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Colorectal cancer is the fourth most common incident cancer and the second most common cause of cancer death in the United States, with approximately 150,000 new cases and 57,000 deaths per year. High calcium intake and magnesium may protect against colorectal cancer and adenoma, however, results have been inconsistent. We found that genetic makeup, associated with magnesium absorption and re-absorption, significantly interacted with the calcium and magnesium ratio in relation to the both adenomatous and hyperplastic polyps. Participants who carried at least one 1482Ile allele (G->A)of TRPM7 and who consumed diets with a high calcium/magnesium ratio were at a higher risk of adenoma and hyperplastic polyps than were participants who did not carry the polymorphism. We hypothesize that the reduction in the dietary Ca/Mg ratio may change the markers directly related to tumorigenesis. The primary aims of this study are to conduct a randomized placebo-controlled intervention trial to test whether reducing the Ca/mg intake ratio through magnesium supplementation has effects on the related biomarkers. We will also examine whether the effect of modulating Ca/Mg intake ratio may be more pronounced among those who carry the 1482Ile allele compared those who don't carry the 1482Ile allele. Results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies to prevent occurrence of colorectal adenoma, and thus, colorectal cancer through dietary change or nutritional fortification.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GG genotype and magnesium treatment | Active Comparator | Participants who have the GG genotype will be assigned to magnesium glycinate. |
|
| GG genotype and placebo | Placebo Comparator | Participants who have the GG genotype will be assigned to placebo group |
|
| GA/AA genotype and magnesium treatment | Active Comparator | Participants who have the GA/AA genotype will be assigned to magnesium glycinate |
|
| GA/AA genotype and Placebo | Placebo Comparator | Participants who have the GA/AA genotype will be assigned to placebo group |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Magnesium glycinate | Dietary Supplement | Oral administration of magnesium glycinate daily for 12 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| TRPM7 Expression Level in Colorectal Mucosa by Mg Treatment Compared With Placebo | Transient Receptor Potential Melastatin 7 (TRPM7) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant). The staining score was computed as "positive cell percentage x reciprocal staining intensity (RSI)", yielding values from 0 to 255, where higher score denoted stronger staining. . Changes (posttreatment-baseline) of TRPM7=log(value at 12 weeks) minus log(value at baseline). | Baseline to 12 weeks |
| COX2 Expression Level in Colorectal Mucosa by Mg Treatment Compared With Placebo | Cyclooxygenase (COX2) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant). The staining score was computed as "positive cell percentage x reciprocal staining intensity (RSI)", yielding values from 0 to 255, where higher score denoted stronger staining. . Changes (posttreatment-baseline) of COX2=log(value at 12 weeks) minus log(value at baseline). | Baseline to 12 week |
| TUNEL Expression in Colorectal Mucosa by Mg Treatment Compared With Placebo | Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant) and computed as count of apoptotic cells/mm2 of epithelial cell nuclei area (cells/mm²). Changes (posttreatment-baseline) of TUNEL =log(value at 12 weeks) minus log(value at baseline). | Baseline to 12 week |
| BAX Expression in Colorectal Mucosa by Mg Treatment Compared With Placebo | BCL2-associated X (BAX) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant). The staining score was computed as "positive cell percentage x reciprocal staining intensity (RSI)", yielding values from 0 to 255, where higher score denoted stronger staining. Changes (posttreatment-baseline) of BAX=log(value at 12 weeks) minus log(value at baseline). |
| Measure | Description | Time Frame |
|---|---|---|
| Serum Magnesium by Mg Treatment Compared With Placebo | Changes (posttreatment-baseline) of serum magnesium (measured continuously using 7D70 Magnesium Reagent Kit from Abbot Laboratories (Abbott Park, IL) ) | Baseline to 12 week |
| Post Treatment Body Magnesium Status by Mg Treatment and Placebo |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Qi Dai, MD, PhD | Vanderbilt University Medical Center | Principal Investigator |
| Chang Yu, PhD | Vanderbilt University Medical Center | Principal Investigator |
| Martha J Shrubsole, Ph.D. | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37203 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40946805 | Derived | Sun E, Zhu X, Ness RM, Murff HJ, Sun S, Yu C, Fan L, Azcarate-Peril MA, Shrubsole MJ, Dai Q. Magnesium treatment increases gut microbiome synthesizing vitamin D and inhibiting colorectal cancer: results from a double-blind precision-based randomized placebo-controlled trial. Am J Clin Nutr. 2025 Nov;122(5):1185-1194. doi: 10.1016/j.ajcnut.2025.09.011. Epub 2025 Sep 12. | |
| 40750038 |
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Participants, aged 40-85 y, with colorectal polyp or polyp-free individuals with high risk of colorectal cancer and had a calcium intake of ≥700 and <2000 mg/d, and their calcium-to-magnesium intake ratio was >2.6 (based on baseline two 24-hour dietary recalls) were recruited from Vanderbilt Vanderbilt University Medical Center (VUMC), Nashville, Tennessee from 2011 to 2024.
