Design and methods of the REMOVAL-HD study: a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HaemoDialysis patients

The primary objective of the REMOVAL-HD study is to determine the change in pre-dialysis concentrations of serum albumin in participants undergoing chronic HD using the MCO Theranova dialyser between baseline and 6 months. This study will also examine the trend of serum albumin change over the 6-month treatment period and the proportion of participants with a drop in serum albumin of > 5% below their baseline value. The study will also assess the efficacy of clearance of the three middle molecules: lambda free light chains (lambda-FLC, MW 45 kDa), kappa free light chains (kappa-FLC, MW 22.5 kDa) and β-2 microglobulin (MW 11 kDa).

REMOVAL-HD is an investigator led, open label, non-randomised, single-arm, multi-centre device study. The study will involve 85 participants from 9 in-centre haemodialysis units in Australia and New Zealand. Table 1 summarizes the inclusion and exclusion criteria for the REMOVAL-HD study. Participants with urine output< 500 mL were included to minimise differences in clearance of measured molecules by residual renal function. The study is coordinated and supported by the Australasian Kidney Trials Network (AKTN) Fig. 1. demonstrates the overall study timeline. The study commenced in January 2017 and successfully completed recruitment in August 2017.

Ethical approval has been obtained from Institutional Ethics Committees (IEC) for each participating site (Protocol version 1.3 11th November 2016). The study will be performed in accordance with the 2013 Fortaleza, Brazil 7th Revision of the Declaration of Helsinki, the National Health and Medical Research Council (NHMRC) Statement on Ethical Conduct of Human Research (2015), Joint NHMRC/AVCC Statement and Guidelines on Research Practice (1997), applicable ICH guidelines, ISO 14155:2011 and Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with Therapeutic Goods Administration (TGA) comments. Informed signed consent will be obtained from all participants. This study is registered with Australian and New Zealand Clinical Trials Registry (ANZCTRN 12616000804482).

The timing of the study visits and changes in study treatment are shown in Fig. 2. All visits will occur when participants attend their usual HD session. Participants will undergo a wash-in, intervention and wash-out period, as outlined below.

The study visit schedule and timing of data collection are summarized in Table 2. Demographic and medical history, including age, gender, height and weight, race, blood pressure, heart rate, cause of ESKD, comorbidities, dialysis and medication history will be collected. Blood samples will be taken pre-dialysis at the mid-week HD session for local and central laboratory testing. Central samples will be centrifuged and stored at − 80 °C until analysed.

The study has been powered to identify a change of 5% in serum albumin concentrations from a median baseline level of 35 g/L (standard deviation of 5 g/L). A 5% decline in serum albumin has been shown to be associated with a doubling of mortality risk in haemodialysis patients [13]. To detect this change with 80% power at the 5% significance level, a sample size of 72 is needed. Allowing for a 15% loss to follow-up, a minimum of 85 participants need to be recruited to achieve the required sample size.

The 95% confidence interval for the mean difference in central serum albumin between 6 months and baseline will be used to assess the change in albumin: a clinically non-meaningful reduction in albumin due to MCO dialysis will be inferred if the lower limit of the confidence interval excludes a reduction in serum albumin that is equal to or exceeds 5% of the median serum albumin at baseline. Change in serum albumin levels over the entire intervention period (weeks 4 to 28) will be analysed using a linear mixed-effects regression model. This analysis will be adjusted for baseline serum albumin levels. Other continuous secondary outcome variables will be analysed using the same methods described above. Secondary outcomes that are categorical will be analysed using McNemar’s test for comparisons between 6 months and baseline and generalised estimating equations for trends across the intervention period. Serious adverse events (SAE), serious adverse device effects (SADE) and unanticipated serious adverse device effects (USADE) will be presented as number (percent) to assess the safety of the MCO dialyser. All hypothesis tests will be assessed at 5% level of significance.

For the purposes of this study, the period of observation for collection of treatment-related SAEs will be from the start of the wash-in period until the end of the wash-out period. All SAEs will be recorded regardless of whether they are related to the study intervention. SADEs, USADEs and SAEs will be recorded as part of the regular data collection activities of the trial.

Safety will be examined through close monitoring of data from individual participants rather than through statistical comparison. This will be achieved by continuous monitoring of serum albumin for any large reductions from baseline (> 25%) in serum albumin level. It will be the responsibility of the Trial Steering Committee (TSC) to protect the safety of trial participants and the scientific integrity of the trial by overseeing the monitoring of albumin levels, SAEs and operational data. For the purpose of data validation, the principal investigators will permit a member of the AKTN or its designee to inspect the source data and compare them with the case report forms. Notification of these audits will be sent to all investigators in advance.

Participants will revert to high-flux HD/HDF at any stage if any of the following occur:

When withdrawn from the study intervention, participants will continue to be followed up as per the trial procedures.

The MCO dialyser is a novel form of HD therapy. There is insufficient evidence regarding the safety and efficacy of this treatment in HD patients. The immediate and long-term effect following exposure to the dialyser will be examined in this single-arm study design. The results will inform the design of future, large-scale randomised trials using the MCO dialysers.

Serum albumin concentration is widely regarded as a surrogate for “health and a good prognosis” in the dialysis population. Serum albumin is strongly associated with survival [15]. Serum albumin concentration has anti-oxidant properties and its concentration represents both a patient’s nutritional status and inflammatory burden [16, 17]. Therefore, any new treatment which can potentially reduce serum albumin concentrations, such as with the MCO dialyser, must be considered with care.

There are two circulating isotypes of free light chain - kappa monomer (22.5 kDa) and lambda dimer (45 kDa) - that are metabolized and cleared by the kidneys. Thus, FLC concentration increases with progressive decline in renal function. There is emerging evidence to support the notion that higher FLCs may drive uraemic inflammation, endothelial dysfunction and ultimately poorer survival in this cohort [18, 19]. In addition, the assays used to measure lambda FLC are well validated and have been used commercially across a wide range of platforms [20]. Of the two FLC isotypes, the higher molecular weight of lambda provides the greatest discriminatory value for comparing the increased clearance of middle molecules offered by Theranova compared with conventional high-flux membranes.

After primary safety and efficacy assessment, this study will provide exploratory measures of the potential for increased removal of larger middle molecules to provide patients with clinical benefit. The measures chosen: restless leg syndrome; six-minute walk test (functional status); malnutrition inflammation score (nutritional status); and quality of life, all have validated tools for measurement and are linked to the retention of larger middle molecules. In addition to these variables, the study will document the clinical end points of hospitalisation (total and infection related) and mortality.