Large-Scale Randomized Controlled Trials to Improve Hemodialysis Care

For patients with end-stage kidney disease, hemodialysis is a life-sustaining treatment that is required for over 2 million people worldwide (~26,000 in Canada). However, the quality of life for these patients can be poor, and often their average life expectancy after starting dialysis is less than five years.

Due to the poor outcomes and complexity of care for patients receiving dialysis, these patients are often excluded from clinical trials. In addition, nephrology has the fewest clinical trials conducted of any medical discipline. Of the limited trials that are conducted in nephrology, many fail to provide conclusive evidence because of small sample sizes, poor patient representation, missing data and poor adherence to allocated interventions. As a result, hemodialysis care is largely based on expert opinion rather than robust trial-based evidence.

As healthcare costs and our need for more-informed healthcare grow, the demand for innovative ways to conduct clinical trials has become a high priority. Our team has focused on conducting large-scale randomized controlled trials (RCTs) to improve hemodialysis care since 2017, with the support of the Canadian Institutes of Health Research (CIHR) Strategy for Patient-Oriented Research (SPOR) innovative Clinical Trials (iCT) Initiative.

Why Randomized Controlled Trials?

RCTs are considered the gold standard for testing the effectiveness of interventions because they can guarantee internal validity of our estimates as it tends to balance the distribution of measured and unmeasured variables between the trial groups in large enough samples. The results, therefore, generate tangible evidence to improve patient outcomes and healthcare provision.

In RCTs, participants are randomly assigned to different interventions (referred to as “arms”), with the aim to obtain valid intervention effect estimates. In some settings, such as hemodialysis centres, participants are naturally grouped together (e.g., into clusters) and randomization can occur at the group-level to assess interventions on a large scale (often referred to as a cluster randomized trials).

Pragmatic Randomized Controlled Trials in Hemodialysis

Pragmatic trials are intended to inform real-world clinical, policy or program choices by embedding the intervention into routine healthcare. This design allows all patients in the clinical setting to participate in the trial, resulting in a trial sample that is similar to the population of interest and trial findings that can be highly generalizable (i.e., external validity).

The use of pragmatic RCTs to answer important healthcare questions has become more popular over time. This is largely due to the expansion of integrated healthcare systems and the standardization of the collection of healthcare data in clinical settings. Researchers can obtain much of the information needed to conduct larger trials through routinely collected data (or ‘registries’).

That’s why a pragmatic registry-based RCT design with follow up through administrative data holdings is appealing in the kidney disease and hemodialysis setting. It allows us to efficiently test interventions used in current practice at a much lower cost than a traditional trial and with administrative ease. This type of trial design also enables our investigators to undertake RCTs by supporting the development and testing of innovative interventions using new methodologies and designs (integrated with SPOR’s principles), and building capacity for research through training.

For further resources regarding pragmatic RCTs, please see:

• Introduction to Pragmatic Clinical Trials, NIH Collaboratory
• Experimental Designs and Randomization Schemes
  • Introduction, NIH Collaboratory – Rethinking Clinical Trials
  • Statistical Design Considerations, NIH Collaboratory – Rethinking Clinical Trials

MyTEMP and MyTEMP Pro

In most hospitals and dialysis centres, the temperature of dialysis fluid, or dialysate, is set at 36.5°C to match body temperature. Based on preliminary evidence showing that using a cooler fluid may have cardiovascular benefits, a growing number of centres worldwide use a cooler temperature of 36°C or lower in routine care.

The MyTEMP Trial

The Major Outcomes with Personalized Dialysate TEMPerature (MyTEMP) trial was conducted as a pragmatic, registry-based cluster randomized trial to determine whether providing dialysis using a cooler dialysis fluid as a centre-wide policy reduces the risk of cardiovascular-related hospital admission or cardiovascular-related death compared with using a standard temperature of 36.5°C. The team included stakeholders from across Ontario.

This trial intervention was embedded into routine hemodialysis care at 84 hemodialysis centres across Ontario, with minimal-to-no interruptions to existing care. Centres were randomized to one of two groups and followed for four years (April 2017 to March 2021).

