Trail design and setting
This is a pilot, single-center, randomized, open-label, controlled trial with balanced randomization (1:1) among patients on PD. The protocol of this study was reported adhering to the ‘Standard Protocol Items: Recommendations for Interventional Trials’ statement. After informed consent, all eligible participants will be randomized to the intervention group with vitamin D supplementation or control group. Participants will be followed for 12 months. Figure 1 shows the schema of the trial.
The study is being conducted in the PD center of Peking University First Hospital.
Ethical approval, trial registration, and dissemination
The study was approved by the Peking University First Hospital Research Ethics Committee (Project-ID:2016), and was registered at Clinicaltrails.gov on 29 August 2017 (Registration number: NCT03264625). The results will be disseminated in peer reviewed journals, lay summaries will be presented on “ScienceOpen”.
All patients who have recovered from a PD-related peritonitis at one month after the episode will be screened for eligibility. Patients will be recruited if they meet all of the following criteria: age at least 18 years; undergoing PD ≥1 month and clinically stable; weekly Kt/V ≥ 1.5 and no clinical uremic symptoms; and, serum 25-hydroxy-vitamin D [25(OH)D] <75nmol/l (30ng/ml). Patients will be excluded if they have any of the following: received vitamin D2/D3 or drugs known to alter serum 25(OH)D levels during the previous 12 months; have history of allergic reaction to cholecalciferol; have current or past malignant disease, active hepatitis or hepatic failure, acute systemic infection, active autoimmune diseases, severe digestive malabsorption or eating disorder, human immunodeficiency virus infection or acquired immune deficiency syndrome (HIV/AIDS); have a high probability (assessed by the recruiting physician) of receiving a kidney transplant or transition to hemodialysis (HD) or drop-out due to socioeconomic causes within 6 months; or women who were pregnant or lactating.
Written informed consent will be required from all study participants before their involvement in the trial. Participants can choose to withdraw from the study at any time without affecting their future treatment. Reasons for non-inclusion and withdrawal will be recorded in detail.
Randomization and blinding
All consenting patients will be registered in the trial and randomized 1:1 to either the vitamin D intervention group or the control group by a computer-generated random number list. An independent medical staff is responsible for participant enrollment and allocation assignment. The sample size for this pilot study will be 30 for both groups. (Fig 1) Due to the nature of medication intervention, neither participants nor researchers can be blinded. However, both the primary outcome (the assessment of feasibility and fidelity) and the key secondary outcome (time to peritonitis occurrence, recovery of peritonitis, peritonitis-related transition to hemodialysis, and peritonitis-related death) will be evaluated by independent medical staff who are blinded to participants’ allocations. In addition, all laboratory parameters for all participants will be measured by laboratory staff who are also blinded to treatment assignment.
The primary outcome is the assessment of feasibility (recruitment success, retention, adherence, safety) and fidelity (change in serum 25-hydroxy vitamin D level during follow-up) for a large, powered randomized controlled trial to determine the effects of vitamin D on the risk of PD-related peritonitis in the future. Secondary outcomes include time to peritonitis occurrence, recovery of peritonitis, peritonitis-related transition to hemodialysis, and peritonitis-related death (defined as death within 30 days of peritonitis onset)
Participants in the intervention group will receive additional vitamin D (Liquid natural vitamin D3, Cholecalciferol; 2000IU) in a dose of 0.08mL orally per day for 12 months following randomization. In order to assess medication adherence, participants will be asked to take the study medication that is left over for weighing on each clinical visit.
Participants in the control group will not receive any study drug and will be asked to not take any form of vitamin D supplementation.
For both the intervention and control groups, all dialysis and other medication prescriptions will be in accordance with routine clinical care and International Society for Peritoneal Dialysis (ISPD) guideline recommendations.
Baseline evaluation and follow-up
Data collection for this study is composed of two phases: baseline evaluation and follow-up. All the data will be recorded by the responsible physician in a uniform case report form (CRF). Detailed information collected in each phase is described below. Table 1 shows an overview of data collection schedule during baseline evaluation and follow-up. All participant information will be collected and maintained by trained medical staff to protect confidentiality.
