Oral magnesium supplements for cancer treatment‐induced hypomagnesemia: Results from a pilot randomized trial

Abstract Background and Aims Optimal management of cancer treatment‐induced hypomagnesemia (hMg) is not known. We assessed the feasibility of using a novel pragmatic clinical trials model to compare two commonly used oral Mg replacement strategies. Methods Patients with grade 1 to 3 hMg while receiving either platinum‐based chemotherapy or epidermal growth factor receptor inhibitors (EGFRI) were randomized to oral magnesium oxide (MgOx) or oral magnesium citrate (MgCit). The trial methodology utilized the integrated consent model. Feasibility would be successful if; accrual rate was ≥5 patients a month and if measures of patient and physician engagement, were > 50%. Secondary endpoints included; comparison of Mg levels, cardiac arrhythmias, and rates of treatment delay/hospitalizations. Results From July 2016 to December 2017, an average of 1 patient a month was accrued. All 15 eligible and approached patients consented to participate in the study (100% engagement) and 7/15 were randomized to MgOx and 8/15 to MgCit. The percentage of physicians who approached patients for the study was 4 of 6 (66.6% engagement). The mean slope of change in Mg (mmol/L/day) was 0.0022 (95% CI: −0.0001 to 0.0044) for MgOx and 0.0006 (95% CI, −0.0012 to 0.0024) for MgCit (P = .2123). Three patients (20%) required IV magnesium while on the study (2 MgCit and 1 MgOx). Grade 1 diarrhea occurred in 3 patients in the MgCit arm. Conclusion Despite oral magnesium tolerability and meeting most of its feasibility endpoints, this study did not meet its target accrual rate. Alternative designs would be necessary for a definitive efficacy study.

Given the absence of comparative randomized trials assessing the most effective oral supplementation for EGFR and platinum-induced hMg, the demonstration of clinical equipoise from surveys, the lack of efficacy of high-dose IV magnesium replacement, and the variable kinetics of different oral replacement strategies, there is a need for robust trials. Unfortunately, performing such trials using traditional clinical trial methodologies are challenging, expensive and unlikely to occur. Our team has been evaluating trial models for comparison of standard of care interventions that are more pragmatic, inexpensive, and practical. 12 In the current study, we assessed the feasibility of performing a pragmatic clinical trial using this novel methodology for comparing two commonly used oral Mg replacement strategies. In addition, given the continued renal losses of magnesium with ongoing both platinum and EGFRI therapies, we wished to evaluate if oral supplementation would blunt the decline in magnesium levels. 2,9,13 2 | METHODS

| Study population
Adult patients receiving palliative cisplatin, carboplatin, panitumumab, or cetuximab at the Ottawa Hospital Cancer Centre (Ottawa, Canada) who developed grade 1 to 3 hMg were potentially eligible for this study.
Patients were recruited from outpatient clinics and the chemotherapy treatment unit from July 13, 2016 to December 31, 2017 and gave consent to participate using the integrated verbal consent model. Grading of hMg was as per Common Terminology Criteria for Adverse Events (CTCAE) v4.03 with grade 1 defined as < Lower Limit Normal (LLN) to 0.5 mmol/L (1.2 mg/dL), grade 2 as <0.5 to 0.4 mmol/L (<1.2-0.9 mg/dL), grade 3 as <0.4-0.3 mmol/L (<0.9-0.7 mg/dL) and grade 4 as <0.3 mmol/L (<0.7 mg/dL). 14 Other inclusion criteria included: expectation of receiving ≥2 months of further therapy, potassium within normal limits, ECOG ≤2, ability to swallow tablets/capsules, and ability to provide verbal consent. Exclusion criteria included: grade 4 hMg (<0.3 mmol/L), baseline creatinine >1.5Â upper limit of normal (ULN) and current use of oral or IV magnesium supplementation. Patients who received 1 g of magnesium with their standard Cisplatin/Carboplatin chemotherapy regimens were eligible. Pre-treatment evaluations included standard of care biochemistry (including K + , Mg 2+ , creatinine) and an ECG.

| Ethical statement
The study was approved by the Ottawa Health Science Network Research Ethics Board (OHSN-REB) at the Ottawa Hospital. The trial was registered on clinicaltrials.gov (NCT02690012). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

| The ReThinking Clinical Trials (REaCT) program
The development of the REaCT program for comparing standard of care interventions is outlined elsewhere. 12 Briefly, after exploring the multiple processes and barriers to performing clinical trials, several issues with conventional clinical trials were identified that, if streamlined, could allow for more efficient, and effective pragmatic trials to be considered. The key components considered in the current study included: selection of a clinically relevant and practical question; demonstration of clinical equipoise through surveys of knowledge users and completion of systematic reviews; simply defined study endpoints and use of an integrated consent model (ICM) incorporating oral consent; establishing web-based randomization and real-time electronic data capture and management. 12,[15][16][17][18] While this methodology has been used before to compare supportive care and palliative agents, this was the first study to evaluate whether such a methodology was feasible for a real world of an intervention for patients with hMg.

| Trial design
This study was a prospective single center, open-label, randomized (1:1) feasibility pilot trial.