In one group, the temperature of the dialysis fluid was set to 0.5°C below each patient’s body temperature. In the other group, the temperature was set to 36.5°C for all treatments. The trial used routinely collected administrative healthcare databases held at ICES to obtain information about the trial participants as well as outcomes. The trial’s protocol and statistical analysis plan were published in the Canadian Journal of Kidney Health and Disease (CJKHD) on February 5, 2020, and August 27, 2021, respectively.

The researchers used several methods to ensure the study results were generalizable and cost-efficient. They:

• Integrated the intervention into routine care with minimal-to-no healthcare disruption for patients or staff,
• Included all patients at the 84 centres in the trial, which comprised of more than 95% of the patients receiving maintenance hemodialysis in Ontario during the trial period, and
• Used routinely collected data from administrative health data sources to assess outcomes.

Because of the methods used to design and implement the trial, MyTEMP is the largest trial of hemodialysis patients published to date, including more than 15,000 patients, with approximately 4.3 million dialysis treatments during the trial period.

“What’s remarkable about the MyTEMP trial is the tremendous support of our community and the methods we used. We embedded the trial into existing healthcare at nearly all hemodialysis centres in Ontario, enabling us to determine whether the intervention would improve outcomes in a real-world setting that represented all patients who receive hemodialysis in routine care.”

Dr. Amit X. Garg

MyTEMP PRO Sub-study

As part of a patient partner-developed and supported MyTEMP sub-study, the MyTEMP team collected information regarding patients’ symptoms at 10 dialysis units affiliated with the London Health Sciences Centre Regional Renal Program. We analyzed symptoms reported on an anonymous, five-minute survey completed by 345 patients. This sub-study provided valuable experience in collecting symptom data using electronic data capture, successfully piloting a data capture plan that will be used in future trials. The sub-study also provided additional and important information about the patient experience that could not have been obtained through routinely collected data.

Findings for MyTEMP and MyTEMP Pro

At the end of the trial, the MyTEMP team examined how many patients had cardiovascular-related hospitalizations or deaths in each group. The team determined that adopting a centre-wide policy of personalised cooler dialysate versus a standard dialysate temperature of 36·5°C did not reduce the risk of major adverse cardiovascular events or death.

In addition, the MyTEMP Pro sub-study found that respondents in the personalised cooler dialysate group were more likely to report feeling uncomfortably cold on dialysis when compared to respondents in the standard-temperature group. They published their findings for the MyTEMP trial and the MyTEMP Pro sub-study in The Lancet on November 4, 2022.

The Impact

Because of the innovative methods used to conduct the MyTEMP trial, investigators were able to generate high-quality evidence in a representative sample of patients. An absence of benefit compounded by the likelihood of patient discomfort indicates that cooler dialysate should not be adopted as a centre-wide policy.

For individual patient care, a practice guideline highly recommends cooler dialysate as a first-line treatment to prevent intradialytic hypotension. In their write-up, the MyTEMP authors do not advocate that cooler dialysate be abandoned. However, given the results of MyTEMP, they call for action to clarify the risks and benefits of this practice in select patients in future trials.

Funding

This study was funded by grants from the Canadian Institutes of Health Research, Strategy for Patient Orientated Research for Innovative Clinical Trials (MYG 151209), the Heart and Stroke Foundation of Canada (G-16-00012589), the Ontario Renal Network, the Ontario Strategy for Patient Orientated Research Support Unit, Dialysis Clinic Inc. (#C-3858), ICES, the Lawson Health Research Institute, and Western University.

Dial-Mag Canada

The concentration of magnesium in dialysis has received little scientific attention until recently, with new research suggesting that a higher dialysate magnesium concentration may benefit patients.

Magnesium is an essential element that supports heart, muscle, and bone health. During dialysis, some magnesium is removed from the blood, but dialysate has magnesium added to replace the magnesium removed during the dialysis process. The concentrations of magnesium in dialysate can vary depending on the dialysate manufacturer and the prescribing physician’s orders. In smaller trials, lower serum concentrations of magnesium were associated with a higher risk of cardiovascular disease, muscle cramps, and fractures.

