Magnesium Supplementation in People With XMEN Syndrome

• ClinicalTrials.gov Identifier: NCT02496676
• Recruitment Status: Completed
• First Posted: July 14, 2015
• Last Update Posted: April 30, 2020
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description

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 <TAB>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, <TAB>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.

Condition or disease	Intervention/treatment	Phase
XMEN Disease	Dietary Supplement: Magnesium Threonate; Other: Placebo	Phase 1; Phase 2

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 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, lacebocontrolled, 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 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 openlabel, 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Placebo-controlled, Crossover Study of Magnesium Supplementation in Patients With XMEN Syndrome
• Actual Study Start Date: May 17, 2016
• Actual Primary Completion Date: April 23, 2020
• Actual Study Completion Date: April 23, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: magnesium threonate; Participants will receive 12 weeks of magnesium threonate and 12 weeks of placebo. Will be dose escalated based on weight.	Dietary Supplement: Magnesium Threonate; In Part I, patients within each cohort will be randomized into 2 arms. Each arm will receive 12 weeks of either oral magnesium L-threonate or placebo followed by crossover treatment for another 12 weeks. Patients in cohort 1 who experience >=0.5-log reduction in the number of EBV-infected B cells and patients in cohort 2 who experience greater than or equal to >=2-fold increase in NKG2D receptor expression on CDS T cells during oral magnesium treatment as compared to placebo will have completed the study. Patients who do not meet these respective criteria will undergo a 2-week washout and transition to Part II in which they will be hospitalized to receive 3 days of IV MgS04. These patients will then restart escalating doses of oral magnesium and continue for 24 weeks, at which point participation will be complete.; Other: Placebo; Participants will receive 12 weeks of placebo and 12 weeks of magnesium threonate. Will be dose escalated based on weight
Placebo Comparator: Placebo; Participants will receive 12 weeks of placebo and 12 weeks of magnesium threonate	Dietary Supplement: Magnesium Threonate; In Part I, patients within each cohort will be randomized into 2 arms. Each arm will receive 12 weeks of either oral magnesium L-threonate or placebo followed by crossover treatment for another 12 weeks. Patients in cohort 1 who experience >=0.5-log reduction in the number of EBV-infected B cells and patients in cohort 2 who experience greater than or equal to >=2-fold increase in NKG2D receptor expression on CDS T cells during oral magnesium treatment as compared to placebo will have completed the study. Patients who do not meet these respective criteria will undergo a 2-week washout and transition to Part II in which they will be hospitalized to receive 3 days of IV MgS04. These patients will then restart escalating doses of oral magnesium and continue for 24 weeks, at which point participation will be complete.; Other: Placebo; Participants will receive 12 weeks of placebo and 12 weeks of magnesium threonate. Will be dose escalated based on weight

Outcome Measures

Primary Outcome Measures :

1. Comparison of NKG2D receptor expression on CD8 T cells after 12 weeks of oral magnesium and after 12 weeks of placebo. [ Time Frame: At the completion of 24 weeks ]
   Difference between NKG2D expression in CDS T cells after 12 weeks of oral magnesium supplementation and after 12 weeks of placebo
2. Comparison of the absolute number of EBV-infected B cells after 12 weeks of oral magnesium and after 12 weeks of placebo. [ Time Frame: At the completion of 24 weeks ]
   Difference between the absolute number of EBV infected B cells (by EBV FISH) after 12 weeks of oral magnesium supplementation and after 12 weeks of placebo

Secondary Outcome Measures :

1. Assess the safety and tolerability of MgSO4 IV infusion and oral magnesium L-threonate [ Time Frame: 12 weeks and 24 weeks after starting Part II (as applicable) ]
   Assess incidence and severity of Res throughout study
2. Evaluate the effects of magnesium supplementation on intracellular free magnesium (Mg2 +) concentrations in peripheral blood T cell lymphocytes [ Time Frame: 12 weeks and 24 weeks after starting Part II (as applicable) ]
   Change in the intracellular pool of free Mg2 + by duration of magnesium supplementation regimen.
3. Evaluate the difference in NKG2D expression between patients with high EBV titers and patients with low or negative titers. [ Time Frame: 12 weeks and 24 weeks after starting Part II (as applicable) ]
   Evaluate the difference in NKG2D expression between patients with high EBV titers and patients with low or negative titers.

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:

All of the following inclusion criteria must be met prior to enrollment:

1. Molecular diagnosis of the MAGT1 genetic defect
2. Greater than or equal to 6 years years of age
3. 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
4. Willingness to go without magnesium supplementation during a 12-week placebo period and during both 2-week washout periods (pre-study and mid-study)
5. Willingness to have samples stored for future research
6. Must have a physician at home for follow-up care

EXCLUSION CRITERIA:

1. Chemotherapy or radiotherapy for lymphoma within 12 months prior to enrollment
2. Rituximab exposure within 6 months prior to enrollment
3. Systemic symptoms suggestive of evolving lymphoma
4. History of clinically significant cardiac arrhythmias or cardiac defects
5. Renal insufficiency (calculated creatinine clearance <50 mL/min or insufficiency requiring dialysis)
6. Advanced heart block
7. Hypermagnesemia, defined as magnesium serum concentrations >2 mmol/L (>5 mg/dL)
8. Human immunodeficiency virus (HIV) seropositivity
9. Signs or symptoms of life-threatening active microbial infection
10. History of hypersensitivity to any of the study agents
11. Any condition that, in the investigator s opinion, may substantially increase the risk associated with study participation or compromise the study s scientific objectives
12. Participation in a clinical protocol which includes an intervention that, in the opinion of the investigator, may affect the results of the current study

Contacts and Locations

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Juan C Ravell Aumaitre, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, Cohen JI, Uzel G, Su HC, Lenardo MJ. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011 Jul 27;475(7357):471-6. doi: 10.1038/nature10246.

Chaigne-Delalande B, Li FY, O'Connor GM, Lukacs MJ, Jiang P, Zheng L, Shatzer A, Biancalana M, Pittaluga S, Matthews HF, Jancel TJ, Bleesing JJ, Marsh RA, Kuijpers TW, Nichols KE, Lucas CL, Nagpal S, Mehmet H, Su HC, Cohen JI, Uzel G, Lenardo MJ. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science. 2013 Jul 12;341(6142):186-91. doi: 10.1126/science.1240094.

Li FY, Chaigne-Delalande B, Su H, Uzel G, Matthews H, Lenardo MJ. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood. 2014 Apr 3;123(14):2148-52. doi: 10.1182/blood-2013-11-538686. Epub 2014 Feb 18. Review.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02496676
• Other Study ID Numbers: 150161; 15-I-0161
• First Posted: July 14, 2015
• Last Update Posted: April 30, 2020
• Last Verified: April 23, 2020

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

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Neoplasia; magnesium transporter 1 (MAGT1); Primary Immunodeficiency; X-linked immunodeficiency; Epstein-Barr virus (EBV) infection