E cacy and Safety of Polysaccharide Iron Complex Capsules in Hemodialysis Patients: Study Protocol for a Randomized, Open-Label, Positive Control, Multicenter Trial (IHOPE)

Renhua Lu (  lurenhua1977@hotmail.com ) Shanghai Jiao Tong University School of Medicine A liated Renji Hospital https://orcid.org/00000003-3555-505X Xu Zhang Taixing People's hospital Xudong Cai Ningbo Hospital of chinese traditional chinese medicine Xiaoxia Wang Tongren Hospital Shanghai Jiaotong University School of Medicine Hua Li Zhejiang University School of Medicine Sir Run Run Shaw Hospital Li Wang Shandong Qianfoshan Hospital Yijun Zhou Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Jianxiao Shen Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Qian Liu Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Haifen Zhang Shanghai Jiao Tong University School of Medicine A liated Renji Hospital Zhaohui Ni Shanghai Jiao Tong University School of Medicine A liated Renji Hospital

Background Kidney disease is a serious threat to the health of people globally. According to the latest epidemiological data published in The Lancet in 2019, the prevalence of chronic kidney disease (CKD) among Chinese adults is 10.8% [1] . Anemia is one of the major complications in patients with chronic kidney disease, especially those undergoing renal dialysis. The incidence of anemia was 51.5% in 2,420 patients with CKD as seen in results from a Chinese cross-sectional epidemiological study, published in 2016 [2] . The study showed a high rate of iron de ciency anemia in Chinese patients with CKD, and the degree of iron de ciency was relatively serious [2] . According to a survey conducted for CKD, the incidence of iron de ciency anemia after dialysis was more than 60% [3] . However, iron de ciency anemia causes tissue health of patients [4] . Several evidence-based data show that iron de ciency anemia results in poor prognosis in patients with end-stage renal disease (ESRD), and it is one of the main reasons for the high rates of hospitalization and mortality in patients with ESRD [5] . There are nearly 800,000 dialysis patients in China, and standardized renal anemia treatment is imperative to slow down exacerbation of complications in patients with CKD post dialysis. The diagnosis and treatment of renal anemia has shaped clinical practice guidelines [6] .
Iron supplementation is an important treatment method to improve symptoms of anemia. The 2020 edition of the guidelines recommends that hemoglobin levels and iron metabolism status should be identi ed rst and addressed with potential causes of iron de ciency, before starting iron therapy [6] . Whether or not they are treated with erythropoiesis-stimulating agents (ESAs), patients with absolute iron de ciency should be treated with iron supplements. Also, patients with functional iron de ciency should be treated with iron supplements after weighing the bene ts and risks of treatment. Commonly used iron agents are intravenous iron and oral iron. However, iron overload still exists in clinical intravenous iron therapy. In 2011, the Japanese Society for Dialysis rst warned about the potential toxicity of intravenous iron maintenance therapy [7] . The issue of iron overload continues to be addressed in several guidelines around the world [8] . Oral iron can avoid iron overload, but the rst and second generation of oral iron have obvious gastrointestinal side effects, poor compliance, and other signi cant problems. Polysaccharide iron complex (PIC) capsule, is a third generation of oral iron agent that has been widely used in clinical practice due its advantages of little or no stimulation of gastrointestinal tract, few side effects, stable coordination, good solubility, and high iron content.
Iron therapy is still a challenge in the clinical treatment of renal anemia, hence it is necessary to conduct clinical studies to explore optimal treatment of renal anemia. This study is the rst multicenter clinical study of PIC in CKD patients with maintenance hemodialysis. It aims to evaluate the clinical e cacy and safety of oral iron and to provide additional drug options in the treatment of anemia in CKD patients. This clinical trial drug PIC, produced by SPH Qingdao Growful Pharmaceutical Co. Ltd, has been approved by the CFDA (national medicine permission number H20030033) and is a new oral iron supplement.

Objective
The objective of this study is to compare the e cacy of oral PIC and intravenous ferric sucrose infusion in maintenance hemodialysis patients with corrected anemia, and to evaluate the safety and costeffectiveness ratio of the two treatment regimens.

Trial design
This study is a multi-center, parallel controlled, randomized, open clinical trial (Version 1.1; Date 11 Dec., 2019, phase IV post-marketing) in China, which has been registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) on March 23 rd , 2020. Trial registration number is ChiCTR2000031166. The detailed owchart is shown in Figure 1. All eligible patients will be randomly divided into two groups in a 1:1 ratio: experimental group (conventional drug therapy + PIC) and control group (conventional drug therapy + iron sucrose injection). Patients will complete the study visit at baseline (within 7 days before the rst treatment), weeks 4, 8, 12, 16, 20, and 24 after the rst treatment or when the visit is terminated early. We used the SPIRIT reporting guidelines [9] in the current study.

