Clinical trial NCT02665117
Conditions: Hypertension
Keywords: Hypokalemia Isoprostanes Insulin resistance Aldosterone Hepatic fat Muscle Magnesium Liver fat
Sponsor: University of Texas Southwestern Medical Center
Start date: 2015-01-01; Completion date: 2022-11-04
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Chlorthalidone (CTD) may produce various metabolic disturbances, including hypokalemia, activation of Renin-Angiotensin- Aldosterone (RAA) system, oxidative stress, dyslipidemia, Fibroblast growth factor 23 (FGF23) synthesis, and magnesium depletion. These factors may interact with each other to contribute to the development of insulin resistances and metabolic syndrome. Smaller studies have suggested that Potassium magnesium Citrate (KMgCit) can ameliorate CTD- induced metabolic side effects independent of correction of hypokalemia. This study will tests if KMgCit ameliorates CTD induced metabolic effects independent of correction of hypokalemia.

Detailed description:
CTD- induced metabolic side effects were though to be dependent on hypokalemia, but subsequent studies suggested that CTD - induced side effects were independent from hypokalemia. On the other hand, magnesium depletion has been linked to increased Renin-Angiotensin- Aldosterone (RAA) system, the development of metabolic syndrome and insulin resistance with magnesium supplementation ameliorating these effects.

Participants will participate in a double-blinded, parallel design study. After baseline evaluation participants will take Chlorthalidone (CTD) alone for 2-3 weeks. They will then be randomized to two equal groups to take KMgCit powder or Potassium Chloride (KCl) powder along with CTD for 4 months.

We speculate that Mg depletion is responsible for hepatic fat deposition, which then produces insulin resistance. Co-administration of KMgCit powder would avert magnesium (Mg) depletion, block hepatic fat deposition by restoring normal Mg status and direct intestinal binding of fat, thereby ameliorating insulin resistance. To test this hypothesis, we shall quantitate muscle Mg status and hepatic fat content by magnetic resonance spectroscopy (MRS) before and after KMgCit. Change in fasting glucose, insulin resistance, serum potassium, FGF23, and aldosterone will be compared between KCL and KMgCit groups after 4 months.

Arms: arm 1: After a run-in period of 2-3 weeks on Chlorthalidone, patients will be randomized to the addition of KMgCit for 4 months. arm 2: After a run-in period of 2-3 weeks on Chlorthalidone, patients will be randomized to the addition of KCl for 4 months.
Interventions: intervention 1: Potassium Magnesium Citrate (KMgCit) intervention 2: Potassium Chloride (KCl) intervention 3: Chlorthalidone
Intervention descriptions: intervention 1: KMgCit will be administer for 4 months with chlorthalidone. intervention 2: KCl will be administer for 4 months with chlorthalidone. intervention 3: Chlorthalidone will be administered for 2-3 weeks. Then either KCL or KMgCit will be added to Chlorthalidone and the combination will be taken for 4 months.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
“Protocol Amendment: New Protocol”: IND 116,208 KMgCit Powder 
IRB Study #: ---; August 31, 2015 [F]  
 
Study Protocol 
7.1. Title of Project: Amelioration of Chlorthalidone-Induced Hypokalemia and 
Metabolic Disturbances by Potassium-Magnesium Citrate (KMgCit) Powder 
Principal Investigator: Wanpen Vongpatanasin, M.D., Hypertension Section, 
Division of Cardiology, Department of Internal Medicine, University of Texas 
Southwestern Medical Center (UTSW) 
Co-Investigator: Orson W. Moe, M.D., Center for Mineral Metabolism and Clinical 
Research, UTSW 
 
In a just completed study (IND 116,208; IRB Study #: STU 072012-001), 
potassium magnesium citrate (KMgCit) powder did not alter blood pressure in 
patients with pre- and Stage I hypertension, while potassium chloride (KCl) 
powder lowered it. However, KMgCit powder reduced urinary 8-isoprostane 
serum FGF23. Chlorthalidone (CTD), a thiazide diuretic widely used for 
treatment of hypertension, produces certain metabolic disturbances associated 
with Type II diabetes and metabolic syndrome. In this “protocol amendment: new 
protocol”, these circumstances led us to explore whether KMgCit powder co-
administered with CTD would correct hypokalemia, and ameliorate metabolic 
disturbances of CTD therapy among patients with Stage I hypertension. We shall 
examine the effect of CTD alone, CTD with KMgCit powder or CTD with KCl 
powder in a parallel design.  
1. Specific Aims: 
  
Aim 1. To compare the effect of KMgCit powder and KCl powder on correction or 
prevention of CTD-induced hypokalemia.  
Aim 2. To examine CTD-induced changes in renin-angiotensin aldosterone (RAA) 
system, oxidative stress, and insulin sensitivity between KMgCit powder and KCl 
powder supplementation.  
Aim 3. To evaluate hepatic fat accumulation by MRS.  
Aim 4. To compare the Mg status from measurement of muscle Mg by MRS 
between CTD + KMgCit powder and CTD + KCl powder.  
 
