Outcomes of a Higher vs. Lower Hemodialysate Magnesium Concentration (Dial-Mag Canada)

• ClinicalTrials.gov Identifier: NCT04079582
• Recruitment Status: Active, not recruiting
• First Posted: September 6, 2019
• Last Update Posted: October 25, 2022
• Sponsor: Lawson Health Research Institute
• Collaborators: ICES; Canadian Institutes of Health Research (CIHR)
• Information provided by (Responsible Party): Lawson Health Research Institute

Tracking Information

• First Submitted Date: September 3, 2019
• First Posted Date: September 6, 2019
• Last Update Posted Date: October 25, 2022
• Actual Study Start Date: April 4, 2022
• Estimated Primary Completion Date: March 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2020)

Composite outcome of cardiovascular-related hospitalization and all-cause mortality [ Time Frame: Three to Four Years ]

Cardiovascular-related hospitalization (for myocardial infarction, ischemic stroke, or congestive heart failure) will be ascertained using primary discharge ICD-10 diagnosis codes in the Canadian Institute for Health Information's Discharge Abstract Database. All-cause mortality is recorded with over 99% accuracy in our data sources.

Original Primary Outcome Measures (submitted: September 3, 2019)

Composite outcome of all-cause mortality [ Time Frame: Three Years ]

The primary study outcome, all-cause mortality, will be evaluated at the patient level and ascertained from the ICES Registered Persons Database, Manitoba Population Research Data Repository, Alberta Health, and Population Data British Columbia.

Current Secondary Outcome Measures (submitted: April 23, 2021)

• Key secondary outcome - patient-reported muscle cramps [ Time Frame: Three to Four Years ]
  Patients will be able to voluntarily and anonymously answer a question on muscle cramps to describe on average how much this symptom bothered them in the past week. Responses will be recorded on a 10-point scale, with 0 indicating absence of the symptom and 10 indicating the symptom is at its worst. The question will be made available in the dialysis centre approximately twice a year. No patient identifiers will be collected and this outcome will be assessed at the level of the centre.
• Components of the primary composite outcome [ Time Frame: Three to Four Years ]
  Each component of the primary composite outcome (all-cause mortality and hospitalizations for myocardial infarction, ischemic stroke, and congestive heart failure) will be examined separately.

Original Secondary Outcome Measures (submitted: September 3, 2019)

• Occurrence and severity of muscle cramps [ Time Frame: Three Years ]
  Information on the occurrence and severity of muscle cramps will be collected using an electronic tablet in dialysis centres; data will be entered and saved into a secure password- protected website hosted by the Lawson Health Research Institute. No patient identifiers will be collected and this outcome will be assessed at the level of the centre.
• Fractures [ Time Frame: Three Years ]
  Many patients on dialysis are frail and prone to falling, which may also predispose them to suffer a fracture. Bone fractures are an important outcome and can result in morbidity, high economic costs, and mortality. Fractures will be defined based on a composite of hip, forearm (radius and ulna), proximal humerus, and pelvic fracture using diagnostic codes from the 10th version of the Canadian Modified International Classification of Disease system. We will estimate the rate of fractures for both arms of the trial.
• Composite outcome of cardiovascular-related hospitalization [ Time Frame: Three Years ]
  Composite outcome of cardiovascular-related hospitalization including: myocardial infarction, ischemic stroke, or congestive heart failure. These events will be ascertained using primary discharge diagnosis codes (International Classification of Diseases, 10th revision, Canadian Enhancement) in the Canadian Institute for Health Information 's Discharge Abstract Database.
• Cardiovascular-related mortality [ Time Frame: Three Years ]
  This outcome will be a composite of cardiovascular-related death. In Ontario, cardiovascular-related death will be primarily ascertained from the Office of the Registrar General-Deaths database, which contains information on cause of death for all deaths in the province; however, there is a 2-year time lag in data availability. Deaths that occur during the last 3 months of follow-up will be identified using the Registered Persons Database, and cause of death will be classified as cardiovascular-related if the patient is hospitalized or visits the emergency department with a cardiovascular event as the main diagnosis and dies in hospital (for the subset of patients who die in the last 3 months of follow-up outside of hospital, cause of death will be unknown).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Outcomes of a Higher vs. Lower Hemodialysate Magnesium Concentration (Dial-Mag Canada)
• Official Title: Outcomes of a Higher vs. Lower Hemodialysate Magnesium Concentration: A Pragmatic Cluster-randomized Clinical Trial in Hemodialysis Centres

Brief Summary

Many patients on hemodialysis have low levels of magnesium. Magnesium is needed to keep the heart, kidneys, and other organs working properly. Patients with low serum magnesium concentration have a higher risk of death, heart issues, muscle cramps and fractures. There are several reasons why patients on dialysis have low levels of magnesium-these include poor diet, medication interference, and the dialysis procedure itself, which leaches small amounts of magnesium from the blood during each treatment.

One way to make sure that patients on dialysis are getting enough magnesium is to increase its concentration in the dialysate. The investigator would like to do a randomized controlled trial to determine the effect of increasing the concentration of magnesium in the dialysate on the risk of people on dialysis dying or being admitted to the hospital due to heart issues. The investigator thinks increasing the magnesium in the dialysate will help patients live longer, have fewer hospitalisations related to heart disease and patients may also experience less cramping associated with dialysis.

This simple adjustment to the dialysis procedure can be done at little cost and may even reduce overall healthcare costs. If the investigator can show that increasing magnesium in the dialysate improves patients' health, then it could become the standard of care for all patients on dialysis.