Sample size
This clinical trial set has a non-inferiority threshold of 7 (%) and a variance of 11 (%) for the positive control group. The real difference between the tested drug and positive control is 2 (%). Unilateral signi cance level is 2.5%, with an assurance of 80%. In the case of 1:1 sample size between the control group and the experimental group, a total of 154 samples will be collected (77 of which will be in the control group and the experimental group, respectively). Considering 20% shedding rate, the actual planned inclusion number will be 186 cases.

Setting and recruitment
A total of 186 subjects will participate in the study and will be recruited in a competitive manner from 9 participating research centers. Prior to recruitment, the investigator will carefully study the past condition, including but not limited to disease diagnosis and previous dialysis status of each patient. Researchers will fully consider the compliance of the patients within 24 weeks. Informed consent forms (ICF) will be obtained before collecting any patient data and patient information. After the patients sign the ICFs, the investigators will also sign the ICFs and record the informed consent process in the medical records. Patients eligible for inclusion in the trial will receive intravenous infusion (100 mg total) of iron sucrose for two weeks after initial screening. If they still meet the inclusion criteria, they will be formally enrolled and started on medication. The treatment follow-up period of each patient is 24 weeks; the follow-up point of screening and treatment period are shown in Figure 2.

Eligibility Criteria
The target population in this study are patients undergoing maintenance hemodialysis, and who can meet the following eligibility criteria.

Inclusion criteria:
Patients must meet all the following criteria to be enrolled in the clinical trial [10]  . Used recombinant human erythropoietin (EPO) and iron at least 12 weeks before enrollment.

Signed ICF voluntarily.
Exclusion criteria: Patients who meet any of the following criteria will not be eligible to participate in this clinical trial: 1. Iron allergy, allergic history, or intolerance to test drugs.
. Severe liver disease (ALT, AST, and TBIL ≥ 2 times the upper limit of normal) or hepatitis B surface antigen positive, or hepatitis C antibody positive.
9. Malignant tumor. 10. Severe bacterial or viral infection that occurred in the last 1 month, prior to signing consent.
11. History of blood transfusion history in the last 1 month.
12. Admitted to hospital or planned a kidney transplant during the trial.
13. History of chronic alcohol abuse, substance abuse or any factors affecting compliance.
1 . Participating or has participated in clinical trials of other drugs within the last 3 months.
17. Gastric and duodenal ulcers and ulcerative colitis.
1 . Presence of conditions that the investigator believes may affect patient compliance or test results.

Randomization and allocation
A central randomization method will be adopted in this study, and the principles of open and randomized control will be followed. All eligible patients will be randomly divided into an experimental group or the control group in a ratio of 1:1. An interactive web response system (IWRS) of the electronic data acquisition system (EDC) will be used to allocate and manage the random number, and the experimental drug (PIC or iron sucrose injection) will be distributed according to the group corresponding to the random number. All information, including failure and success of patient screening, will be recorded, registered, and managed in the EDC system.

Intervention
Experimental group PIC will be taken orally, 2 capsules per day, for 24 weeks. Patients will be treated with EPO intravenously with a single dose of 10,000U once a week during the maintenance period. At the same time, EPO dosage will be adjusted according to the measured hemoglobin concentration, as follows [6] .
1. Discontinue EPO if Hb ≥ 130 g/L. Hb levels will be checked once every two weeks. If the Hb level drops to 110-130 g/L, the original EPO dose will be reduced by 25% or extended to once in 10 days for continuation.
2. If Hb < 110 g/L, TSAT, and SF are met, EPO will be administered as a single dose of 10,000U at least three times, every two weeks. Also, the Hb values of patients will be evaluated once every two weeks.
The maximum dose of EPO will be 10,000U twice a week. If TSAT and SF fail to meet the standard, the iron de ciency will be corrected rst, and the EPO treatment regimen will be adjusted once TSAT and SF are normal.
Control group 100 mg of iron sucrose injection dissolved in 100 mL 0.9% sodium chloride solution will be intravenously administered at the end of dialysis once every two weeks for 24 weeks. During this period, patients will continue to receive intravenous EPO treatment in the same way as the experimental group. For the rst intravenous infusion of iron sucrose injection, a small test dose will be performed. The test method refers to the drug instructions of iron sucrose injection, which are as follows.
1. Dosage: 1-2.5 ml (20-50 mg iron content) for adults. Children should be given 1 mL (iron content 20 mg) each time with body weight > 14 kg and given half of the daily dose (body weight kg×1.5 mg/kg) each time with body weight < 14 kg.
2. Caution: cardiopulmonary resuscitation equipment should be available during the test. If no adverse reactions occur after 15 minutes of administration, the remaining administration can be continued.
Dose adjustment during the trial If TSAT < 20% occurs during the test, the dosage of iron agent will be adjusted as follows.
1. PIC: The PIC prescription will be adjusted from one capsule daily to two capsules twice daily.
2. Iron sucrose injection: the prescription of iron sucrose injection will be adjusted from "100 mg/time, intravenous drop, once every two weeks" to "100 mg/time, once a week". If SF ≥ 500 μg/L and/or TSAT ≥ 50% after the above treatment, iron supplementation therapy will be stopped and SF and TSAT will be reevaluated twice a week. If SF < 200 μg/L and/or TSAT < 20%, or SF 200-500 mg/L and/or TSAT 20%-50% are found twice consecutively, iron supplementation therapy will be restarted. Iron supplementation therapy is iron sucrose injection 100 mg/time, intravenous drip, once a week Endpoints Primary endpoint 1. TSAT will be measured at 12 weeks after patients receive either PIC or iron sucrose injection.