The Trial

The Dialysate Magnesium (Dial-Mag) Trial is a large-scale randomized pragmatic clinical trial focused on determining whether different concentrations of magnesium in dialysate are associated with improved outcomes for dialysis patients. Dial-Mag is currently running in four provinces in over 160 hemodialysis centres across Canada. Through this trial, we hope to determine the optimal concentration of dialysate magnesium for patient health.

Dial-Mag is designed to be embedded into routine hemodialysis care. The allocated therapy will be supplied to the unit with no alterations to existing treatment or additional patient visits. Instead of using research coordinators at each centre across the country to collect data, Dial-Mag will leverage routinely collected data that is already being captured as a part of standard healthcare practice, requiring no additional data collection as part of the trial. As a result, the implementation of Dial-Mag creates very few, if any, disruptions to the workflow of ongoing healthcare to dialysis patients.

We anticipate sharing results on more than 8 million hemodialysis sessions by the of Fall 2027.

RESOLVE

The Randomized Evaluation of SOdium dialysate Levels on Vascular Events (RESOLVE) trial is an ongoing collaboration with The George Institute for Global Health in Australia, involving more than 300 hemodialysis centres worldwide. This multi-national initiative trial aims to establish whether treatment with a dialysate sodium concentration of 137 mmol/L, rather than 140 mmol/L, reduces cardiovascular events and death in hemodialysis patients. To date, 12 participating Ontario hemodialysis centres have been randomly allocated to a dialysate sodium concentration of 137 mmol/L or 140 mmol/L.

We are continuing further recruitment at other sites and are finalizing the analytic plan to aggregate data from Canada with global data. The trial started in 2017 with follow-up expected to end within four to six years.

Our team focuses on cultivating the next generation of researchers and enriching the talents of investigators by running a unique training program. This program enhances research capacity by providing investigators, patients, clinicians and healthcare administrators the knowledge, skill and support to prepare promising interventions for large-scale RCTs in hemodialysis and test innovative methodologies and designs.

The following trials, which are products of this unique training program, are currently being developed.

PREFERRED-1 (PRevEnting FracturEs in REnal Disease-1)

PI: Dr. Kristin Clemens

Patients on hemodialysis live with a fragility fracture risk that is more than 10-fold higher than the general population, but there remains a surprising lack of research into fracture prevention in this population. The PRevEnting FractuRes in REnal Disease 1 (PREFERRED-1) pilot trial is meant to address this knowledge gap. The team advancing this trial is comprised of endocrinologists, nephrologists, geriatricians, researchers, and patients. They are testing the intervention in a randomized, controlled pilot, looking at the use of denosumab, a monoclonal antibody commonly used in the treatment of osteoporosis (alongside supplemental calcium, vitamin D, and close bloodwork monitoring).

The intervention will be embedded in routine care delivered by the participants’ existing kidney care staff. The trial follows participants in six dialysis centres, capturing outcomes using ICES databases including the CIHI-DAD (hospital encounters), NACRS (emergency department encounters), OLIS Database (lab data) and the Ontario Drug Benefits Database (medication data). The PREFERRED-1 pilot will help investigators determine if a larger fracture-outcomes trial of denosumab is feasible in routine care.

DIURESED

PI: Melissa Schorr

Patients living with chronic kidney disease often struggle with extracellular sodium, or water retention, which can cause hypertension, undue cardiovascular stress and increased mortality. If the patient is receiving dialysis, a portion of this fluid retention can be managed by taking extra fluid off during dialysis. However, aggressive fluid removal can be hard for patients to tolerate and can cause significant drops in blood pressure or muscle cramps. Furthermore, changes in hemodynamics can have a significant negative impact on cardiovascular and neurological outcomes.

These patients are often prescribed diuretics to manage fluid retention. While diuretics are commonly used in patients with CKD and fluid overload due to heart failure, their role in patients on hemodialysis is unknown.

