protocol
Combination with intravenous iron supplementation or doubling erythropoietin dose for patients with chemotherapy-induced anaemia inadequately responsive to initial erythropoietin treatment alone: study protocol for a randomised controlled trial
  1. Lin Chen1,
  2. Hong Jiang1,
  3. Wei Gao2,
  4. Ye Tu1,
  5. Ying Zhou1,
  6. Xi Li1,
  7. Zhe Zhu2,
  8. Qixin Jiang2,
  9. Haifeng Zhan3,
  10. Jiangming Yu4,
  11. Chuangang Fu2,
  12. Yong Gao1
  1. 1Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
  2. 2Department of Gastrointestinal Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
  3. 3Department of Gynecology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), Shanghai, China
  4. 4Department of Orthopaedics, Changzheng Hospital, Shanghai, China
  1. Correspondence to Dr Yong Gao; drgaoyong{at}163.com

Abstract

Introduction Erythropoietin (EPO) is a commonly used option in the treatment of chemotherapy-induced anaemia (CIA). However, ∼30–50% of patients fail to achieve an adequate response after initial treatment. Prior studies have demonstrated that intravenous iron might synergistically improve therapeutic response to EPO treatment in this patient population.

Methods and analysis We will perform this multicentre, randomised, open-label, parallel-group, active controlled non-inferiority study to compare the two combination therapies of EPO plus intravenous iron regimen versus doubling the dose of EPO in patients with CIA who have an inadequate response to initial EPO treatment at a routine dose. A total of 603 patients with an increase in haemoglobin (Hb) <1 g/dL will be enrolled and randomised to one of the three study treatment groups at a 1:1:1 ratio Group 1: EPO treatment at the original dose plus intravenous iron dextran 200 mg every 3 weeks (Q3W) for 15 weeks; Group 2: EPO treatment at the original dose plus intravenous iron dextran 100 mg, twice a week for 5 weeks; Group 3: the control group, doubling the EPO dose without preplanned iron supplementation. The primary outcome measure to compare is the Hb response rate at week 15 and the secondary end points involve therapeutic blood transfusions. Time-to-progression, adverse events and quality of life will also be evaluated.

Ethics and dissemination All participants will provide informed consent; the study protocol has been approved by the independent ethics committee of Shanghai East Hospital. This study would clearly demonstrate the potential benefit of combining epoetin treatment with intravenous iron supplementation. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of CIA in China.

Trial registration number NCT02731378.

  • erythropoietin
  • iron supplementation
  • inadequately responsive
  • chemotherapy-induced anaemia
  • randomized controlled trial

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/bmjopen-2016-012231

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    Strengths and limitations of this study

    • An adequately powered randomised controlled trial.

    • A specific subpopulation that until now has not seemingly been studied well.

    • Focus on Chinese population alone, which might limit extrapolations of study findings.

    Introduction

    Chemotherapy-induced anaemia (CIA) is a significant health problem for patients with cancer undergoing chemotherapy, causing fatigue and reducing quality of life (QoL).1 ,2 Up to 75% of patients with cancer undergoing chemotherapy and/or radiotherapy reportedly experience mild-to-moderate anaemia (defined by a haemoglobin level of 9–11 g/dL).1 ,3 In clinical trials, erythropoietins (EPOs) have been shown to increase haemoglobin levels and improve anaemia and QoL in patients with cancer.2 ,4–7 However, recent meta-analyses have highlighted possible safety issues regarding EPO exposure. Preclinical studies have pointed towards the role of EPO in augmenting tumorigenesis, metastasis, risk of thrombosis and drug resistance in certain tumour types (eg, breast cancer), as it can activate important antiapoptotic pathways (eg, AKT, ERK, JAK/STAT) targeted by current antineoplastic therapies, thus counteracting their effects.8–12 Current guidelines in western countries13–16 and China17 recommend restricted usage of EPOs and reduction/prevention of blood transfusions in the treatment of CIA. Furthermore, it appears that patients with cancer experience a blunted EPO response to anaemia, in addition to inadequate EPO production.18 Around 30–50% of patients receiving epoetin α therapy for CIA do not achieve a clinically meaningful haematological response.2 ,5 ,19 ,20