Secondary endpoints
1. TSAT of patients at 24 weeks of treatment.
2. Hb, SF, Hct, and Hs-CRP values of patients before and at 12 and 24 weeks of treatment.

Drug costs for patients at 24 weeks of treatment (including rHuEPO and iron supplementation).
4. Quality of life scale scores EQ5D-5L of patients prior to treatment and at 24 weeks of treatment [11] .

Withdrawal and drop-out
Patients can withdraw from the clinical trial at any time for any reason without prejudice to the investigator's right to treat their disease. After fully considering the bene t of the patient, the investigator has the right to request the patient to withdraw for any reason, such as the occurrence of concomitant disease, adverse events, or treatment failure. The ethics committee reserves the right to request withdrawal of the patient for program violation, administrative reasons, or other valid and ethical reasons. All patients withdrawing from the clinical trial must complete a nal trial evaluation. And the reason for withdrawal will be stated in the eCRF with all other appropriate and valuable information. Speci c discontinuation and exit criteria are listed below.
Discontinuation criteria: 1. Patients with serious non-compliance to discharge criteria.

2.
Patients not having used the drug even once.
3. Without any test records or follow-up data, no safety and e cacy data records.
4. Affecting the trial evaluation by using prohibited treatments and drugs in the protocol during the trial.

Other serious breaches of the scheme.
Exit criteria: 1. Exit requested by the patient.
5. Poor compliance, failure to comply to protocol thus affecting e cacy.
. Study observations could not be continued due to unforeseen circumstances occurring during the test.

Statistical methods
The detailed contents of the statistical analysis methods of this clinical trial are as follows.
Data Set Category 1. Full Analysis Set (FAS): The case of using drugs at least once and main analyzing e cacy indexes after drug administered.

Per Protocol Set (PPS):
Good compliance case data that meets the main inclusion and exclusion criteria without affecting the main curative effects of prohibiting drugs during the trial.
3. Safety Set (SS): Case data involving usage of investigational drug product at least once, including safety evaluation.

Statistical analysis technique
The number of patients selected and completing follow-up visits in the population and centers will be listed separately, and the three analysis data sets (FAS, PPS, SS) as speci ed above will be identi ed [11] . Cases of protocol violation should also be listed and the reasons indicated. In terms of outcome indicators analysis, continuous variable indicators will count the number of cases (n), mean (), standard deviation (SMD), median (M), minimum (min), and maximum (max). The difference between groups will be analyzed using Student's-t-test. Counting and grading data will be used to calculate the frequency and composition ratio. χ2 test / Chi-square test will be used for differences between groups. Unless otherwise stated, all statistical tests will be conducted in a bilateral manner. For example, if P ≤ 0.05, the difference between groups is statistically signi cant. Results of this clinical trial will be analyzed using SAS version 9.2 or above software.

Harms
Intravenous iron has the risk of potentially fatal allergic reactions, so we will conduct a small dose test before the rst administration to ensure the safety of the patients. Safety endpoints are related directly to changes in laboratory safety indicators and incidence of adverse events between the treatment and control groups during follow-up. These endpoints will be listed according to the treatment received and recorded in detail. Patients will be followed up in detail, if any complications arise, appropriate treatment will be provided in accordance with current routine medical procedures.

Ethics and dissemination
This clinical study has been approved by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (approval number: 2019-048). Other participating sub-centers must also obtain ethics committee approval documents prior to the start of clinical trials. The Good Clinical Practice (GCP) principles and guidelines shall be strictly followed during the test implementation [12] . At the same time, any problems related to the clinical trial must be reported to the ethics committee in a timely manner, such as changes in the trial protocol or patient information page, serious adverse events, termination or early termination of the clinical trial, etc. After the publication of study results, the study report will be published in a peer-reviewed journal and/or at a national or international conference. All researchers involved in the design, writing and discussion of this clinical trial protocol, are listed as the authors.