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| ID | Title | Description |
|---|---|---|
| FG000 | GG Participants in Magnesium Treatment | Participants with GG genotype were assigned to magnesium glycinate. Oral administration of magnesium glycinate daily for 12 weeks. The dose is personalized based on the baseline assessment of dietary intakes. |
| FG001 | GG Participants in Placebo | Participants with GG genotype were assigned to placebo group Oral administration of identical-appearing placebo daily for 12 weeks. |
| FG002 | GA/AA Participants in Magnesium Treatment | Participants with GA/AA genotype were assigned to magnesium glycinate. Oral administration of magnesium glycinate daily for 12 weeks. The dose is personalized based on the baseline assessment of dietary intakes. |
| FG003 | GA/AA Participants in Placebo | Participants with GA/AA genotype were assigned to placebo group. Oral administration of identical-appearing placebo daily for 12 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | GG Participants in Magnesium Treatment | Participants with GG genotype were assigned to magnesium glycinate. Magnesium glycinate: Oral administration of magnesium glycinate daily for 12 weeks |
| BG001 | GG Participants in Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | TRPM7 Expression Level in Colorectal Mucosa by Mg Treatment Compared With Placebo | Transient Receptor Potential Melastatin 7 (TRPM7) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant). The staining score was computed as "positive cell percentage x reciprocal staining intensity (RSI)", yielding values from 0 to 255, where higher score denoted stronger staining. . Changes (posttreatment-baseline) of TRPM7=log(value at 12 weeks) minus log(value at baseline). | Participants with pre and post intervention samples available | Posted | Median | Inter-Quartile Range | log (arbitrary units) | Baseline to 12 weeks |
|
In the 12 weeks trial, we conducted safety and compliance calls to collect adverse event data.
The definition of adverse event and/or serious adverse event is from the clinicaltrials.gov Definitions.
We conducted safety and compliance calls to collect adverse event data.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | GG Participants in Magnesium Treatment | Participants with GG genotype were assigned to magnesium glycinate. Magnesium glycinate: Oral administration of magnesium glycinate daily for 12 weeks |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| abdominal pain | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Qi Dai | Vanderbilt University Medical Center | (615)936-0707 | qi.dai@vanderbilt.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 8, 2022 | Sep 30, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
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| ID | Term |
|---|---|
| C091418 | magnesium diglycinate |
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| Placebo | Dietary Supplement | Oral administration of identical-appearing placebo daily for 12 weeks |
|
| Baseline to 12 week |
| pMLKL Expression in Colorectal Mucosa by Mg Treatment Compared With Placebo | Phosphorylated Mixed Lineage Kinase Like (pMLKL) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant). The staining score was computed as "positive cell percentage x reciprocal staining intensity (RSI)", yielding values from 0 to 255, where higher score denoted stronger staining. Changes (posttreatment-baseline) of pMLKL=log(value at 12 weeks) minus log(value at baseline). | Baseline to 12 week |
| Ki67 Expression in Colorectal Mucosa by Mg Treatment Compared With Placebo | Ki67 levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant) and calculated as positive nuclei area / epithelial cell nuclei area * 100 (%). Changes (posttreatment-baseline) of Ki67=log(value at 12 weeks) minus log(value at baseline). | Baseline to 12 week |
Post treatment body magnesium status obtained using magnesium tolerance test (MTT) Mg retention rate (%)=[1-(post-infusion Mg excretion - pre-infusion Mg excretion) / total Mg infused]*100. |
| At week 12 |
