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

Conditions

Hypomagnesemia, Osteoporosis

Keywords

Bone mineral density

Brief summary

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

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.

Related papers

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Interventions

DRUGEffCaMgCit

Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.

OTHERPlacebo

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

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.

Eligibility

Sex/Gender

ALL

Age

21 Years to 99 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Endogenous Creatinine Clearance at 2 Years	Baseline and 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))
Change From Baseline in Bone Mineral Density (BMD) T-Score at 2 Years	Baseline and 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.
Change From Baseline in Bone Mineral Density (BMD) Z-Score at 2 Years	Baseline and 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.
Change From Baseline in the Fractional Excretion of Magnesium (FEMg) at 2 Years	Baseline and 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.
Change From Baseline in Free Muscle Magnesium at 2 Years	Baseline and 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).

Secondary

Measure	Time frame	Description
Change From Baseline in Serum Parathyroid Function (PTH) at 2 Years	Baseline and 2 years	Change from baseline in serum parathyroid function (PTH) at 2 years will be measured by Biomerica Intact-PTH ELISA.
Change From Baseline in Serum Bone Resorption Marker C-terminal Telopeptide (CTX) at 2 Years	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).
Change From Baseline in Serum Magnesium at 2 Years	Baseline and 2 years	Change from baseline in serum magnesium at 2 years will be measured by ion selective electrode.
Change From Baseline in Urine Magnesium at 2 Years	Baseline and 2 years	Change from baseline in urine magnesium at 2 years was measured by by atomic absorption.
Change From Baseline in Serum Bicarbonate at 2 Years	Baseline and 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.

Countries

United States

Participant flow

Pre-assignment details

Out of the 62 participants enrolled, only 44 met the inclusion criteria and were randomized to the treatment.

Participants by arm

Arm	Count
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.	22
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.	22
Total	44

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Early termination of study	14	14
Overall Study	Protocol Violation	3	3
Overall Study	Withdrawal by Subject	5	4

Baseline characteristics

Characteristic	Placebo	Total	EffCaMgCit
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	6 Participants	16 Participants	10 Participants
Age, Categorical Between 18 and 65 years	16 Participants	28 Participants	12 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	1 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	21 Participants	43 Participants	22 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	21 Participants	41 Participants	20 Participants
Region of Enrollment United States	22 participants	44 participants	22 participants
Sex: Female, Male Female	15 Participants	27 Participants	12 Participants
Sex: Female, Male Male	7 Participants	17 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 22	0 / 22
other Total, other adverse events	1 / 22	0 / 22
serious Total, serious adverse events	0 / 22	0 / 22

Outcome results

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.