Discussion
Anemia is one of the complications in patients on maintenance hemodialysis. The de ciency of hematopoietic iron is an important reason for this complication. Therefore, iron supplements are important to correct renal anemia [13] . Long-term iron de ciency anemia can cause serious consequences to the treatment and prognosis of patients with CKD. Normal hemoglobin levels will not only improve the quality of life of patients, but also reduce the probability of cardiovascular and cerebrovascular complications, thus reducing the hospitalization and mortality rate in patients [14] . The commonly used iron preparations in clinical practice include intravenous and oral iron agents. Compared to oral iron, intravenous iron has the advantages of faster onset and better absorption. But it also has some limitations, such as an increase in the risk of infectious complications [15] and increase in oxidative stress response. Moreover, intravenous iron dosage needs to be carried out in professional medical places, which require relatively high time and place of administration. At the same time, the health economics evaluation found that intravenous iron is more expensive than oral iron [16] . Accordingly, intravenous iron agent is inferior to oral iron agent in terms of the economic and convenience aspect of the treatment. At present, the main oral iron agent is divalent iron agent, which has some shortcomings such as low iron absorption rate, large gastrointestinal stimulation response, and relatively slow onset effect, which affect the therapeutic effect to some extent [17] . PIC, as an oral iron trivalent supplement, has the advantages of high iron content (46%), and gastrointestinal metabolism in the form of iron molecules without containing free iron ions.
The KDIGO Clinical Practice Guideline mentions that correction of iron de ciency with oral or intravenous iron supplementation can reduce the severity of anemia in patients with CKD. However, the guidelines do not explicitly mention the method of replacing intravenous iron with oral iron. The reason is the lack of high-quality comparative study on the e cacy of oral and intravenous iron [18] .
The same is true at home. Most of the domestic clinical evidence against PIC in China are based on bivalent oral iron as a control, which cannot fully con rm the application value and advantages of PIC in the treatment of anemia in maintenance hemodialysis patients [19][20] . Therefore, it is necessary to carry out further clinical trials to clarify the e cacy and safety of PIC in correcting anemia in the maintenance of hemodialysis patients. In this study, intravenous injection of iron agent-iron sucrose will be used as the control group, and it is assumed that the e cacy and safety of PIC in anemia and in maintenance hemodialysis patients will be not inferior to that of iron sucrose injection. The purpose of this study is to increase the head-to-head data of oral iron compared with intravenous iron treatment and provide highquality theoretical support for treatment of CKD patients with renal anemia. It is expected that this clinical trial will provide strong evidence as to the safety level and e cacy of PIC in the treatment of anemia in maintenance hemodialysis patients. Further it will provide a strong evidence-based basis for the development of guidelines in the treatment of chronic kidney disease complicated with renal anemia. Availability of data and materials

Abbreviations
The investigator must properly handle all the data obtained during the clinical trial, and truthfully record all adverse events and serious adverse events during the clinical trial, to ensure the rights and privacy of the patients participating in the clinical trial. In accordance with the regulations, the right to access all test records belongs to National Medical Products Administration, hospital ethics committee, medical inspection authorities, project managers, clinical research associate, etc., who verify the accuracy of the original data and understand the progress of the test during the trial. If the original records cannot be effectively veri ed, the investigator must assist the inspector/auditor in further verifying the quality of the data.
The group leader of this study has set up a data monitoring committee (DMC) for the purpose of ensuring the safety of patients and the quality of study data. The DMC is composed of clinicians and biostatisticians from the Clinical Center for Investigation, Renji Hospital, and School of Medicine, Shanghai Jiao Tong University who are not involved in this study. After publication of trial results, the trial report will be published in peer-reviewed journals and / or in national or international conferences.

Competing interests
None declared.

Funding
This research received no speci c grant from any funding agency including from the public, commercial, or not-for-pro t sectors.
Authors' contributions ZN is responsible for the integrity of the whole research work, participation in the clinical trial protocol drafting, clinical trial concept design and evaluation, interpretation of trial data, revision, and submission of trial protocol manuscript. RL, XZ, XC, XW, HL and LW are responsible for drafting the test plan, research design, data interpretation, and participation in writing and modifying the test plan manuscript. YZ, JS, QL, and HZ are responsible for research management, data collection, coordination, and quality control.
RL are in charge of writing the manuscript of the experimental schema. All authors have read and approved the nal manuscript. Flowchart of test scheme. Experimental group (routine treatment of CKD anemia + PIC), control group (routine treatment of CKD anemia + iron sucrose injection). Primary outcome: TSAT 12 weeks after treatment. Secondary outcomes: iron metabolism, oxidative stress, safety evaluation, pharmacoeconomic evaluation, quality of life score, etc.