Safety and efficacy of PG102P for the control of pruritus in patients undergoing hemodialysis (SNUG trial): study protocol for a randomized controlled trial

This is a multicenter, randomized, double-blind, placebo-controlled trial in which one group will be treated with PG102P (1.5 g/day) and the other with a placebo. It is an investigator-initiated clinical trial. The overall study algorithm is illustrated in Fig. 1. A superiority trial is planned to test the hypothesis that PG102P is effective in relieving pruritus for patients with end-stage renal disease undergoing HD. Nine tertiary university hospitals (Seoul National University Boramae Medical Center, Seoul National University Hospital, Seoul National University Bundang Hospital, Ewha Womans University Mokdong Hospital, Severance Hospital, Chungnam National University Hospital, Gachon University Gil Medical Center, Kyungpook National University Hospital, and Dongguk University Ilsan Hospital) will participate in the trial. It was retrospectively registered at http://​www.​clinical trials.​gov/ (NCT03576235). Patients aged over 19 years who have chronic pruritus despite conventional antipruritic treatment undergoing HD will be screened for the study participation. During the study period, antipruritic drugs which had been started before this study were administered in all of the study populations without changing the dosage of the drugs.

The inclusion criteria include the following:

The exclusion criteria are outlined below:

Randomization will be performed by an independent statistician using a computerized random number generator through the block randomization method of SAS 9.3 software (SAS Institute, Cary, NC, USA). Eligible participants will be randomly assigned 1:1 to either a placebo group or a treatment group. All subjects eligible for selection/exclusion criteria at visit 2 (baseline visit, week 0) will be assigned to a group according to the allocation codes of the blocked randomization method. Each patient will be given a unique study number. An independent data manager who is not involved with the clinical practice or patient recruitment will create the randomization sequence. The practitioners, participants, outcome assessors, and statisticians will be kept blinded to treatment allocation throughout the trial. The randomization lists will be computer-generated and concealed from the investigators by an independent data manager not involved in the study. This information will remain confidential and will not be available to the researchers. In this trial, emergent unblinding is not applicable.

The participants will visit the hospital seven times during the study: a screening visit (visit 1), visits during active treatment (visits 2, 3, 4, and 5), and a follow-up visit (visit 6). Each interval between visits is 2 weeks, except that between visits 4 and 5 (which is 4 weeks).

The primary endpoint is the change in VAS between visit 2 (week 0) and visits 3, 4, 5, and 6 (weeks 2, 4, 8, 10)—VAS change from baseline.

Itch severity will be measured by the patients using a VAS. A VAS consisting of a 10-cm horizontal line with 1-cm scale markings will be used. The patients will be asked to mark the intensity of their itch on the scale, with the strongest possible itch marked at the right end of the line (10 cm) and no itch marked at the left end (0 cm). The patients will be asked to mark the VAS value to record the worst degree of itch experienced during the previous day. Patients with an average VAS value of 4 or more for 5 consecutive days before visit 2 (week 0) will be enrolled. The average value of VAS measured 3 consecutive days before each visit (visits 3 to 7) will be used to evaluate itching.

Total immunoglobulin E, eosinophil count, eosinophil cationic protein, phosphorus, calcium/potassium, intact parathyroid hormone, Kidney Disease Quality of Life, and Beck Depression Inventory will also be assessed between week 0 and week 8.

Physical examination, comorbidity, and medication will be reviewed. Laboratory evaluations, including complete blood cell count, serum glucose, uric acid, total protein, albumin, total bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, blood urea, creatinine, total cholesterol, urinalysis, urine human chorionic gonadotrophin, and HIV status, will also be performed at visit 1.

Information on adverse events (AEs) will be obtained through nondirective questioning to every participant at each visit. The safety assessments include laboratory tests (hematology/blood chemistry, urinalysis), electrocardiogram, chest x-ray, physical examination, blood pressure, pulse rate, and changes in body weight. At least once after randomization, any AEs that occur after administration of the investigational drug will be assessed. All AEs will be summarized and presented with regard to severity, relationship to the investigational drug, and outcome. The schedule of enrollment, interventions, and assessments is presented in Fig. 2.

The enrolled participants will be randomly divided into two groups by at a 1:1 ratio. Under the assumption of 2.1 cm (with a pooled standard deviation of 2.4 cm) in the mean change difference in VAS values between the PG102P and placebo groups in a preceding pilot study with 0.9 of power, two-sided, and 0.05 of alpha, 28 participants will be allocated to each group. Considering a dropout rate of 30%, 80 participants will be needed (40 participants per group).

All data will be recorded by trained clinical investigators from each participating hospital in a standardized electronic case report form using a web-based database (Bethesdasoft Co., Ltd., http://​www.​mytrial.​co.​kr). Data will be handled confidentially and anonymously by qualified data managers. Quality control will involve collecting data on adherence to the intervention, patient inclusion and follow-up, as well as monitoring the quality of the data entry. Missing data or inconsistencies in the data will be detected by programs, and the results will be reported back to the investigator for resolution. If any given case is missing a main variable, the results of the closest observation are carried forward to the absence of the test data (last observation carried forward). Through this iterative process, we will clean the data and finally perform a database lock. All database backups of the electronic case report form will be done in real time.

Three analysis sets will be used for analyzing data. First, a safety analysis set will be applied to analyze safety evaluation parameters. Safety analysis will be performed for a group of subjects who have ingested at least one treatment after random assignment. Second, a full analysis set will be applied, which refers to the ideal set of subjects as close as possible to the principle of intentionality analysis (including all of the subjects randomized to enroll and receive at least one treatment). Third, a per-protocol set will be applied when all of the factors are in accordance with the research plan; patients show good compliance using 80–120% of the prescribed dose. All of the baseline variables must be available, and there must be no major violation of the test plan.

For the primary endpoint, the degree of change of the VAS averaged after treatment from baseline will be analyzed using the paired t test or Wilcoxon signed rank test in each group. The difference between the groups will be analyzed with the two-sample t test or Wilcoxon rank sum test. Additionally, an analysis of covariance will be conducted with adjustments for covariates. Similar to the primary endpoint, the same analyses will be performed for the secondary endpoints. For categorical variables, the McNemar test will be carried out to evaluate the change from baseline in each group.

Demographic and clinical characteristics will be reported in terms of mean ± standard deviation for continuous variables, or as frequencies and percentages for categorical variables. Differences between groups will be analyzed using the two-sample t test or Wilcoxon rank sum test for continuous variables and the χ² test or Fisher’s exact test for categorical variables.

AEs and adverse drug reactions will be tabulated for each treatment group in accordance with the system organ class and preferred terms of the Medical Dictionary for Regulatory Activities. The AEs and adverse drug reactions will then be classified according to severity, seriousness, and causal relationship to the study drug. Intergroup comparisons will be conducted using the χ² test or Fisher’s exact test.