For all eligible and consenting patients, information regarding demographic data (age, gender, body mass index [BMI], education, marital status, occupation, income, health insurance), dialysis duration, primary disease, co-morbidities, current medication, and history of PD-related peritonitis will be recorded. Baseline biochemistry indices (including blood routine, serum creatinine, albumin, alanine transaminase, lipids, electrolytes, parathyroid hormone, and serum 25(OH)D levels), dialysis adequacy (including urea clearance index [Kt/V] and creatinine clearance rate [Ccr]) and inflammatory biomarkers (interleukin-6, plasminogen activator inhibitor-1) will be evaluated. After randomization, the assigned treatment should be recorded in detail.
Follow-up and Outcomes Evaluation
All participants are planned to be followed-up for 12 months, with clinic visits every month. During the follow-up, clinical information including self-reported symptoms, and physical examination will be gathered. Biochemistry indices (including blood routine, serum creatinine, albumin, alanine transaminase, lipids, electrolytes, parathyroid hormone, and serum 25(OH)D levels) and dialysis adequacy will be evaluated every three months. Participants will be evaluated for compliance by weighing residual liquid vitamin D3 every month. All outcomes and adverse events will be recorded. Please refer to the following sections for detailed outcomes and adverse events.
The primary outcome is assessment of feasibility (recruitment success, retention of participants for 12 months, patient adherence, and safety), and fidelity (change in serum 25(OH)D level between baseline and 12 months). Secondary outcomes include time to peritonitis occurrence, recovery of peritonitis, peritonitis-related transition to HD, and peritonitis-related death (defined as death within 30 days of peritonitis onset). Death not associated with peritonitis, transition to HD not associated with peritonitis, and receiving a kidney transplant will be recorded as competing outcomes.
Recruitment will be determined as the proportion (percentage) of potentially eligible patients recruited into the trial: the numerator would be the number of patients recruited in the trial; the denominator would be the number of patients diagnosed with PD-related related peritonitis during the recruitment period. Successful recruitment will be defined as greater than 40%, the 95% CI (Confidence Interval) for this cut-point is 28% - 52%. Reasons for non-participation from those who were diagnosed with peritonitis but were not recruited will be recorded. Retention will be evaluated by measuring attrition during the follow-up at each clinic visit. Retention rate will be calculated as the percentage of patients who completed the trial among patients recruited in the trial. Successful retention will be defined as >80% at the end of the 12 months follow-up period. Adherence of taking vitamin D will be evaluated by weighing of vitamin D that is left over on each clinical visit. Adherence rate will be calculated as the percentage of patients who are adherent to the dosing regimen among patients recruited in the interventional group. Participants taken an average dose over 70% of the required dose are considered adherent to the dosing regimen. Acceptable adherence will be defined as greater than 80%. Fidelity will be measured by the difference of change in serum 25(OH)D level over time between the interventional group and the control group.
For the assessment of safety, both severe and non-severe pre-specified adverse events during the study course, including allergic reaction to vitamin D, hypercalcemia, and hyperphosphatemia, will be recorded. Severe adverse events include AE which fulfils at least one of the followings: life-threatening, requires hospitalization, results in disability or congenital abnormality, requires medical intervention to prevent one of the above outcomes.
The recovery of peritonitis was defined as complete resolution of peritonitis (normalization of body temperature, resolution of abdominal pain, clearing of dialysate, and PD effluent white blood cell count＜100 cells/µL with＜50% polymorphonuclear cells by using antibiotics alone without relapse within 4 weeks of completion of therapy).
Biochemical testing methods
Blood samples will be analyzed at Peking University First Hospital, Beijing. Biochemical profiles will be tested using an automatic Hitachi chemistry analyzer. Serum 25(OH)D levels will be measured using an electrochemiluminescence method (Roche Diagnostics, E601, Germany).
Statistical analysis will be conducted using SPSS (version 22.0, SPSS Inc.) and SAS software (version 9.4, SAS Institute). Continuous variables will be expressed as mean ± standard deviation, median with interquartile range, and percentages. Student’s t-test, Mann-Whitney U test, and the Chi-square test will be used to compare differences in baseline characteristics between intervention and control groups.
Recruitment rate, retention rate, and adherence rate will be reported as percentages and associated 95% CI. Adverse events will be recorded as event rate per patient-year. Linear mixed-effects regression models will be used to analyze change in serum 25(OH)D levels between the two groups. Competing risks Cox regression models will be used to compare time to peritonitis between the two groups. Logistic regression models will be applied to compare the short-term outcome of subsequent peritonitis.
For all statistical analysis, the level of significance will be set at 0.05.