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The study was terminated due to a severe decrease in enrollment over the years 2020 and 2021. The major obstacle which hindered participation of subjects was the COVID-19 pandemic. Research was halted. Remaining study patients were withdrawn.
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Proton pump inhibitors (PPIs) are widely used for the control of gastric ulcer-gastritis, erosive esophagitis (gastroesophageal reflux disease), peptic ulcer disease (duodenal ulcer), and heartburn. Despite their efficacy, their use has been implicated in possibly causing fragility fractures (osteoporosis), hypomagnesemia (magnesium deficiency) and increased risk of chronic kidney disease (CKD). The current trial represents the investigators' ongoing effort to discern whether these complications could be averted by effervescent calcium magnesium citrate (EffCaMgCit).
In a single-dose bioavailability study, the investigators showed previously that provision of calcium and magnesium in a soluble form as EffCaMgCit improved intestinal absorption of calcium and magnesium and suppressed parathyroid function during PPI treatment, compared with calcium carbonate. In a multidosing trial with esomeprazole 40 mg/day for 28 days, EffCaMgCit suppressed parathyroid function and bone turnover, and increased serum and urinary magnesium, compared with placebo. Moreover, EffCaMgCit co-administered with PPI conferred an alkali load, and averted apparent acid load conferred by PPI (when given with placebo).
In the current proposal, the investigators wish to conduct a 2-year treatment trial, directed at obtaining more definitive evidence that EffCaMgCit overcomes all three complications of PPI.
Aim 1. To test the hypothesis that EffCaMgCit would prevent/treat osteoporosis, by suppressing parathyroid function and bone resorption, thereby stabilizing bone mineral density (BMD). The critical endpoint will be BMD. Secondary endpoints will be serum PTH and C-terminal telopeptide (CTX).
Aim 2. To test the hypothesis that EffCaMgCit would prevent/treat hypomagnesemia/magnesium deficiency, by providing bioavailable magnesium. The critical endpoint will be fractional excretion of magnesium (FEMg) and free muscle magnesium by MRS. Secondary endpoints will be serum and urinary magnesium.
Aim 3. To test the hypothesis that EffCaMgCit would reduce the risk of CKD during PPI use by averting putative hypomagnesemia/magnesium deficiency and neutralizing acid load. The investigators propose that PPI causes hypomagnesemia/magnesium deficiency and confers an acid load, - factors implicated for incident CKD and its progression. EffCaMgCit is expected to avert incident CKD by providing bioavailable magnesium and alkali load. Critical endpoints will be endogenous creatinine clearance, FEMg, free muscle magnesium and acid-base status.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| EffCaMgCit | Experimental | 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D. |
|
| Placebo | Placebo Comparator | Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EffCaMgCit | Drug | Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Bone Mineral Density (BMD) T-Score at 2 Years | Change from baseline in bone mineral density (BMD) T-Score at 2 years as measured by dual photon absorptiometry. The range, as defined by the World Health Organization (WHO), for T-Score is: -1 and above = Normal, Between -1 and -2.5 = Osteopenia, -2.5 and below = osteoporosis. | Baseline and 2 years |
| Change From Baseline in Bone Mineral Density (BMD) Z-Score at 2 Years | Change from baseline in bone mineral density (BMD) Z-score at 2 years as measured by dual photon absorptiometry. Outcome is considered positive if the Z Score after two years of treatment becomes less negative (less than -2). There is no specific score range for the Z Score. | Baseline and 2 years |
| Change From Baseline in the Fractional Excretion of Magnesium (FEMg) at 2 Years | Change from baseline in the fractional excretion of magnesium (FEMg) at 2 years as measured by the ratio of magnesium clearance and creatinine clearance, using 24-h urinary magnesium and creatinine and corresponding serum magnesium and creatinine obtained post meal/load. | Baseline and 2 years |
| Change From Baseline in Free Muscle Magnesium at 2 Years | Change From baseline in free muscle magnesium at 2 years as assessed by measuring intracellular Mg in a calf muscle, by using 31P (Phosphorous) magnetic resonance spectroscopy (MRS). | Baseline and 2 years |
| Change From Baseline in Endogenous Creatinine Clearance at 2 Years | Change from baseline in endogenous creatinine clearance at 2 years will be measured. Endogenous creatinine clearance will be obtained by using 24-h urinary creatinine and post-meal/load venous blood sample ((uCr, mg/24hr) / (sCr,mg/dL * 14.4)) |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Serum Parathyroid Function (PTH) at 2 Years | Change from baseline in serum parathyroid function (PTH) at 2 years will be measured by Biomerica Intact-PTH ELISA. | Baseline and 2 years |
| Change From Baseline in Serum Bone Resorption Marker C-terminal Telopeptide (CTX) at 2 Years |
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Inclusion Criteria:
Exclusion Criteria:
Inclusion/exclusion of other drugs or conditions will be considered on an individual basis.
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| Name | Affiliation | Role |
|---|---|---|
| Khashayar Sakhaee, MD | UTSW | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Texas Southwestern Medical Center | Dallas | Texas | 75390 | United States |
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Out of the 62 participants enrolled, only 44 met the inclusion criteria and were randomized to the treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | EffCaMgCit | 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D. EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate. |
| FG001 | Placebo | Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | EffCaMgCit | 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D. EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate. |
| 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 | Change From Baseline in Bone Mineral Density (BMD) T-Score at 2 Years | Change from baseline in bone mineral density (BMD) T-Score at 2 years as measured by dual photon absorptiometry. The range, as defined by the World Health Organization (WHO), for T-Score is: -1 and above = Normal, Between -1 and -2.5 = Osteopenia, -2.5 and below = osteoporosis. | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | T-Score | Baseline and 2 years |
|
From the participant's first dose at baseline (0 month) to the end of 24 months
A severe decrease in the enrolled participants due to COVID restrictions and consequently a suspension of research activities resulted in the early termination of this study.
