Averting Complications of Proton Pump Inhibitor Therapy by Effervescent Calcium Magnesium Citrate

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Averting Complications of Proton Pump Inhibitor Therapy by Effervescent Calcium Magnesium Citrate

Conditions
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Osteoporosis, Hypomagnesemia

Intervention / Treatment
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* Drug: EffCaMgCit
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have taken PPI (omeprazole or equivalent ≥ 20 mg/day, ≥ three times per week, for at least 2 months) Expected to continue at a similar dosage Stage 1 hypertension (with systolic blood pressure <140 and diastolic <90) controlled diabetes mellitus Type II with HbA1C less than 7% Exclusion Criteria: end-stage renal failure on dialysis hypercalcemia hypophosphatemia (serum P < 2.5 mg/dL) hypertension stage 2 or higher diabetes Type II with HbA1C ≥ 7% treatment with adrenocorticosteroids, diuretics, non-steroidal anti-inflammatory agents regular dose of magnesium supplements, bisphosphonate, teriparatide, denosumab or selective estrogen receptor modulators. Inclusion/exclusion of other drugs or conditions will be considered on an individual basis.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EffCaMgCit<br>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. | Drug: EffCaMgCit<br>* Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.<br>* Other names: Effervescent calcium magnesium citrate;|
| Placebo Comparator: Placebo<br>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. | Other: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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)) | Baseline and 2 years | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone mineral density