    However, the inadequate response to erythropoietic therapy has not been well characterised through rigorous studies and hence remains poorly handled in routine clinical practice. A major cause for not responding to EPO treatment is most likely functional iron deficiency (FID), which is defined as the failure to provide iron to the erythroblasts despite sufficient iron stores.21–23 Patients with FID require supplementation of usable iron to optimise response to erythropoietic therapy, which might not be accomplished with oral iron.24 In a recent prospective, open-label trial, patients receiving epoetin α for CIA who were treated with intravenous iron dextran had a significantly greater Hb response compared with those receiving oral iron.25 Meanwhile, in patients with CIA and no iron deficiency, intraveous iron supplementation significantly reduced treatment failures to darbepoetin without additional toxicity.26 However, whether that intraveous iron supplementation increases the risk of disease progression, incidence of thrombosis and heart failure, as well as iron overload, is under careful investigation. Though the association between intraveous iron and serious adverse events (AEs)27 and mortality28 remains unclear, Zitt et al29 found that the use of intraveous iron was associated with a 22% reduction in mortality. Therefore, we designed this multicentre randomised trial to investigate EPOs in combination with intraveous iron with regard to an increase of Hb levels in patients who have inadequate responses to initial treatment with routine doses of EPOs. The optimal strategies for intravenous iron supplementation may warrant further investigation.30 ,31 To the best of our knowledge, a cumulative intravenous iron dose of 1000 mg administrated in our study is frequently used among prior reports32 ,33 in an intensive mode (eg, accomplish total dose in the first 5 weeks) or a uniform one (eg, for a duration of 15 weeks); it should also be acceptable in our clinical practice. However, it seems that there is a lack of specific study to compare these various dosing regimens.30–34 As a result, we included the two iron arms of equal total dose in our study, which makes it possible to carry out direct pairwise comparisons with the control in a single clinical trial.

    Methods and analysis

    Study design

    This is a multicentre, randomised, open-label, parallel-group, active controlled non-inferiority study, which will be conducted at approximately six study centres in China and will enrol ∼603 eligible participants. The study flow chart is summarised in figure 1. Its study objectives are to assess the efficacy, safety and tolerability of two combination therapies of EPO plus intravenous iron regimen compared to doubling the dose of EPO in patients with CIA who are inadequately responsive with initial treatment of routine EPO dose. An additional key objective is to ascertain the potential effects of administrating aggressive (100 mg, twice a week for 5 weeks) or sustained (200 mg every 3 weeks for 15 weeks) intravenous iron supplementation in the selected subpopulation. The study consists of a 2-week screening period, a 4-week initial treatment lead-in period with a prerandomisation visit, and a 15-week open-label treatment period (6 visits) and multiple post-treatment follow-up visits of up to 2 years until tumour progression, death or the study period ends.

    Figure 1
    Figure 1

    Study flow chart. CIA, chemotherapy-induced anaemia; ECOG, Eastern Cooperative Oncology Group; EPO, erythropoietin; FACT-An, Functional Assessment of Cancer Therapy-Anaemia; Hb, haemoglobin; IU, International Unit; KPS, Karnofsky Performance Status Scale; LASA, Linear Analogue Self-assessment; Q3W, Every 3 weeks.

