Reporting of key methodological and ethical aspects of cluster trials in hemodialysis require improvement: a systematic review

We conducted this systematic review using a pre-specified protocol and reported our results according to published guidelines (PRISMA Checklist: Additional file 1: Appendix 2) [15].

We did not set any limits on country of study and included published primary reports of CRTs or study protocols of CRTs with an unpublished primary report. We aimed to include English-language reports published between January 2000 and November 2019 that involved (1) patients on in-center hemodialysis or( 2) patients on in-center hemodialysis as a subgroup in a larger study of non-in-center hemodialysis patients. When we found a study protocol of a CRT with an identified completed trial, we used the protocol to supplement any missing information from the final published report. Other reports such as secondary analyses, conference abstracts, and pilot or feasibility CRTs were excluded. We excluded feasibility and pilot trials because they have different methodological [16] and ethical considerations than full scale CRTs.

We implemented a search syntax on November 30, 2019, to identify published reports in MEDLINE and Embase.

Our search strategy combined two published search filters designed to identify publications related to CRT [17] and dialysis [18] studies (Additional file 1: Appendix 3). Two reviewers (AAA and KC) screened titles and abstracts of articles. AAA manually searched for additional articles in bibliographies of all included articles, list of articles that cited the included studies in Google Scholar, and “Similar articles” feature in PubMed. The complete list of included studies was also reviewed by an expert in the field (AXG) to capture additional studies that may have been missed.

We retrieved the full text of any article considered potentially relevant by any reviewer. Full-text articles were assessed for study eligibility by two reviewers (AAA and KC), with disagreements resolved through discussion. Agreement between the two reviewers was evaluated using the Kappa statistic [19].

We utilized a data abstraction form that was pilot tested on three studies by three reviewers (AAA, KC, and CEG). Thereafter, two reviewers (AAA and either KC or CEG) independently extracted data from each manuscript. Extracted details on trials considering the effect of clustering during sample size estimation and analysis were completed by AAA and either MT or SND. After each set of three studies, data extractions were compared within the pair and disagreements resolved by consensus. Details of extracted data are highlighted in Additional file 1: Appendix 4. We extracted data on study characteristics, methodological characteristics, data collection method, justification for using a CRT design, type of intervention, information regarding research ethics committee review, gatekeepers (i.e., an individual or body that represents the interests of cluster members, clusters, or organizations [20]), informed consent procedures, and any information about harm-benefit assessment or protection of vulnerable populations. Kidney disease disproportionally affects individuals traditionally considered vulnerable (e.g., patients with dementia). We defined vulnerable participants as any research participants who “may have increased likelihood of being wronged or of incurring additional harm,” as per the CIOMS international ethics guidelines [21]. This includes persons who have “impairments in decisional capacity, education, resources, strength, or other attributes needed to protect their own interests [21]”. We coded the presence of any vulnerable participants as clearly present, potentially present or unclear, and clearly absent or not relevant. If a vulnerability was clearly or potentially present, we looked for any reporting of additional protections provided by the authors.

We summarized results using frequencies for categorical variables and medians with interquartile ranges for continuous variables. Given the small number of included studies, we did not test changes in reporting over time nor association between reporting of ethical elements and study characteristics. For all our analyses, we used R (Version 3.6.2) [22].

The study flow diagram is presented in Fig. 1. We screened 777 citations and retrieved 29 full-text articles to assess eligibility. We identified another seven articles by reviewing citation links (n total = 36). We had almost perfect between-reviewer agreement on which studies met the criteria for review (kappa statistic 0.96, 95% confidence interval: 0.91 to 1.00). Five articles were excluded after full-text review [23‐27]. Thus, 31 articles were included in this review: 26 completed studies and 5 study protocols [28‐58].

Study characteristics for the included trials are presented in Table 1. The 31 trials were published in 19 journals. Nineteen trials (61%) recruited patients from the USA, three (10%) were from the UK, three (10%) from Australia/New Zealand, and seven (23%) from other countries (some trials were multi-national and these categories are not mutually exclusive).

Table 2 provides a description of the reporting of study characteristics. Thirty trials (97%) utilized a parallel arm design and one trial (3%) used a stepped-wedge design. All trials were designed as superiority trials. The types of randomized clusters were hemodialysis centers (n = 17; 55%), hemodialysis shifts or sessions (n = 12; 39%), providers or professionals (n = 1; 3%), and nephrology units (n = 1; 3%; it was not clear how a “nephrology unit” was defined). Clusters were randomly allocated to the treatment arm using unrestricted (n = 8; 26%), pair-matched (n = 4; 13%), stratified (n = 4; 13%), split-cluster (n = 11, 35% [i.e., day shifts within centers]), covariate-constrained randomization (n = 1, 3%), or an unreported method of allocation (n = 3, 10%).