The Trial

The DIURESED Trial team hopes to determine if diuretic medications can reduce all-cause and cardiovascular mortality, and major adverse cardiovascular events in patients on hemodialysis who have residual renal function or ongoing urine output. The team also wants to know if these medications help preserve urine output and residual renal function, lead to lower interdialytic weight gain (and therefore lower ultrafiltration rates), and improve patient-reported outcomes such as muscle cramps

Prior to conducting a full-scale, multi-centre pragmatic clinical trial to answer these questions, the team will complete the following studies to lay the necessary groundwork and guide trial development:

1. A narrative review to summarize current knowledge regarding diuretic use in CKD and ESRD
2. An ICES study using observational data to summarize the capture of urine output in the database, the natural history of urine output in hemodialysis, current prescribing patterns of diuretics in hemodialysis patients, and explore relationships between urine output, diuretic prescriptions and cardiovascular outcomes and death.
3. A proof-of-concept study to determine whether diuretic medications augment urine output or residual renal function.
4. A multi-centre pilot trial aiming to evaluate the feasibility of a pragmatic clinic trial, to be conducted following the proof-of-concept study.

Dial-Bicarb

PIs: Amber Molnar & Sam Silver

Guidelines suggest that providers should use a pre-dialysis blood bicarbonate concentration target >=22 mmol/L, but these guidelines are based on weak evidence. Research conducted in small trials suggests correcting metabolic acidosis has positive effects on nutrition, muscle mass, insulin sensitivity and bone metabolism. However, large observational studies show that a higher dialysate bicarbonate concentration is associated with increased mortality.

The Trial

Designed as a large-scale pragmatic RCT, the Dial-Bicarb Trial will address this knowledge gap, intending to determine which dialysate concentration of bicarbonate is best for patient health. To inform the trial design, a retrospective cohort study is being completed, using ICES databases including:

• the Canadian Organ Replacement Registry (CORR – vital organ transplantation and renal dialysis activity),
• Discharge Abstract Database (DAD – hospital encounters),
• Ontario Health Insurance Plan Claims (OHIP – paid claims),
• Ontario Laboratories Information System (OLIS – lab data),
• the Registered Persons Database (RPDB – demographics),
• NephroCare® (dialysate session data) and
• the Ontario Drug Benefits Claims (ODB – medication data).

With the help of our patient partners, Brenden Cote, Austin Kinsella, and George Fontaine, and the support of ethicists Dr. Monica Taljaard and Dr. Cory Goldstein, this trial is designed to improve the quality of life for patients on dialysis.

During the last seven years, our team has worked with ethicists, patients, nephrologists, and other stakeholders to develop a responsible ethical framework for conducting pragmatic cluster randomized trials in the hemodialysis setting. A virtual consensus conference is being planned for the Spring of 2023 and will include a panel of international experts. The goal of the conference is to create a guidance document specific to the hemodialysis setting in the form of an extension to the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials.

In advance of the consensus conference, we have completed a literature review of published cluster randomized trials in hemodialysis, conducted interviews with key stakeholders including trialists, methodologists, and research ethics board members, held interviews and focus group discussions with patient partners and their families, conducted an in-depth ethical analysis, and appointed a patient advisory board.

Our work has resulted in four published manuscripts so far:

• Ethical issues in pragmatic cluster randomized trials in dialysis facilities, Cory Goldstein, Charles Weijer, Monica Taljaard, Ahmed Al-Jaishi, Erika Basile, Jamie Brehaut, Charles Cook, Jeremy Grimshaw, Eduardo Lacson Jr, Craig Lindsay, Meg Jardine, Laura Dember, and Amit Garg.
• Reporting of key methodological and ethical aspects of cluster trials in hemodialysis require improvement: a systematic review, Ahmed Al-Jaishi, Kelly Carroll, Cory Goldstein, Stephanie Dixon, Amit Garg, Stuart Nicholls, Jeremy Grimshaw, Charles Weijer, Jamie Brehaut, Lehana Thabane, P. J. Devereaux, and Monica Taljaard. 
• Patient Partner Perspectives Regarding Ethically and Clinically Important Aspects of Trial Design in Pragmatic Cluster Randomized Trials for Hemodialysis, Stuart Nicholls, Kelly Carroll, Cory Goldstein, Jamie Brehaut, Charles Weijer, Merrick Zwarenstein, Stephanie Dixon, Jeremy Grimshaw, Amit Garg, and Monica Taljaard.
• Ethical Issues in the Design and Conduct of Pragmatic Cluster Randomized Trials in Hemodialysis Care: An Interview Study With Key Stakeholders, Stuart Nicholls, Kelly Carroll, Charles Weijer, Cory Goldstein, Jamie Brehaut, Manish Sood, Ahmed Al-Jaishi, Erika Basile, Jeremy Grimshaw, Amit Garg, and Monica Taljaard.

