- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02496676
Magnesium Supplementation in People With XMEN Syndrome
A Double-blind, Placebo-controlled, Crossover Study of Magnesium Supplementation in Patients With XMEN Syndrome
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.
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center, 9000 Rockville Pike
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Magnesium, then placebo
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.
|
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.
In Part I, participants will receive 12 weeks of oral placebo; will be dose escalated based on weight.
In Part II, participants will be hospitalized to receive 3 days of IV magnesium sulfate (MgS04).
|
Placebo Comparator: Placebo, then magnesium
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.
|
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.
In Part I, participants will receive 12 weeks of oral placebo; will be dose escalated based on weight.
In Part II, participants will be hospitalized to receive 3 days of IV magnesium sulfate (MgS04).
|
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
Time Frame: After 12 weeks of each intervention
|
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
Time Frame: After 12 weeks of each intervention
|
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
Time Frame: After 12 weeks of each intervention
|
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
Time Frame: 24 weeks, during phase 2 of study
|
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
Time Frame: 24 weeks, during phase 2 of study
|
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
Time Frame: 1 year
|
Participants with adverse events by grade using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4) grading criteria.
|
1 year
|
Participants With Severe Adverse Events
Time Frame: 1 year
|
Participants with severe adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4) to evaluate severity.
|
1 year
|
Collaborators and Investigators
Investigators
- Principal Investigator: Juan C Ravell Aumaitre, M.D., National Institute of Allergy and Infectious Diseases (NIAID)
Publications and helpful links
General Publications
- 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, 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.
- 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.
- 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.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Central Nervous System Depressants
- Peripheral Nervous System Agents
- Analgesics
- Sensory System Agents
- Anesthetics
- Membrane Transport Modulators
- Anticonvulsants
- Calcium-Regulating Hormones and Agents
- Reproductive Control Agents
- Calcium Channel Blockers
- Tocolytic Agents
- Magnesium Sulfate
Other Study ID Numbers
- 150161
- 15-I-0161 (Other Identifier: National Institutes of Health)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Magnesium L-threonate
-
Stanford UniversityMagceutics, Inc.CompletedDementia | Alzheimer's DiseaseUnited States
-
Miami Research AssociatesCompleted
-
Hartford HospitalUnknownQuality of Life | Arrhythmia | HypomagnesemiaUnited States
-
Hartford HospitalCompletedCoronary Artery Disease | Hypertension | Diabetes | DyslipidemiaUnited States
-
Massachusetts General HospitalNeurocentria, Inc.CompletedADHD | Attention Deficit/Hyperactivity DisorderUnited States
-
Lawson Health Research InstituteCanadian Institutes of Health Research (CIHR); ICESActive, not recruitingKidney Diseases | Hemodialysis | End-Stage Kidney DiseaseCanada
-
Pharmalyte Solutions LLCNot yet recruitingHypomagnesemia in Type 2 Diabetic Patients
-
Neurocentria, Inc.Ohio State UniversityCompleted
-
Iain BressendorffCompletedEndstage Renal DiseaseDenmark