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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 | EffCaMgCit | 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D. EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gas, smelly gas and bloating | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Khashayar Sakhaee, MD | UT Southwestern Medical Center | 214-648-0324 | Khashayar.Sakhaee@UTSouthwestern.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 | Sep 1, 2020 | Jul 13, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010024 | Osteoporosis |
| ID | Term |
|---|---|
| D001851 | Bone Diseases, Metabolic |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D008659 | Metabolic Diseases |
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| ID | Term |
|---|---|
| C000707788 | effervescent calcium magnesium citrate |
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To provide adequate blinding, each medication sachet will be labelled with the study name, IRB number, principal investigator's name, expiration date and identification number of the study subject. Labels will be applied to the appropriate medication sachets once the subject has been randomized and assigned to a treatment group. Labelling of the sachets will be done by personnel who are not engaged in patient care.
| Placebo | Other | Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. |
|
| Baseline and 2 years |
Change from baseline in serum bone resorption marker C-terminal telopeptide (CTX) at 2 years will be measured by lab finding utilizing ELISA CTX-I (CrossLaps). |
| Baseline and 2 years |
| Change From Baseline in Serum Magnesium at 2 Years | Change from baseline in serum magnesium at 2 years will be measured by ion selective electrode. | Baseline and 2 years |
| Change From Baseline in Urine Magnesium at 2 Years | Change from baseline in urine magnesium at 2 years was measured by by atomic absorption. | Baseline and 2 years |
| Change From Baseline in Serum Bicarbonate at 2 Years | Change from baseline in serum bicarbonate at 2 years will be measured to see improvement in acid based status in lowering kidney function impairment. | Baseline and 2 years |
| Early termination of study |
|
| BG001 | Placebo | Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. |
|
|
| Primary | Change From Baseline in Bone Mineral Density (BMD) Z-Score at 2 Years | Change from baseline in bone mineral density (BMD) Z-score at 2 years as measured by dual photon absorptiometry. Outcome is considered positive if the Z Score after two years of treatment becomes less negative (less than -2). There is no specific score range for the Z Score. | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | Z-Score | Baseline and 2 years |
|
|
|
| Primary | Change From Baseline in the Fractional Excretion of Magnesium (FEMg) at 2 Years | Change from baseline in the fractional excretion of magnesium (FEMg) at 2 years as measured by the ratio of magnesium clearance and creatinine clearance, using 24-h urinary magnesium and creatinine and corresponding serum magnesium and creatinine obtained post meal/load. | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | percentage | Baseline and 2 years |
|
|
|
| Primary | Change From Baseline in Free Muscle Magnesium at 2 Years | Change From baseline in free muscle magnesium at 2 years as assessed by measuring intracellular Mg in a calf muscle, by using 31P (Phosphorous) magnetic resonance spectroscopy (MRS). | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | mmol/L | Baseline and 2 years |
|
|
|
| Primary | Change From Baseline in Endogenous Creatinine Clearance at 2 Years | Change from baseline in endogenous creatinine clearance at 2 years will be measured. Endogenous creatinine clearance will be obtained by using 24-h urinary creatinine and post-meal/load venous blood sample ((uCr, mg/24hr) / (sCr,mg/dL * 14.4)) | Because of severe decrease in enrolled participants due to COVID-19 restrictions and consequently a suspension of research activities resulted in the early termination of this study. Only 1 subject completed the 2 year timepoint for which the data is summarized here. | Posted | Number | ml/min | Baseline and 2 years |
|
|
|
| Secondary | Change From Baseline in Serum Parathyroid Function (PTH) at 2 Years | Change from baseline in serum parathyroid function (PTH) at 2 years will be measured by Biomerica Intact-PTH ELISA. | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | pg/ml | Baseline and 2 years |
|
|
|
| Secondary | Change From Baseline in Serum Bone Resorption Marker C-terminal Telopeptide (CTX) at 2 Years | Change from baseline in serum bone resorption marker C-terminal telopeptide (CTX) at 2 years will be measured by lab finding utilizing ELISA CTX-I (CrossLaps). | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | ng/ml | Baseline and 2 years |
|
|
|
| Secondary | Change From Baseline in Serum Magnesium at 2 Years | Change from baseline in serum magnesium at 2 years will be measured by ion selective electrode. | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | mg/dL | Baseline and 2 years |
|
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|
| Secondary | Change From Baseline in Urine Magnesium at 2 Years | Change from baseline in urine magnesium at 2 years was measured by by atomic absorption. | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | mg/day | Baseline and 2 years |
|
|
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| Secondary | Change From Baseline in Serum Bicarbonate at 2 Years | Change from baseline in serum bicarbonate at 2 years will be measured to see improvement in acid based status in lowering kidney function impairment. | Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here. | Posted | Number | mmol/L | Baseline and 2 years |
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| 0 |
| 22 |
| 0 |
| 22 |
| 1 |
| 22 |
| EG001 | Placebo | Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D. | 0 | 22 | 0 | 22 | 0 | 22 |
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| D009750 |
| Nutritional and Metabolic Diseases |
| Title | Measurements |
|---|---|
|
| Radial 1/3rd Z-Score |
|