Cultivating the next generation of clinical researchers is vitally important for the betterment of health and healthcare, the continuation of research, and the growth of knowledge and further research capacity. Thus, tending the seeds that our program has planted with new researchers is vital for the continued success of our research program. We are pleased to showcase two seeds that have flourished into saplings.

Featured Research by Trainees

Higher Concentration of Dialysate Magnesium to Reduce Muscle Cramps

Many patients living with kidney disease who receive hemodialysis experience muscle cramps. The cause for these cramps is not clearly understood and there are no proven prevention or treatment strategies available. One potential cause for muscle cramps experienced by patients receiving hemodialysis is a low concentration of serum magnesium. In fact, studies have shown that a low concentration serum magnesium is associated with poor health outcomes, including muscle cramps. 

As a part of the Dial-Mag Trial, internal medicine resident, Akshay Varghese and his team conducted a narrative review of hypomagnesemia and muscle cramps that included relevant articles in bibliographic databases, reference lists of relevant articles, and other sources.

Generally, this narrative review supports the need for a large, multicentre, RCT such as the Dial-Mag Trial, to determine appropriate concentrations of dialysate magnesium to prevent or treat muscle cramps caused by dialysis. Reviews such as this are necessary to ensure that trials are supported by previous research, furthering research that has already been conducted to advance healthcare for patients on dialysis.

Cluster Trials Considerations

Dr. Ahmed Al-Jaishi, a recent PhD graduate and post-doctoral fellow, focuses his research on cluster trial designs. In his PhD research, he evaluated factors that researchers consider when developing and utilizing a cluster randomized trial design in the hemodialysis setting.

As a part of this research, Dr. Al-Jaishi developed a machine-learning algorithm that could identify cluster randomized trials in bibliographic databases, even when authors did not explicitly identify the design as a cluster randomized trial in titles and abstracts. The algorithms identify cluster randomized trial reports with high sensitivity and moderately high specificity. This is important for researchers in the initial planning stages of cluster randomized trials. This tool has been made accessible to all researchers through an online portal.

Another project from Dr. Al-Jaishi’s PhD research focused on identifying best practices for randomizing hemodialysis units. He compared whether covariate-constrained randomization outperformed simple randomization in balancing baseline characteristics (e.g., demographics, illnesses). Simple randomization (e.g., flipping a coin) randomly allocates units to two treatment arms and is the easiest randomization method to use. Yet, there is a moderate to high chance of imbalance in baseline characteristics when a small number of units are available for randomization. For covariate-constrained randomization methods, the baseline characteristics are considered during the randomization process, and “good” schemes are identified from a list of possible randomization schemes. One scheme is then randomly chosen from the “good” schemes for the trial.

In this project, Dr. Al-Jaishi and his team conducted a mock three-year cluster-randomized trial with no active interventions, using historical data collected between April 1, 2014, and March 31, 2017. The trial included 11,832 patients from 72 hemodialysis units in Ontario, and the units acted as the clusters for the trial. The team applied the simple randomization method and two covariate-constrained methods to the patient cohort.

The study found that covariate-constrained randomization achieved a better balance of baseline characteristics when compared with simple randomization. Still, the magnitude of benefit was modest when there were 72 randomized units. The authors created a guidance document from this study that can be used when implementing covariate-constrained randomization. Dr. Al-Jaishi has contributed this research and his findings to the NIH Pragmatic Trials Collaboratory Rethinking Clinical Trials Living Textbook in the ‘Experimental Designs and Randomization Schemes‘ chapter.

Dr. Al-Jaishi’s research provides support to research planning to conduct cluster randomization trials. By providing the means for researchers to quickly identify cluster randomized trials in bibliographic databases, Dr. Al-Jaishi and his team have improved access to significant research findings. And by comparing randomization methods, Dr. Al-Jaishi and his team have helped inform the best design to randomize hemodialysis units. This work enables the design of impactful research that is less prone to bias.

