Clinical trial NCT02837328
Conditions: Premature Atrial Contraction
Keywords: Magnesium Supplementation Magnesium Dietary Supplement Arrhythmia
Sponsor: University of Minnesota
Start date: 2017-03-01; Completion date: 2017-09-15
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this research is to determine whether oral magnesium supplementation in healthy, community-living individuals will be associated with reductions in the burden of arrhythmias in the upper chambers of the heart (supraventricular arrhythmias).

Detailed description:
To evaluate the primary objective, the Investigator will conduct a double-blind randomized trial assigning participants to receive 400 mg of oral magnesium in the form of magnesium citrate once daily or placebo. The investigators will recruit 60 individuals 55 years of age and older without a prior history of cardiovascular disease. At baseline, participants will undergo a basic examination, answer questionnaires and provide a blood sample to determine circulating magnesium levels. Participants will then wear an FDA-approved heart rhythm monitor (Zio ® XT Patch) for 2 weeks. At the end of 2 weeks they will begin taking their assigned treatment (magnesium or placebo), and will continue doing so for a total of 12 weeks (through study week 14). After 10 weeks of taking the supplement or placebo (study week 12), they will have a final study visit in which the participants will provide another blood sample for assessment of circulating magnesium, and will be asked to wear the heart rhythm monitor for another 2 weeks (through study week 14). The primary endpoint will be the change in burden of premature atrial contractions (PACs), measured in episodes per day, between baseline and final follow-up visit. A secondary outcome will be the change in circulating magnesium between both exams.

Arms: arm 1: 400 mg Magnesium Citrate 1x daily for 12 weeks arm 2: Placebo pill resembling 400 mg Magnesium Citrate 1x daily for 12 weeks
Interventions: intervention 1: Oral Magnesium Supplement intervention 2: Placebo
Intervention descriptions: intervention 1: 400 mg Magnesium Citrate 1x daily for 12 weeks intervention 2: Placebo pill resembling 400 mg Magnesium Citrate 1x daily for 12 weeks

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
A pilot randomized trial of oral magnesium supplementation 
on supraventricular arrhythmias 
 
 
 
 
NCT 02837328 
 
 
 
July 5th, 2018 


Materials and Methods 
The study was registered at Clinicaltrials.gov (# NCT02837328). The study protocol was 
approved by the University of Minnesota Institutional Review Board, and all participants 
provided written informed consent.  
 
Study participants 
Participants 55 years of age or older were recruited using fliers, the University of Minnesota 
StudyFinder website, invitations to individuals enrolled in the ResearchMatch research volunteer 
database, and invitations to University of Minnesota School of Public Health employees. 
Exclusion criteria included a prior history of heart disease (coronary heart disease, heart failure, 
AF), stroke, known kidney disease; use of type I or III antiarrhythmic drugs or digoxin; current 
use of magnesium supplements; any prior history of allergy or intolerance to magnesium; lactose 
intolerance; prior history of inflammatory bowel disease or any severe gastrointestinal disorder. 
Use of multivitamins was allowable, since these typically contain relatively low dosages of Mg 
(e.g. 50 mg).  
 
Eligible participants attended a baseline visit where measurements were conducted and a 
Zio® XT Patch (ZioPatch; iRhythm Technologies, Inc., San Francisco, California) heart rhythm 
monitor was applied by trained staff. After wearing the ZioPatch for 2 weeks, participants were 
randomized 1:1 to either 400 mg magnesium oxide or placebo using block randomization within 
two strata of age (younger than 65 and 65 and older). The randomization was carried out 
separately for the two randomization strata, age younger than 65 and 65 and older. In each group, 
a randomization schedule was generated using randomly permuted blocks of random sizes. 


Block sizes of 2, 4 or 6 were permitted. The randomization was implemented using the 
blockrand package in R.  
 
Following randomization, participants were mailed the study intervention, which they took 
for a total of 12 weeks. Ten weeks after beginning the study intervention, participants took part 
in a follow-up clinic visit, and a second ZioPatch was applied. Participants continued the study 
intervention until the second ZioPatch was removed (2 weeks after the follow-up clinic visit) 
(Figure 1). 
 