| Serum C-reactive Protein (CRP) by Mg Treatment Compared With Placebo | Changes (posttreatment-baseline) of CRP (measured continuously using turbidimetric immunoassay (Pointe Scientific, Inc, Canton, MI) | Baseline to 12 week |
| Urine Prostaglandin E2 Metabolite (PGE-M) by Mg Treatment Compared With Placebo | Changes (posttreatment-baseline) of PGE-M (measured continuously using a liquid chromatography/tandem mass spectrometric method). | Baseline to 12 week |
| Derived |
| Sun S, Zhu X, Huang X, Yu C, Su T, Murff HJ, Ness RM, Azcarate-Peril MA, Shrubsole MJ, Dai Q. The Association of Gut Microbiota With TRPM7 Genotype, Colorectal Polyps, and Magnesium. J Nutr. 2025 Nov;155(11):3713-3725. doi: 10.1016/j.tjnut.2025.07.015. Epub 2025 Jul 30. |
| 36223712 | Derived | Fan L, Zhu X, Sun S, Yu C, Huang X, Ness R, Dugan LL, Shu L, Seidner DL, Murff HJ, Fodor AA, Azcarate-Peril MA, Shrubsole MJ, Dai Q. Ca:Mg ratio, medium-chain fatty acids, and the gut microbiome. Clin Nutr. 2022 Nov;41(11):2490-2499. doi: 10.1016/j.clnu.2022.08.031. Epub 2022 Sep 12. |
| 34038556 | Derived | Fan L, Zhu X, Rosanoff A, Costello RB, Yu C, Ness R, Seidner DL, Murff HJ, Roumie CL, Shrubsole MJ, Dai Q. Magnesium Depletion Score (MDS) Predicts Risk of Systemic Inflammation and Cardiovascular Mortality among US Adults. J Nutr. 2021 Aug 7;151(8):2226-2235. doi: 10.1093/jn/nxab138. |
| 33487303 | Derived | Fan L, Yu D, Zhu X, Huang X, Murff HJ, Azcarate-Peril MA, Shrubsole MJ, Dai Q. Magnesium and imidazole propionate. Clin Nutr ESPEN. 2021 Feb;41:436-438. doi: 10.1016/j.clnesp.2020.12.011. Epub 2021 Jan 7. |
| Adverse Event |
|
| Lost to Follow-up |
|
Participants with GG genotype were assigned to placebo group.
Placebo: Oral administration of identical-appearing placebo daily for 12 weeks
| BG002 | GA/AA Participants in Magnesium Treatment | Participants with GA/AA genotype were assigned to magnesium glycinate. Magnesium glycinate: Oral administration of magnesium glycinate daily for 12 weeks |
| BG003 | GA/AA Participants in Placebo | Participants with GA/AA genotype were assigned to placebo group. Magnesium glycinate: Oral administration of magnesium glycinate daily for 12 weeks |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | GG Participants in Placebo | Participants with GG genotype were assigned to placebo: oral administration of identical-appearing placebo daily for 12 weeks |
| OG002 | GA/AA Participants in Magnesium Treatment | Participants with GA/AA genotype were assigned to magnesium glycinate: oral administration of magnesium glycinate daily for 12 weeks |
| OG003 | GA/GA Participants in Placebo | Participants with GA/AA genotype were assigned to placebo: oral administration of identical-appearing placebo daily for 12 weeks |
|
|
|
| Primary | COX2 Expression Level in Colorectal Mucosa by Mg Treatment Compared With Placebo | Cyclooxygenase (COX2) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant). The staining score was computed as "positive cell percentage x reciprocal staining intensity (RSI)", yielding values from 0 to 255, where higher score denoted stronger staining. . Changes (posttreatment-baseline) of COX2=log(value at 12 weeks) minus log(value at baseline). | Participants with pre and post intervention samples available. | Posted | Median | Inter-Quartile Range | log (arbitrary units) | Baseline to 12 week |
|
|
|
|
| Primary | TUNEL Expression in Colorectal Mucosa by Mg Treatment Compared With Placebo | Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant) and computed as count of apoptotic cells/mm2 of epithelial cell nuclei area (cells/mm²). Changes (posttreatment-baseline) of TUNEL =log(value at 12 weeks) minus log(value at baseline). | Participants with pre and post intervention samples available. | Posted | Median | Inter-Quartile Range | log(cells/mm^2) | Baseline to 12 week |
|
|
|
|
| Primary | BAX Expression in Colorectal Mucosa by Mg Treatment Compared With Placebo | BCL2-associated X (BAX) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant). The staining score was computed as "positive cell percentage x reciprocal staining intensity (RSI)", yielding values from 0 to 255, where higher score denoted stronger staining. Changes (posttreatment-baseline) of BAX=log(value at 12 weeks) minus log(value at baseline). | Participants with pre and post intervention samples available. | Posted | Median | Inter-Quartile Range | log (arbitrary units) | Baseline to 12 week |