    The study will be initiated in April 2016 and may require a 2-year recruitment period. In the screening, patients who are diagnosed as having CIA (Hb <10 g/dL while undergoing chemotherapy) will be recruited for further eligibility assessment. In the lead-in period, the preliminarily screened patients are to be receiving EPO treatment for a planned 4-week period (routine dose 10 000 IU, three times weekly through subcutaneous injections). Thereafter, the patients with an increase of Hb <1 g/dL would be eligible and randomised to one of the following three groups at a 1:1:1 allocation ratio Group 1: EPO treatment at the original dose plus intravenous iron dextran 200 mg every 3 weeks (Q3W) for 15 weeks; Group 2: EPO treatment at the original dose plus intravenous iron dextran 100 mg, twice a week for 5 weeks; Group 3: the control group, doubling the EPO dose with no preplanned iron supplementation according to the current Chinese guidelines.17 After the end of the 15-week study treatment period, long-term follow-up through a combination of outpatient on-site visits and telephone visits will be conducted for tumour assessment. It is expected that the intravenous iron added in Group 1 and Group 2 would increase the rate of response to EPO, and reduce the risk of required transfusions.1 ,21

    The study has been registered and the registration is ClinicalTrials.gov number, NCT02731378.

    Patients

    Patients with cancer undergoing adjuvant or palliative chemotherapy are potential participants for the study. Patients who meet the following inclusion criteria will be considered eligible to recruit:

    • Aged 18 years or older;

    • Had a histologically, cytologically or clinically diagnosed malignant tumour and measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1;35

    • Undergoing adjuvant or palliative chemotherapy with an expected survival of at least 3 months;

    • Inadequately responsive or unresponsive to routine dosages of EPO treatment. Inadequate responders or non-responders are defined as those patients with CIA with an increase of Hb <1 g/dL after 4 weeks of treatment with 10 000 IU of EPO, three times weekly by subcutaneous injection.

    • Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2;

    • Are compliant and can understand the research and sign an informed consent form.

    Patients with the following conditions will be excluded from the study:

    • History of thromboembolism in the previous 12 months;

    • Family history of haemochromatosis;

    • Anaemia diagnosed with myelodysplastic syndrome or haematological diseases such as Mediterranean anaemia;

    • Received EPO treatment in the prior 3 months;

    • Received erythrocyte suspension transfusion in the prior 2 weeks;

    • Women who are pregnant or lactating;

    • Have a history of hypertension or mental illness.

    Withdrawal management

    Patients with CIA who have any of the following conditions will be allowed (or may be required) to withdraw from the study:

    • Non-compliance in receiving the study drugs as required by study protocol;

    • After enrolment, patients are found to meet major exclusion criteria; or

    • Patients refuse to follow the study process.

    Study early termination

    The study might be terminated early if any of the following conditions occur:

    • Unexpected and uncontrolled adverse reactions happen in the course of the trial; or

    • Significant protocol deviations are reported in the course of study conduct, which might substantially affect the treatment efficacy evaluation.

    Recruitment process

    Recruitment of study participants will take place at the medical oncology department of all participating sites. Each participant will be assigned a unique identification number during the screening visit. At least one medical oncologist at each site will evaluate each of the screened patients for participation in the study based on inclusion and exclusion criteria.

    Randomisation process

    Inadequate responders after 4-week EPO treatment will be randomly assigned to one of three study treatment groups at a 1:1:1 ratio. A stratified block randomisation with randomly varying block size will be performed, stratified according to study site, cisplatin-containing chemotherapy (yes vs no) and iron deficiency status at baseline (absolute vs functional). Random assignment is generated by a statistician from Shanghai Knowlands MedPharm Consulting Co, and implemented via random envelopes assigned to each site. In order to avoid potential selection bias, the sequence is concealed from both clinical staff and patients until assignment. Hence, neither investigators nor participants can influence which group the patients are assigned to.

    Description of the intervention

    Intervention Group 1

    Patients in this group will be administrated intravenous iron dextran 200 mg via a 30 min infusion, Q3W, a maximum of five doses during the planned 15-week treatment period, together with a routine dose 10 000 IU of EPO, three times weekly by subcutaneous injections. Previous studies25 ,26 ,36 show that intravenous administration of 100–300 mg of elemental iron every 3 weeks for a total dose of 1000 mg during the correction phase of anaemia will maximise the effectiveness of EPO. The single dose of iron 200 mg Q3W means an average dose of 67 mg per week, which is much lower than that in Group 2 (200 mg per week), since the 3-week administration interval results in a low calculated weekly iron dose in this group. Sensitivity analyses showed that intravenous iron-containing strategies remain cost-effective even with wide variations in the assumptions, particularly for cost savings with regard to EPO.37 All of the EPO and intravenous iron supplementations administrated in the study are provided by Shenyang 3SBio, but the company will neither participate in data collection, analysis or editing, nor make decisions about any publication strategies.

    At baseline prior to the start of treatment and thereafter every 3 weeks in the study treatment period, we will perform the following testing: complete peripheral blood cell count, physical examination, KPS (Karnofsky Performance Status Scale) & ECOG (Eastern Cooperative Oncology Group) scale, QoL, serum iron level (ferritin and transferrin saturation), and liver and kidney function.

    Intervention Group 2

    The EPO treatment for intervention Group 2 is the same as that for intervention Group 1, except for the intravenous iron dextran dosage. Patients here will receive iron dextran 100 mg twice a week through 30 min of intravenous infusion, and the total dose for the possibly consecutive 5-week treatment is 1000 mg (200 mg per week on average). Similar to those in Group 1, peripheral blood cell count will be assessed every week after the start of treatment; QoL and serum iron levels will be evaluated at baseline and at weeks 3, 6, 9, 12 and 15.

    Intervention Group 3 (controls)

    Study patients in the control group will receive double EPO dosage to 20 000 IU, three times a week by subcutaneous injections with a maximum of five doses for the entire study treatment period. Additional study measurements include EPO treatment dose and cumulative EPO costs.37 ,38

    Outcome measures

    All of the baseline, in-treatment and follow-up evaluations will be performed by experienced investigators in the study. The primary outcome measure is Hb response rate at week 15. A patient with CIA would be defined as an Hb responder to study treatment if either the Hb concentration of this patient is at least 12 g/dL or there is an increase in Hb levels of more than 2 g/dL compared to baseline level without blood transfusions initiated in the previous 28 days.36This definition was also adopted in prior studies of EPOs among patients with CIA.5 ,38

    Secondary outcome measures include the proportions of patients requiring therapeutic blood transfusions and the volume of transfused blood. Administration of EPO could significantly reduce the requirement for blood transfusions. In addition, we will also assess QoL of study patients using the Linear Analogue Self-Assessment (LASA) test and the Functional Assessment of Cancer Therapy-Anaemia (FACT-An) test. LASA is a self-assessment tool, with a graduation of 8 mm. It is designed to measure physical status, activities of daily living and overall QoL. FACT-An is a questionnaire which contains 55 tumour-related items, including a subscale for assessing fatigue-related anaemia. For cost-effectiveness analysis, dose of the study drug (EPO and intravenous iron supplementation) actually prescribed will be collected for each individual patient.

    Given the safety concerns regarding EPOs related to survival and tumour progression, we will additionally measure time-to-progression, which is defined as the time interval from randomisation until objective tumour progression. Tumour assessment according to RECIST35 will be performed at baseline, week 15 and then once per 3 months in the first year and thereafter per 6 months. As in some other trials, AEs related to study treatment will be recorded and collected at each visit. The safety profile of EPO and intravenous iron is evaluated by examining the incidence of AEs according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, VERSION V.4.0).39

    Sample size calculation

    We used R V.3.2.3 (R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2014. http://www.R-project.org/ (last accessed 10 Dec 2015) to conduct sample size estimation. The primary outcome measure is Hb response rate at week 15. With a sample size of 181 patients per group randomised, the pairwise comparison will be powered at 80% to establish non-inferiority for the primary end point, at a one-sided α level of 0.025, with a non-inferiority margin of 12%, assuming that the true effects are the same between treatments. Given an expected dropout rate of 10%, a total of 603 patients (201 patients per group) will be required to enrol into the study. Using this 12% non-inferiority margin might keep 75% efficacy of weekly EPO 36 000 IU over placebo among patients with CIA.40

    Statistical analysis

    The full analysis set according to the intent-to-treat principle will be established as the primary analysis population. Such data as demographics, baseline characteristics, safety and QoL will be summarised according to treatment group. The primary efficacy outcomes will be analysed using the Cochran-Mantel-Haenszel (CMH) test with study site, cisplatin-containing chemotherapy used or not and iron deficiency status at baseline as stratification factors. A logistic regression model will also be used to compare treatment effects by means of OR after adjusting for the aforementioned stratification factors. The TTP as survival data will be described with the use of the Kaplan-Meier curve, and analysed with log-rank test as well as the Cox proportional hazards model if proportional hazard assumptions hold true. Mixed-model repeated measure containing terms for treatment group, time, baseline measurement and time by treatment group interaction will be used to compare QoL data in the study.

    The Holm-Bonferroni method41 will be applied to account for multiple testing of the primary outcomes in the two non-inferiority pairwise comparisons. Therefore, a p value of <0.025 will be considered to indicate statistical significance for the lower p value, and a p value of <0.05 will be considered to indicate significance for the higher p value. R, V.3.2.3 and SAS software, V.9.2 (SAS Institute, North Carolina, USA) will be used for the statistical analysis.

    Ethics and dissemination

    Ethical considerations

    The independent ethics committee of Shanghai East Hospital approved the study protocol for all the participating centres (Approval No 2016003). The ethics committee agreed that this study will not raise patients' risk or cause extra harm to patients. It also agreed that the study is in accordance with the Declaration of Helsinki and that the study will be conducted without ethics problems. Written informed consent must be signed by patients or patients' proxies in cases of impaired decision-making capacity prior to enrolment.

    Relevance and dissemination

    Our study is to specifically target inadequate responders to erythropoietic therapy at a routine dose alone, a subpopulation that until now has not seemingly been studied well. It is expected that this multicentre, adequately powered randomised controlled trial will clearly demonstrate the potential benefit of combining epoetin treatment with intravenous iron supplementation.

    First, the intravenous iron supplementation is expected to replace EPO values or reduce the cumulative EPO dose. A cost benefit could be achieved with intravenous iron supplementation added instead of the EPO alone regimen.42 On the other hand, two regimes of iron supplementation will be compared so as to optimise iron administration for patients with CIA. Overall, as expected, the three treatment regimens will raise haemoglobin levels, reduce the proportion of patients requiring transfusions and improve patients' QoL. Second, collecting TTP information is in response to widespread concern regarding shortened overall survival and/or TTP due to EPOs.43–49 Such safety issues have been discussed by regulatory authorities in the USA and Europe for several years.40 In addition, as regards analysis, for the purpose of controlling any possible biases resulting from varied tumour type, chemotherapy agent/regimen, baseline iron level, etc we will use stratified randomisation technique as is appropriate for this study. This had better help set up any statistical modelling for data analysis. Multiplicity issues would also be controlled using the Holm-Bonferroni method.41

    In summary, intravenous iron supplementation might be considered to be administered concurrently with EPO therapy in patients with CIA. The study findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of CIA in China.

    Acknowledgments

    The authors wish to thank Sam Zhong (SZ) for his generous assistance with this study.

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    Footnotes

    • LC, HJ and WG contributed equally.

    • Contributors YG and LC conceived and designed the study. HJ and SZ supervised the power analyses and wrote the data analyses section. WG and LC bear overall responsibility for the design, ethical conduct and publication of the study. Administrative, technical and material support was provided by FCG and YJM. All authors edited the draft and contributed substantially to the manuscript; they all approved this submission.

    • Funding This study was funded by the National Natural Science Foundation of China (approval number 81573004); the Outstanding Leaders Training Programme of Pudong Health Bureau of Shanghai (PWRl2013-02); the Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (PWZxq2014-04); the National Natural Science Foundation of China Youth Science Fund (approval number 81301537); and the Shanghai Young Physicians Training Programme.

    • Competing interests None declared.

    • Ethics approval Independent ethics committee of Shanghai East Hospital.

    • Provenance and peer review Not commissioned; externally peer reviewed.