Erythropoietin and Iron Supplementation for Patients With Chemotherapy-induced Anaemia

Study Overview
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Brief Summary
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A multicentre, randomized, open-label, parallel-group, active controlled non-inferiority study

Detailed Description
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Chemotherapy-induced anaemia (CIA) is a significant health problem for patients with cancer undergoing chemotherapy, causing fatigue and reducing quality of life (QoL). Up to 75% of cancer patients undergoing chemotherapy and/or radiotherapy reportedly experience mild-to-moderate anaemia (defined by a haemoglobin level of 9 to 11 g/dL). In clinical trials, erythropoietins (EPOs) have been shown to increase haemoglobin levels and improve anaemia and QoL in cancer patients. 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 tumor types (e.g., breast cancer), as it can activate important antiapoptotic pathways targeted by current antineoplastic therapies, thus counteracting their effects. Current guidelines in western countries and China recommend restricted usage of EPOs and reduction / prevention of blood transfusions in the treatment of cancer-induced anaemia. However, the inadequate response to erythropoietic therapy has not been well-characterized through rigorous studies and hence remains poorly handled in routine clinical practice. A major cause for not responding to EPO treatment is likely functional iron deficiency (FID), which is defined as a failure to provide iron to the erythroblasts despite sufficient iron stores. Patients with FID require supplementation of usable iron to optimize response to erythropoietic therapy, which might not be accomplished with oral iron. In a recent prospective, open-label trial, patients receiving epoetin alfa for CIA who were treated with IV iron dextran had a significantly greater Hb response compared with those receiving oral iron. Meanwhile, in patients with CIA and no iron deficiency, IV iron supplementation significantly reduced treatment failures to darbepoetin without additional toxicity. However, whether that IV 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 IV iron and serious AEs and mortality remains unclear, Zitt et al. found that the use of IV iron was associated with a 22% reduction in mortality. Therefore, investigators designed this multicentre, randomized trial to investigate EPOs in combination with IV iron with regard to an increase of Hb levels in patients who have inadequate responses to initial treatment with routine doses of EPOs.

Official Title
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Combination With Intravenous Iron Supplementation or Doubling Erythropoietin Dose for Patients With Chemotherapy-induced Anaemia Inadequately Responsive to Initial Erythropoietin Treatment Alone

Conditions
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Chemotherapy-induced Anaemia

Intervention / Treatment
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* Drug: Erythropoietins (EPO)
* Drug: Aggressive iron dextran supplementation
* Drug: Erythropoietins (EPO)
* Drug: Sustained iron dextran supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older; Had histologically, cytologically or clinically diagnosed malignant tumour and measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; 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 nonresponders are defined as those CIA patients with an increase of Hb < 1g/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. Exclusion Criteria: History of thromboembolism in the previous twelve months; Family history of hemochromatosis; Anaemia diagnosed with myelodysplastic syndrome or hematologic diseases such as Mediterranean anaemia; Received EPO treatment in the prior three months; Received erythrocyte suspension transfusion in the prior two weeks; Women who are pregnant or lactating; Have a history of hypertension or mental illness.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPO plus sustained iron dextran<br>Group 1, EPO treatment at the original dose plus IV iron dextran 200 mg every three weeks (Q3W) for 15 weeks | Drug: Erythropoietins (EPO)<br>* A routine dose 10,000 IU of EPO, three times weekly by subcutaneous injections.<br>Drug: Sustained iron dextran supplementation<br>* Iron dextran 200 mg, Q3W, through 90 minutes of IV infusion and a maximum of 5 doses<br>|
| Experimental: EPO plus aggressive iron dextran<br>Group 2, EPO treatment at the original dose plus IV iron dextran 100 mg, twice a week (BIW) for five weeks | Drug: Erythropoietins (EPO)<br>* A routine dose 10,000 IU of EPO, three times weekly by subcutaneous injections.<br>Drug: Aggressive iron dextran supplementation<br>* Iron dextran 100 mg, BIW, through 90 minutes of IV infusion, for the first consecutive 5 weeks<br>|
| Active Comparator: Double EPO<br>Group 3, the control group, doubling the EPO dose without preplanned iron supplementation | Drug: Erythropoietins (EPO)<br>* Doubling EPO dosage to 20,000 IU, three times weekly by subcutaneous injections with a maximum of 5 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hb response rate | A CIA patient would be defined as an Hb responder to study treatment if either 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. | up to week 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportions of patients requiring therapeutic blood transfusions |  | Within 15 weeks | 
| Time-to-progression (TTP) |  | Baseline, week 15, and then once per 3 months in the first year and once per 6 months thereafter up to 2 years | 
| Volume of transfused blood |  | Within 15 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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erythropoietin, iron supplementation, inadequately responsive, chemotherapy-induced anaemia