|
|
|
|
| Primary | pMLKL Expression in Colorectal Mucosa by Mg Treatment Compared With Placebo | Phosphorylated Mixed Lineage Kinase Like (pMLKL) levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant). The staining score was computed as "positive cell percentage x reciprocal staining intensity (RSI)", yielding values from 0 to 255, where higher score denoted stronger staining. Changes (posttreatment-baseline) of pMLKL=log(value at 12 weeks) minus log(value at baseline). | Participants with pre and post intervention samples available. | Posted | Median | Inter-Quartile Range | log (arbitrary units) | Baseline to 12 week |
|
|
|
|
| Primary | Ki67 Expression in Colorectal Mucosa by Mg Treatment Compared With Placebo | Ki67 levels were evaluated quantitatively using a computer-based imaging system composed of an Olympus BX40 Microscope and BioQuant NOVA Prime imaging software (BioQuant) and calculated as positive nuclei area / epithelial cell nuclei area * 100 (%). Changes (posttreatment-baseline) of Ki67=log(value at 12 weeks) minus log(value at baseline). | Participants with pre and post intervention samples available. | Posted | Median | Inter-Quartile Range | log(percentage of positive nuclei area) | Baseline to 12 week |
|
|
|
|
| Secondary | Serum Magnesium by Mg Treatment Compared With Placebo | Changes (posttreatment-baseline) of serum magnesium (measured continuously using 7D70 Magnesium Reagent Kit from Abbot Laboratories (Abbott Park, IL) ) | Participants with pre and post intervention samples available. | Posted | Median | Inter-Quartile Range | mg/dL | Baseline to 12 week |
|
|
|
|
| Secondary | Post Treatment Body Magnesium Status by Mg Treatment and Placebo | Post treatment body magnesium status obtained using magnesium tolerance test (MTT) Mg retention rate (%)=[1-(post-infusion Mg excretion - pre-infusion Mg excretion) / total Mg infused]*100. | 78 participants with samples available. | Posted | Median | Inter-Quartile Range | percentage of Mg administered dose | At week 12 |
|
|
|
|
| Secondary | Serum C-reactive Protein (CRP) by Mg Treatment Compared With Placebo | Changes (posttreatment-baseline) of CRP (measured continuously using turbidimetric immunoassay (Pointe Scientific, Inc, Canton, MI) | Assays of CRP only for 150 participants with pre and post intervention samples available. | Posted | Median | Inter-Quartile Range | mg/L | Baseline to 12 week |
|
|
|
|
| Secondary | Urine Prostaglandin E2 Metabolite (PGE-M) by Mg Treatment Compared With Placebo | Changes (posttreatment-baseline) of PGE-M (measured continuously using a liquid chromatography/tandem mass spectrometric method). | Assays of PGE-M only for 79 participants with pre and post intervention samples available. | Posted | Median | Inter-Quartile Range | ng/mg creatinine | Baseline to 12 week |
|
|
|
|
| 0 |
| 77 |
| 0 |
| 77 |
| 1 |
| 77 |
| EG001 | GG Participants in Placebo | Participants with GG genotype were assigned to placebo. Placebo: Oral administration of identical-appearing placebo daily for 12 weeks | 0 | 78 | 0 | 78 | 2 | 78 |
| EG002 | GA/AA Participants in Magnesium Treatment | Participants with GA/AA genotype were assigned to magnesium glycinate. Magnesium glycinate: Oral administration of magnesium glycinate daily for 12 weeks | 0 | 47 | 0 | 47 | 3 | 47 |
| EG003 | GA/AA Participants in Placebo | Participants with GA/AA genotype were assigned to placebo. Placebo: Oral administration of identical-appearing placebo daily for 12 weeks | 0 | 48 | 0 | 48 | 1 | 48 |
| Bleeding after the rectal biopsy procedure | Gastrointestinal disorders | Systematic Assessment |
|
| Feel sick | Gastrointestinal disorders | Systematic Assessment |
|
| Having an adverse effect on his blood pressure medication | General disorders | Systematic Assessment |
|
| Weight gain, migraine and swelling with arthritic pain in fingers | General disorders | Systematic Assessment |
|
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| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |