Magnesium Supplementation in People With XMEN Syndrome

NCT02496676 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 15016115-I-0161
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

XMEN

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• Participants With 2-fold or Greater Increase in NKG2D Expression in CD8 T+ Cells After Magnesium Supplementation as Compared to Placebo - Phase 1

  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

  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

  24 weeks, during phase 2 of study

• Participants With Adverse Events by Grade

  1 year

• Participants With Severe Adverse Events

  1 year

Study Arms (2)

Magnesium, then placebo

ACTIVE COMPARATOR

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; Other: Placebo; Drug: Intravenous (IV) magnesium sulfate (MgSO4)

Placebo, then magnesium

PLACEBO COMPARATOR

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; Other: Placebo; Drug: Intravenous (IV) magnesium sulfate (MgSO4)

Interventions

Magnesium L-threonate DIETARY_SUPPLEMENT

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.

Magnesium, then placebo; Placebo, then magnesium

Placebo OTHER

In Part I, participants will receive 12 weeks of oral placebo; will be dose escalated based on weight.

Magnesium, then placebo; Placebo, then magnesium

Intravenous (IV) magnesium sulfate (MgSO4) DRUG

In Part II, participants will be hospitalized to receive 3 days of IV magnesium sulfate (MgS04).

Magnesium, then placebo; Placebo, then magnesium

Eligibility Criteria

• Age: 6 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 21796205 BACKGROUND

• 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.

  PMID: 23846901 BACKGROUND

• 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.

  PMID: 24550228 BACKGROUND

• Chauvin SD, Price S, Zou J, Hunsberger S, Brofferio A, Matthews H, Similuk M, Rosenzweig SD, Su HC, Cohen JI, Lenardo MJ, Ravell JC. A Double-Blind, Placebo-Controlled, Crossover Study of Magnesium Supplementation in Patients with XMEN Disease. J Clin Immunol. 2022 Jan;42(1):108-118. doi: 10.1007/s10875-021-01137-w. Epub 2021 Oct 16.

  PMID: 34655400 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms; Primary Immunodeficiency Diseases; Epstein-Barr Virus Infections; Infections

Interventions

threonic acid; Magnesium Sulfate

Condition Hierarchy (Ancestors)

Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Magnesium Compounds; Inorganic Chemicals; Sulfates; Sulfuric Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Ravell Aumaitre, Juan
• Organization: National Institute of Allergy and Infectious Diseases

juan.ravell@nih.gov

+1 301 761 6669

Study Officials

• Juan C Ravell Aumaitre, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 9, 2015
• First Posted: July 14, 2015
• Study Start: May 17, 2016
• Primary Completion: April 23, 2020
• Study Completion: April 23, 2020
• Last Updated: March 2, 2022
• Results First Posted: January 26, 2022

Record last verified: 2020-04

Locations

US (1)