Detailed Description

1. Statement of the health problem or issue

   In end-stage kidney disease, dialysis is needed to remove toxins and electrolytes that would otherwise accumulate in a patient's blood. The fluid used in dialysis, the dialysate, contains magnesium, and the lower the concentration of dialysate magnesium, the more magnesium is removed from a patient's body during dialysis. Understanding the optimal amount of magnesium to include in the dialysate is crucial as magnesium regulates more than 300 enzymes in the body and is vital to heart, muscle, and bone health.

   In Canada, the dialysate is prepared by central suppliers and contains magnesium in concentrations of 0.38, 0.5, or 0.75 mmol/L. In the absence of clinical trial evidence, there is no consensus on what magnesium concentration is best, and all 3 concentrations are used today in Canadian hemodialysis centres.

2. Objective of the project

   In outpatients receiving conventional hemodialysis, to determine if providing a higher versus lower dialysate magnesium concentration (0.75 vs. ≤0.5 mmol/L) as a centre policy alters outcomes important to patients and their providers.

3. Outline

   This is a pragmatic, two-arm, parallel-group, cluster-randomized, open-label, multicentre, comparative-effectiveness trial embedded into routine care in hemodialysis centres in Canada. Centres have been randomized to, and are receiving a dialysate magnesium concentration of 0.75 mmol/L or ≤0.5 mmol/L in the intervention and control groups, respectively. Patients receiving maintenance hemodialysis at these centres will be followed for study outcomes during the trial follow-up period.

   The trial is highly pragmatic to facilitate high intervention adherence and extensive uptake of the findings; pragmatic features include (i) broad eligibility criteria and a large representative sample of hemodialysis centres and patients, (ii) intervention implementation within routine clinical care delivered by dialysis unit personnel rather than researchers, (iii) follow-up of patient outcomes using routinely collected data sources, (iv) an intent-to-treat analysis using all available data, and (v) outcomes highly relevant to patients.

4. What is unique/innovative about the project?

   The investigator usually needs to study a large number of patients in a clinical trial to reliably understand the effects of a treatment. Normally, a study with 15,000 patients would cost more than $15 million dollars to conduct; however, this study will provide a reliable answer to the question being asked and cost less than $4 million. This is because the majority of data is already being collected by the healthcare system. For example, when a patient is hospitalized for a heart attack or stroke, this information is recorded in a secure healthcare database. The investigator will be able to analyze these healthcare data at the end of the study (and link patient outcomes to the type of dialysis treatment received (i.e. treatment or control). This innovative study design means that the study will be much larger (but cost much less) than a traditional clinical trial.

   This pragmatic trial includes all patients who receive chronic in-centre hemodialysis patients in participating centres. High-risk patients with multiple comorbidities, including cognitive impairments or disabilities, who are often excluded from trials because of their high-risk status are eligible for participation in the Dialysate Magnesium trial. By including patients from a variety of medical, ethnic, geographic, and socioeconomic backgrounds, the results of the trial should be broadly generalizable.

5. What is the impact of the proposed research?

For patients with severe kidney failure (10,000 in Ontario and >2 million worldwide), hemodialysis provides a life-saving treatment option; however a tragic 20-40% of patients die within one year of starting hemodialysis. The dialysate is a critical component of hemodialysis, yet little evidence is available to guide its optimal formulation. Dialysate magnesium in particular has received little scientific attention until recently, with new research suggesting that a higher dialysate magnesium concentration may benefit patients. Outcomes that may be improved include mortality, cardiovascular outcomes, and muscle cramps.

While it is possible to raise the concentration of serum magnesium through oral supplements, using dialysis to do this is simpler and safer. It has no additional cost, does not add to a patient's pill burden, is not dependent on an adherent patient taking their pills, and avoids the gastrointestinal side effects of oral magnesium supplements.

If the investigator is able to demonstrate that a higher dialysate magnesium concentration improves patient outcomes, this formulation can be readily adopted to improve the care of ∼2 million patients receiving hemodialysis worldwide.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention

Condition

• Kidney Diseases
• End-Stage Kidney Disease
• Hemodialysis

Intervention

• Other: Dialysate magnesium formulation of 1.5 mEq/L (0.75 mmol/L).
  (Dialysate magnesium concentration currently used in Canada and the United States)
• Other: Dialysate magnesium formulation of ≤1.0 mEq/L (≤0.5 mmol/L).
  (Dialysate magnesium concentration currently used in Canada and the United States)

Study Arms

• Experimental: Higher dialysate magnesium
  Intervention: Other: Dialysate magnesium formulation of 1.5 mEq/L (0.75 mmol/L).
• Active Comparator: Lower dialysate magnesium
  Intervention: Other: Dialysate magnesium formulation of ≤1.0 mEq/L (≤0.5 mmol/L).

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: January 6, 2020): 25000
• Original Estimated Enrollment (submitted: September 3, 2019): 15000
• Estimated Study Completion Date: March 2026
• Estimated Primary Completion Date: March 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria: This pragmatic cluster randomized controlled trial has only two inclusion criteria:

1. The hemodialysis centre, or a group of hemodialysis centers combined into one cluster, must care for at least 15 outpatients being treated with in-centre maintenance hemodialysis.
2. The medical director of the hemodialysis centre must be willing for their centre to be randomized and to adopt the allocated dialysate Mg protocol as their standard solution for the duration of the trial.

Exclusion Criteria:

• The centre, or group of hemodialysis centres cares for less than 15 patients being treated with conventional in-centre hemodialysis.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT04079582
• Other Study ID Numbers: R-13-999
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Lawson Health Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Lawson Health Research Institute
• Original Study Sponsor: Same as current

Collaborators

• ICES
• Canadian Institutes of Health Research (CIHR)

Investigators

• Principal Investigator: Amit X Garg, PhD, MD; ICES, Lawson, London Health Sciences Centre

• PRS Account: Lawson Health Research Institute
• Verification Date: October 2022