Magnesium Supplementation in People With XMEN Syndrome

Study Overview
=================
Brief Summary
-----------------
Background: - X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia syndrome is called XMEN syndrome. In this genetic condition, the cells have less magnesium than normal. This makes it hard for the body to fight infections. Researchers want to see if magnesium supplements can make it easier for the body to fight infection. Objective: - To see if magnesium supplements can strengthen the immune system and reduce the amount of Epstein-Barr virus in people with XMEN syndrome. Eligibility: - People ages 6 and older who have XMEN syndrome Design: Participants will be screened with: Medical history Physical exam CT scan: Participants will drink a contrast and may get dye through an IV in the arm. They will lie in a machine that takes pictures of the body. EKG: Small sticky patches on the body will trace heart rhythm. Blood tests The study has 2 parts. Participants doing both parts will participate for 1 year and visit the clinic about 15 times. These visits will include a physical exam and blood and urine tests. Participants doing only the first part finish in 6 months and have fewer visits. For study part 1, participants will take magnesium pills for 3 months and placebo pills for another 3 months. At 3 and 6 months, they will have physical exam, medical history, blood and urine tests, and an EKG. If the magnesium pills are not helpful, participants will do study part 2. They will be admitted to the hospital for 4 5 days to get magnesium for 3 days through an arm vein. They will take magnesium pills for another 6 months.

Detailed Description
-----------------
X-linked immunodeficiency magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) syndrome is a primary immunodeficiency caused by the loss of expression of the magnesium transporter 1 (MAGT1). This syndrome is associated with cluster of differentiation 4 (CD4) lymphopenia, chronic EBV infection in most patients, and EBV-related lymphoproliferative disorders. The loss of MAGT1 leads to impaired T cell activation and decreased expression of the activator receptor, NKG2D on natural killer (NK) cells and CD8 T cells, leading to decreased EBV-specific cytolytic function of these cells. Results of previous studies suggest that magnesium supplementation may be a viable therapeutic option for patients with XMEN. The proposed study has 2 parts, and patients will be divided into 2 cohorts. Patients in cohort 1 (high EBV group) will have baseline blood EBV viral load greater than or equal to 5,000 copies/mL or EBV log greater than or equal to 3.7 IU/mL. Patients in cohort 2 (low/no EBV group) will have baseline blood EBV viral load <5,000 copies/mL or EBV log <3.7 IU/mL. Part I is a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of oral magnesium L-threonate in patients with XMEN syndrome. Within each cohort, patients will be randomized to receive escalating doses of either placebo or oral magnesium L-threonate for 12 weeks. Patients will then receive the crossover treatment (magnesium or placebo) for an additional 12 weeks. For patients who experience a 0.5-log decrease in the number of EBV-infected B cells (cohort 1) or a greater than or equal to 2-fold increase in NKG2D receptor expression on cluster of differentiation 8 (CD8+) T cells (cohort 2) with oral magnesium as compared to placebo, the study will be complete. Patients who do not meet this efficacy outcome will undergo a 2-week washout period and proceed to Part II, an open-label, non-randomized evaluation of intravenous magnesium sulfate (MgSO4) followed by oral magnesium L-threonate. These patients will be hospitalized to receive 3 days of intravenous MgSO4 in 3 daily doses totaling 30 mg/kg/day. They will then restart escalating doses of oral magnesium L-threonate and continue for the remaining 24 weeks of Part II. If conducted, Part II will allow for secondary analyses to compare different durations of magnesium supplementation.

Official Title
-----------------
A Double-blind, Placebo-controlled, Crossover Study of Magnesium Supplementation in Patients With XMEN Syndrome

Conditions
-----------------
XMEN

Intervention / Treatment
-----------------
* Dietary Supplement: Magnesium L-threonate
* Other: Placebo
* Drug: Intravenous (IV) magnesium sulfate (MgSO4)


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: All of the following inclusion criteria must be met prior to enrollment: Molecular diagnosis of the MAGT1 genetic defect Greater than or equal to 6 years years of age Willingness to stop magnesium supplements (other than the study agent) and any multivitamins or over-the counter-supplements that may contain magnesium for the duration of the study Willingness to go without magnesium supplementation during a 12-week placebo period and during both 2-week washout periods (pre-study and mid-study) Willingness to have samples stored for future research Must have a physician at home for follow-up care EXCLUSION CRITERIA: Chemotherapy or radiotherapy for lymphoma within 12 months prior to enrollment Rituximab exposure within 6 months prior to enrollment Systemic symptoms suggestive of evolving lymphoma History of clinically significant cardiac arrhythmias or cardiac defects Renal insufficiency (calculated creatinine clearance <50 mL/min or insufficiency requiring dialysis) Advanced heart block Hypermagnesemia, defined as magnesium serum concentrations >2 mmol/L (>5 mg/dL) Human immunodeficiency virus (HIV) seropositivity Signs or symptoms of life-threatening active microbial infection History of hypersensitivity to any of the study agents Any condition that, in the investigator s opinion, may substantially increase the risk associated with study participation or compromise the study s scientific objectives Participation in a clinical protocol which includes an intervention that, in the opinion of the investigator, may affect the results of the current study