Our team considers patient engagement to be vital to the nourishment and growth of our program. As such, cultivating relationships with our patient partners continues to be a priority. In 2022, we engaged with over 25 patients from four provinces across 10 projects. Through virtual meetings, patient partners have been involved in all research stages, including identifying research priorities, refining our research questions, finalizing our study plans, and assisting with interpretation of findings and knowledge translation.

Our patient partners help identify priority areas and are engaged in developing and implementing innovative, pragmatic controlled randomized trials that use ICES administrative health databases, hosting SPOR patient partner training sessions, and supporting the creation of the patient partner platform with Lawson Health Research Institute that will streamline patient engagement in research.

We appreciate all that our patient partners have done with us and look forward to continued collaboration. If you would like to engage with patients in your research and would like support, please contact pragmatictrials@lhsc.on.ca.

Dr. Amit Garg and advisors from Western University, ICES Western, Lawson Health Research Institute, and London’s academic hospitals are developing the Accelerating Randomized Trials (“ART”) Platform, to support researchers. The platform will help researchers conduct high-impact trials in multiple areas of healthcare, acting as a unique researcher-support and training program that gives investigators, patients, clinicians and healthcare administrators the knowledge, skills and aid to prepare promising interventions for RCTs.

One of the ART Platform’s streams, the Pragmatic Trials Stream, will build capacity and leverage existing expertise and data assets to conduct large-scale pragmatic RCTs testing simple, scalable, sustainable, and streamlined solutions. Meant to be ‘disease-agnostic,’ this platform will be available to support investigators as they conduct pragmatic trials testing real-world solutions across all medical disciplines.

Understanding how these trials are executed will help researchers avoid the many logistical barriers that can impede multi-centre traditional trials where hired research staff must manage patient recruitment and visits, intervention delivery and substantial data collection.

By leading the research team through a six-step program, the platform will enable teams to design, lead and execute large-scale RCTs in a better, faster, and cheaper way, ultimately, proving some interventions work, supporting their broad adoption in healthcare and contributing to healthier people and societies.

Specifically, the RCTs that will be supported through the Pragmatic Trials Stream often:

• use a simplified method of patient consent,
• are easily embedded into ongoing healthcare provision,
• do not require full-time research staff at recruiting centres to run,
• are easily run by routine healthcare providers without additional training,
• cost less,
• can be quickly implemented worldwide if the results of the trial show improved patient care or outcomes, and
• leverage existing data sources (i.e. large healthcare databases) for analysis.

On April 30, 2022, the ART Platform was launched through a virtual workshop that brought together the Western University research community to discuss the advancement of research that has the potential to impact the quality of health and healthcare delivery. Our team is currently building the structure and capacity to support the ART Platform and the Pragmatic Trials Stream, with the hope of a full-scale launch in or before 2024.  

In June of 2018, we held the inaugural Gardener’s Grove conference, where we gathered a coalition of the willing from researchers, patients, healthcare providers and other stakeholders to discuss exciting new ideas for patient-centred research. A number of those ideas have since been implemented as large-scale trials: an exciting legacy from the conference and something for the participants to be proud of.

Gardener’s Grove is returning!

Save the dates in your calendar: March 27-30, 2023, 10 am to 3 pm (EST) daily. A free, fully virtual, and accessible experience will bring together patients, caregivers, researchers, industry partners and policymakers who want to help develop and launch large-scale trials that have real promise to improve the lives of hemodialysis patients.

Much like at the first Gardener’s Grove in 2018, we will be bringing together a talented group of individuals to present exciting new ideas for pragmatic trial opportunities and to discuss patient-centred research. The goal is to identify ideas that need to be operationalized and advanced.

Gardener’s Grove 2023 is also inviting all attendees to showcase their pragmatic trial ideas and ideas with other attendees and speakers as part of the Attendee Showcase.

By attending this event, you will have the opportunity to:

• Present your idea for a pragmatic trial embedded into routine hemodialysis care.
• Socialize and network with individuals across the entire spectrum of hemodialysis care,
• Learn about and contribute to new clinical trial ideas being developed for implementation into routine hemodialysis care,
• Learn about and discuss the challenges faced with designing and implementing large-scale clinical trials, and
• Hear patient and caregiver perspectives.

For more information, visit www.gardenersgrove.ca. We look forward to seeing you there!

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