Study intervention and blinding 
The University of Minnesota Institute for Therapeutics Discovery and Drug Development 
produced the active study intervention (400 mg magnesium oxide) and matched placebo (lactose) 
according to Good Manufacturing Practices. The University of Minnesota Investigational Drug 
Service managed bottling per the randomization scheme. Study participants and all study staff 
were blinded to the treatment given. 
 
Measurements 
At the baseline and follow-up clinic visits, participants completed questionnaires and trained 
study staff conducted physiological measurements (i.e., anthropometry, blood pressure), 
phlebotomy, and applied the ZioPatch device. Treatment compliance was assessed by a pill 
count at the follow-up visit. At intervention days 21, 42 and 80 participants were also emailed 
unique links to online questionnaires, administered via REDCap [15], which queried compliance 
and asked the following open-ended question about adverse effects: “Since starting the study, 


have you experienced anything out of the ordinary?” Participant blinding was also assessed on 
intervention day 80, the last day of the study. 
 
The ZioPatch was used to identify premature atrial contractions (PACs). PACs are 
supraventricular arrhythmias associated with the future risk of AF [16-18] and are considered an 
intermediate phenotype of the arrhythmia, reflecting the underlying cardiac substrate that 
facilitates the development of AF [19]. Participants were asked to wear the ZioPatches for 2 
weeks after each clinic visit. Information obtained from the ZioPatch devices was processed by 
the ZEUS algorithm, a comprehensive system that analyzes electrocardiographic data received 
from the device [20]. We counted as PACs isolated supraventricular ectopic beats, 
supraventricular ectopic couplet total count, and supraventricular ectopic triplet total count. Total 
PACs were then divided by number of hours the ZioPatch recorded analyzable data, which 
yielded PACS per hour. 
 
Participants were asked to fast for 8 hours prior to blood draws. Serum magnesium and 
glucose were measured using the Roche Cobas 6000 at the University of Minnesota Advanced 
Research and Diagnostic Laboratory. Blood pressure was measured with the participant sitting, 
after a 5 minute rest, with a random zero sphygmomanometer (Omron Digital Blood Pressure 
Monitor HEM-907XL). Three measurements were taken; all three measurements were averaged 
for use in analyses. Height and weight were measured with participants in light clothing, and 
shoes removed. Height was measured with a research stadiometer and weight with a scale. 

SAP_001.pdf: 
 
 
 
 
 
A pilot randomized trial of oral magnesium supplementation 
on supraventricular arrhythmias 
 
 
 
 
NCT 02837328 
 
 
 
July 5th, 2018 


Statistical analysis 
The goal of the pilot study was to assess adherence to the Mg supplement, and feasibility of 
using the ZioPatch and collect preliminary data on PACs, a predictor of AF. The targeted sample 
size of 60 was determined to detect a difference in the change in log PACs (follow-up minus 
baseline) between treatment groups of 0.79 standard deviation units with 80% power and 5% 
type I error (2-sided), assuming 5 participants would not complete follow-up. 
 
All analyses were intent-to-treat. Descriptive statistics are provided according to treatment 
assignment for baseline characteristics, adherence, Mg concentrations and other outcomes. 
Differences in baseline characteristics between groups were assessed using t-tests for continuous 
variables and Fisher's exact tests for categorical variables. Linear regression was used to evaluate 
whether change in outcomes differed according to treatment assignment, adjusting for the 
randomization stratification factor (age ≥65 vs <65) and baseline value of the outcome with 
robust variance estimates for confidence intervals and P-values. Post-hoc sensitivity analyses 
further adjusted for sex. As PAC burden is highly skewed, we pre-specified using log PAC 
burden for analysis and reported the ratio of geometric means. Pre-specified subgroup analyses 
were also performed, stratified by baseline magnesium concentration (< vs. ≥ median). A 2-sided 
p-value of <0.05 was used to indicate statistical significance. Analyses were conducted using R 
[21] version 3.4.0 (R Foundation, Vienna, Austria).