Ages Eligible for Study
-----------------
Minimum Age: 6 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Magnesium, then placebo<br>In phase 1, participants received oral magnesium L-threonate for 12 weeks then crossover to placebo for 12 weeks, followed by a 2-week washout period. In phase 2, all participants received 3 days of intravenous MgSO4 in 3 daily doses totaling 30 mg/kg/day followed by oral magnesium L-threonate for 24 weeks. | Dietary Supplement: Magnesium L-threonate<br>* In Part I, participants will receive 12 weeks of oral magnesium L-threonate; will be dose escalated based on weight. In Part 2, participants will receive 24 weeks of oral magnesium L-threonate; will be dose escalated based on weight.<br>Other: Placebo<br>* In Part I, participants will receive 12 weeks of oral placebo; will be dose escalated based on weight.<br>Drug: Intravenous (IV) magnesium sulfate (MgSO4)<br>* In Part II, participants will be hospitalized to receive 3 days of IV magnesium sulfate (MgS04).<br>|
| Placebo Comparator: Placebo, then magnesium<br>In phase 1, participants received oral placebo for 12 weeks then crossover to oral magnesium L-threonate for 12 weeks, followed by a 2-week washout period. In phase 2, all participants received 3 days of intravenous MgSO4 in 3 daily doses totaling 30 mg/kg/day followed by oral magnesium L-threonate for 24 weeks. | Dietary Supplement: Magnesium L-threonate<br>* In Part I, participants will receive 12 weeks of oral magnesium L-threonate; will be dose escalated based on weight. In Part 2, participants will receive 24 weeks of oral magnesium L-threonate; will be dose escalated based on weight.<br>Other: Placebo<br>* In Part I, participants will receive 12 weeks of oral placebo; will be dose escalated based on weight.<br>Drug: Intravenous (IV) magnesium sulfate (MgSO4)<br>* In Part II, participants will be hospitalized to receive 3 days of IV magnesium sulfate (MgS04).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With a ≥0.5 Log Reduction in the Number of EBV-infected B Cells After Magnesium Supplementation as Compared to Placebo - Phase 1 | Participants with a ≥ 0.5 log decrease in the absolute number of Epstein-Barr virus (EBV) infected B-cells by flow cytometric Fluorescence in situ hybridization (FISH) assay after 12 weeks of oral magnesium supplementation compared to 12 weeks of placebo. | After 12 weeks of each intervention | 
| Participants With 2-fold or Greater Increase in NKG2D Expression in CD8 T+ Cells After Magnesium Supplementation as Compared to Placebo - Phase 1 | Participants with difference of a 2-fold or greater increase in NKG2D expression in cluster of differentiation 8 (CD8+) T cells after 12 weeks of oral magnesium supplementation versus 12 weeks of placebo. | After 12 weeks of each intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With 2-fold or Greater Increase in NKG2D Expression in CD8 T+ Cells After Magnesium Supplementation as Compared to Placebo - Phase 1 | Participants with difference of a 2-fold or greater increase in NKG2D expression in cluster of differentiation 8 (CD8+) T cells after 12 weeks of oral magnesium supplementation versus 12 weeks of placebo. | After 12 weeks of each intervention | 
| Participants With a Decrease in the Absolute Number of EBV Infected B Cells Before and After Magnesium Supplementation - Phase 2 | Participants with a ≥ 0.5 log decrease in the absolute number of Epstein-Barr virus (EBV) infected B-cells by flow cytometric Fluorescence in situ hybridization (FISH) assay before and after 24 weeks of magnesium supplementation | 24 weeks, during phase 2 of study | 
| Participants With 2-fold or Greater Increase in NKG2D Expression in CD8 T+ Cells Before and After Magnesium Supplementation - Phase 2 | Participants with a 2-fold or greater increase in NKG2D expression in CD8+ T cells before and after magnesium supplementation for 24 weeks in phase 2 of study | 24 weeks, during phase 2 of study | 
| Participants With Adverse Events by Grade | Participants with adverse events by grade using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4) grading criteria. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL Grade 4 Life-threatening consequences; urgent intervention indicated Grade 5 Death related to adverse event (AE) | 1 year | 
| Participants With Severe Adverse Events | Participants with severe adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4) to evaluate severity. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
magnesium transporter 1 (MAGT1), Primary Immunodeficiency, X-linked immunodeficiency, Epstein-Barr virus (EBV) infection, Neoplasia