The objective of this study is to compare the efficacy of oral PIC and intravenous ferric sucrose infusion in maintenance hemodialysis patients with corrected anemia, and to evaluate the safety and cost-effectiveness ratio of the two treatment regimens.
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 23rd, 2020. Trial registration number is ChiCTR2000031166. The detailed flowchart 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 first treatment), weeks 4, 8, 12, 16, 20, and 24 after the first treatment or when the visit is terminated early. We used the SPIRIT reporting guidelines in the current study.
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 significance 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.
The target population in this study are patients undergoing maintenance hemodialysis, and who can meet the following eligibility criteria.
Patients must meet all the following criteria to be enrolled in the clinical trial:
- Age 18-75, either gender.
- Maintenance hemodialysis patients (≥ 3 months), dialysis frequency 3 times/week.
- Hemoglobin concentration 110–130 g/L (excluding 130 g/L).
- Transferrin saturation 20%–50% (excluding threshold value).
- Serum ferritin 200–500 μg/L (excluding threshold value).
- Used recombinant human erythropoietin (EPO) and iron at least 12 weeks before enrollment.
- Signed ICF voluntarily.
Patients who meet any of the following criteria will not be eligible to participate in this clinical trial:
- Iron allergy, allergic history, or intolerance to test drugs.
- Having erythrocyte aplastic anemia, other hematopoietic and hemolytic diseases,
- Acute and chronic bleeding.
- Serum albumin < 35g/L.
- Hypersensitive C-reactive protein >10 mg/L.
- Severe secondary hyperparathyroidism (iPTH ≥800 pg/mL).
- Severe cardiac dysfunction (NYHA score > 3) and poor control of hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg).
- 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.
- Malignant tumor.
- Severe bacterial or viral infection that occurred in the last 1 month, prior to signing consent.
- History of blood transfusion history in the last 1 month.
- Admitted to hospital or planned a kidney transplant during the trial.
- History of chronic alcohol abuse, substance abuse or any factors affecting compliance.
- Pregnant or breastfeeding woman.
- Life expectancy less than 12 months.
- Participating or has participated in clinical trials of other drugs within the last 3 months.
- Gastric and duodenal ulcers and ulcerative colitis.
- 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.
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.
- 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.
- 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 deficiency will be corrected first, and the EPO treatment regimen will be adjusted once TSAT and SF are normal.
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 first 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.
- 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.
- 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.
- PIC: The PIC prescription will be adjusted from one capsule daily to two capsules twice daily.
- 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
- TSAT will be measured at 12 weeks after patients receive either PIC or iron sucrose injection.
- TSAT of patients at 24 weeks of treatment.
- 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).
- Quality of life scale scores EQ5D-5L of patients prior to treatment and at 24 weeks of treatment.
- Indicators of oxidative stress, including malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), will be measured in patients before and at 12 and 24 weeks of treatment.
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 benefit 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 final trial evaluation. And the reason for withdrawal will be stated in the eCRF with all other appropriate and valuable information. Specific discontinuation and exit criteria are listed below.
- Patients with serious non-compliance to discharge criteria.
- Patients not having used the drug even once.
- Without any test records or follow-up data, no safety and efficacy data records.
- Affecting the trial evaluation by using prohibited treatments and drugs in the protocol during the trial.
- Other serious breaches of the scheme.
- Exit requested by the patient.
- Recurring intolerable adverse reactions.
- SF ≤ 200 μg/L or TSAT ≤ 20% within 2 consecutive months.
- Hb concentration < 90 g/L or > 130g/L within 2 consecutive months.
- Poor compliance, failure to comply to protocol thus affecting efficacy.
- Study observations could not be continued due to unforeseen circumstances occurring during the test.
The detailed contents of the statistical analysis methods of this clinical trial are as follows.
Data Set Category
- Full Analysis Set (FAS): The case of using drugs at least once and main analyzing efficacy 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.
- 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 specified above will be identified. 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 significant. Results of this clinical trial will be analyzed using SAS version 9.2 or above software.
Intravenous iron has the risk of potentially fatal allergic reactions, so we will conduct a small dose test before the first 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. 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.