| Consent process
Potentially eligible patients were informed about the risks of hMg and the two different standard of care oral Mg replacement strategies available to them. The physician would provide the patient a consent template that briefly outlined the study and explain both the idea of randomization and the patient's right to decline study entry (see Data S1). Patients consented orally and this clinical interaction was documented in the patient's electronic health record. 12 Informed oral consent was obtained from all individual participants included in the study.

| Data collection
Data were collected both from the patient's electronic medical record (EMR) and emails sent to the treating physician when the patient returned to the clinic. Mg levels were collected retrospectively every 2 weeks for patients receiving panitumumab/ cetuximab and every 3 weeks for those receiving cisplatin/ carboplatin.

| Primary outcomes
A combination of endpoints was collected to evaluate the feasibility of performing a study with this novel methodology. These included: accrual rates (defined as the percentage of eligible and approached patients who consented to participate in the study) and measures of patient and physician engagement. Patient engagement was defined as the percentage of patients approached for the study that agreed to be randomized to the study intervention, while physician engagement was defined as the percentage of medical oncologists who agreed to participate in the study at study commencement and who approached patients and/or allowed their patients on the study. This study would be deemed feasible if ≥5 patients per month were accrued and the patient and physician engagement was >50%.

| Secondary outcomes
Secondary outcomes were clinical in nature and included: comparison of the slope of change in Mg levels (from baseline) over time between the two regimens. In addition, the association of baseline QTc and grade of hypomagnesemia at baseline was assessed as well as the rates of treatment delays and hospital admissions due to hMg.

| Sample size and statistical analysis
A convenience sample size was calculated from the estimated incidence of hMg at our center. Approximately 242 patients a year receive palliative systemic therapy platinum or EGFR inhibitor-based at our center. Of these patients around 80% will receive platinum-based therapy and given the incidence of hMg in this population 1,2 it was estimated the 10 patients/month would develop hMg. As not all patients would choose to enter the study and others would be ineligible (eg, high creatinine, low potassium) a practical accrual rate of 5 patients per month (ie, 60 patients over a year) was established as being an accrual rate that may allow future expansion of the study with adequate power to compare Mg-replacement strategies and therefore current analyses were considered exploratory. Study results are presented descriptively, and following the recommendation of the CONSORT extension statement for randomized pilot and feasibility trials. 19 Patients were stratified by EGFRI or platinum containing systemic therapy. For each participant, a linear regression was fitted to change in Mg level from baseline with time from baseline being the independent variable. The slopes obtained from the regression were compared between groups using Wilcoxon rank sum test. An exploratory sensitivity analysis (mixed effects model) was also performed.
All analyses used SAS 9.4 by SAS Institute Inc. Cary, NC, USA.

| RESULTS
The trial ran from July 2016 to December 2017 and during the study period, the trial investigators were contacted about 24 potentially eligible patients. Of these patients, 15 (62.5%) were eligible ( Figure 1).
The reasons for ineligibility were; low potassium level, 2 high creatinine level, 2 lactose allergy, 1 inability to swallow tablets/capsules, 1 patient on the last cycle of planned treatment, 1 patient declined systemic therapy 1 and patient not receiving any of the specified therapies. 1 The baseline characteristics of the study population are shown in Table 1.  consented to participate in the study and agreed to the study intervention (100% engagement).

| Physician engagement
While all medical oncologists agreed to allow their eligible patients to be approached and participate in the study, the percentage of physicians who actually approached patients was 4 of 6 (66.6% engagement).

| Secondary outcomes measures
Clinical endpoint data are reported in Table 2

| QTc assessments
Baseline ECGs showed incidental long QTc in 3/15 (20%) patients and with no patients developing arrhythmias on the trial. There was a nonsignificant negative correlation between baseline Mg levels and QTc (Frederica) À0.11 (P = .63). Follow-up ECGs were not routinely obtained for a significant number of patients for comparison of on trial effects.

| Treatment delays and hMg-induced hospitalization
There were no treatment delays or hospitalizations for hMg during the study in either study arm.

| CONCLUSION
This study did not meet its feasibility endpoint due to the low number of patients accrued, which suggests that the integrated consent model is not optimal for randomization when the topic of interest occurs after initial management decisions. Oral Mg replacement strategies for patients who develop hMg from platinum and EGFRI based therapies are effective at preventing further Mg decline and are well tolerated. The optimal oral Mg supplement strategy is yet to be determined.

ACKNOWLEDGEMENTS
We are grateful for patients and their families for their assistance with this study, as well as physicians for approaching patients.

CONFLICTS OF INTEREST
AA reports participating in the Novartis Canada Advisory Board on the use of Ribociclib, BH consults for Cornerstore Research, not related to this research project. All other authors have nothing to disclose. Dr Michael Vickers had full access to all the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
Dr. Michael Vickers affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.

DATA AVAILABILITY STATEMENT
Due to the small number of participants, this study dataset contains potentially identifying and sensitive patient information. Access to data requests can be made to the Ottawa Health Science Network Research Ethics Board (613-798-5555 ext. 16 719 or rebadministration@toh.ca).