The median (25th, 75th percentile) number of clusters included per trial was 28 (12, 43), and all trials used 1:1 randomization. One trial (3%) had one cluster per arm, and six trials (19%) had fewer than the minimum recommendation of four clusters per arm [7, 8]. The median number of participants per trial was 228 (120, 1723). All trials included patients (as opposed to providers alone) as the research participants with a median number of 20 (8, 32) patients per cluster.

One study (3%) reported the intra-class correlation coefficient (ICC) for their primary outcome. Table 3 describes whether and how clustering was accounted for during sample size estimation and analysis. Fourteen trials (45%) accounted for clustering during sample size estimation for the primary outcome, three (10%) did not account for clustering, two (6%) accounted for clustering but using a different outcome measure than the primary outcome, one (3%) was unclear, and 11 (35%) did not report a sample size or power estimate. At the analysis stage, 22 trials (71%) accounted for clustering using either an individual-level analysis adjusting for clustering or using a cluster-level summary method. The remaining nine trials (29%) either did not account for clustering in their primary analysis or it was unclear if clustering was accounted for in the analysis. A total of 13 trials (42%) accounted for clustering in both the sample size calculation and analysis.

Of all 31 trials, 15 trials (48%) reported a justification for using a cluster randomized design (Table 3). Thirteen trials (42%) reported using a CRT design to avoid contamination and two trials (6%) reported using a CRT design to avoid contamination and for logistical/administrative convenience.

Table 4 lists the types of intervention used in each arm of included trials. The most common type of study intervention was health promotion or an educational intervention (n = 22 trials; 71%) for which patients were the intended recipients. Six trials (19%) examined a direct patient therapeutic intervention—for example, intradialytic resistance training or antimicrobial barrier caps for central venous catheters. Among all trials, the intervention was necessarily administered at the cluster-level (e.g., education of providers) for 18 trials (58%). In the control arm, 23 trials (74%) utilized “usual care,” four (13%) used some form of augmented care (usual care plus some minimal elements of active intervention), three (10%) used an active control, and one (3%) used an attention-placebo. Four trials (13%) utilized interventions that included an educational or quality improvement component targeting health professionals (e.g., transplant education and engagement activities). Both prevalent and incident patients on hemodialysis were included in 22 trials (71%), eight trials (26%) included only prevalent patients, and one trial (3%) included only incident patients on hemodialysis.

Data collection procedures in the intervention and control arm were similar for most trials (Table 4). In the intervention arm, 30 (97%) trials used local routinely collected data (e.g., medical charts or electronic medical records) as the primary source for data collection. Eleven trials (35%) used clinical registry data and 24 (77%) supplemented routinely collected data with additional sources: self-administered questionnaires (n = 18; 58%), interviewer administered questionnaires (n = 9; 29%), specimen collection or physical examination not required for usual patient care (n = 4; 13%), as well as active data collection (n = 5; 16%), for example, using case report forms.

Five trials (16%) reported that a gatekeeper provided permission for clusters to participate in the study (Table 5). For the remaining trials (84%), no information about gatekeepers was provided.

We found that 26 trials (84%) reported research ethics committee approval, one (3%) reported that the study was exempt from review, and four (13%) did not report whether the study was reviewed by a research ethics committee (Table 5).

One trial (3%) reported they received an exemption from ethics review, three (10%) received a waiver of consent from the research ethics committee (see Additional file 1: Appendix 5), 22 trials (71%) reported obtaining consent from patients, and five (16%) trials either did not discuss the consent process or it was unclear if patients provided informed consent. For the 22 trials (71%) that reported obtaining consent from patients, written or verbal informed consent was reported in 10 trials (45%) for the study intervention and eight (36%) for data collection; the remaining trials provided no details about the method of consent for study intervention and/or for data collection (Table 4).

Among the remaining 27 trials that did not receive an exemption from ethics review or had a waiver of consent, the timing of consent took place before randomization for seven trials (26%), after randomization for 10 (37%), and was unclear for the remaining 10 trials (37%).

The ability for participants to opt out of the data collection was reported in seven trials (23%); three trials (10%) reported patients could not opt out of data collection, and ability to opt out was unclear for the remaining 21 trials (68%) (Table 5).

Vulnerable participants were clearly present in 6 trials (20%); in another 24 (77%), vulnerable participants were considered to be potentially present or their presence could not be clearly ruled out (Table 5). None of the trials reported additional protections for vulnerable patients.