It is expected that: (a) KMgCit powder would be equally effective in 
correcting/preventing CTD-induced hypokalemia as KCl powder, without 
incurring hypochloremic metabolic alkalosis. (b) Compared to KCl powder plus 
CTD, KMgCit powder added to CTD would reveal lower serum aldosterone, 
urinary isoprostanes, serum glucose, and HOMA-IR and serum FGF23. (c) 
Hepatic fat content would increase on CTD plus KCl powder, but would decline 
on CTD + KMgCit powder. (d) Muscle Mg would increase on KMgCit powder + 


2 
 
CTD, but would be decreased on KCl powder + CTD. It is hypothesized that CTD 
produces various metabolic disturbances that interact with each other or act 
independently to alter the propensity for Type II diabetes and metabolic 
syndrome, and that KMgCit powder ameliorates these disturbances or 
propensity. This protocol will put a special focus on testing a scheme that links 
Mg depletion from CTD to hepatic fat accumulation and insulin resistance.   
2. Background: 
  
The idea for this study came from a just completed trial (IND 116,208 
KMgCit Powder; IRB #STU 072012-001). We examined whether KMgCit powder 
could lower blood pressure in patients with pre- and Stage I hypertension, by 
providing three components of the “DASH” diet (potassium, magnesium and 
alkali) that have been shown to lower blood pressure (Sacks, 2001). KMgCit 
powder was compared with potassium citrate (KCit) powder, KCl powder and 
placebo. KMgCit powder was shown to be ineffective in lowering blood pressure.   
 
However, the above study disclosed that KMgCit powder might have other 
usefulness, since it seemed to ameliorate some of the metabolic disturbances 
associated with CTD.  
Metabolic disturbances of CTD 
 
CTD is a thiazide (TZ) type diuretic advocated by many guidelines for the 
treatment of hypertension (NICE 2011), owing to its longer half-life and greater 
antihypertensive efficacy at the clinically recommended doses than other 
thiazide diuretics (Vongpatanasin, 2015). Despite these favorable properties and 
increasing popularity, CTD and other TZ diuretics are known to cause various 
metabolic disturbances, such as hypokalemia, activation of renin-angiotensin 
system and sympathetic nervous system (RAA-SNS) (Menon, 2009), oxidative 
stress (Ribeiro, 2013; Reungjui, 2007), dyslipidemia (Eriksson, 2008; Price, 
2013), increased FGF23 synthesis (Pathare, 2012), insulin resistance (Xie, 2005; 
Price, 2013; Raheja, 2012; Menon, 2009), and Mg depletion (Sheehan, 1982; 
Hollifield, 1987).   
Mechanism for various metabolic disturbances of CTD/TZ ultimately 
contributing to the development of type II diabetes and metabolic syndrome are 
unknown. The traditional explanation implicating hypokalemia has been 
questioned.  
  
CTD/TZ-induced potassium depletion and hypokalemia are thought to be 
the main cause of hyperglycemia by impairing insulin secretion. However, serum 
insulin increases rather than decreases with TZ diuretics (Carter 2008, Raheja 
2012). The maintenance of normokalemia during CTD administration by K 
supplementation failed to prevent CTD-induced increase in fasting plasma 
glucose and HOMA-IR, an index of insulin resistance (Raheja, 2012; Menon, 
2009). CTD is known to induce a sustained activation of RAA-SNS in 


3 
 
hypertensive patients (Menon 2009, Raheja 2012). This neurohormonal 
activation is independent of serum potassium as it is unaffected by K 
supplementation (Menon 2009, Raheja 2012). Thiazide diuretic has been shown 
to increase renal oxidative stress, which cannot be accounted for by the presence 
of hypokalemia alone (Reungjui, 2007).  
  
Various metabolic disturbances of CTD/TZ might be pathogenetically 
linked, involving a pathway independent of hypokalemia. Some metabolic 
disturbance might directly cause insulin resistance and Type II diabetes. Other 
factors might do so indirectly by affecting other metabolic disturbances.  
Activation of RAA system has also been implicated in the pathogenesis of 
insulin resistance by inhibiting insulin signaling pathway in the adipocytes and 
skeletal muscle (Wada, 2009; Hitomi, 2007), resulting in impaired insulin 
mediated glucose uptake (Luther, 2011; Selvaraj, 2009). The deleterious effect of 
RAA system activation is mediated at least in part by increased oxidative stress 
(Sowers, 2009). Activation of the SNS system may further promote insulin 
resistance by reducing skeletal muscle glucose uptake both by flow-dependent 
(Jamerson, 1993; Sartori, 1999) and flow-independent (Lembo, 1994; 
Navegantes, 2003) mechanisms. 
  
Mg depletion from CTD/TZ may cause renal potassium loss and refractory 
hypokalemia (Whang, 1977). Magnesium supplementation alone without 
potassium ameliorated TZ-induced hypokalemia (Ruml, 1999). Activation of RAA 
system by CTD or TZ may contribute to Mg depletion. Inverse correlation between 
plasma renin activity and serum Mg has been demonstrated in a cross sectional 
study of patients with untreated essential hypertension (Resnick, 1983). In 
normal volunteers, serum aldosterone at baseline and after angiotensin II 
infusion was significantly higher on Mg-deficient diet than on Mg-replete diet 
(Nadler, 1993). Co-infusion of Mg with angiotensin II attenuated the rise in 
serum aldosterone, suggesting direct inhibitory effect of Mg on the RAA system. 
KMgCit powder as a countermeasure for metabolic disturbances of CTD 
Effective strategy in preventing the metabolic disturbances of CTD/TZ has 
not been fully developed.  
  
KCl supplementation is ineffective. Correction of hypokalemia by KCl did 
not reverse CTD-induced fasting hyperglycemia and increased HOMA-IR (Raheja, 
2012; Menon, 2009). CTD-induced activation of RAA-SNS was unaffected by KCl 
supplementation (Menon 2009, Raheja 2012).  In TZ-treated patients with 
hypertension, KCl supplementation did not reduce serum aldosterone (Kaplan, 
1985).  
  
KMgCit powder possesses distinct properties apart from KCl powder in 
overcoming deleterious metabolic disturbances of CTD therapy. Considerable 
data on physiological-clinical action of this drug have been obtained by this 


4 
 
investigative group using a tablet formulation (under IND 32,284 & 36,276; NDA 
20-964), as summarized below.     
 
Physiological properties of KMgCit. This preparation was shown to confer 
equivalent potassium bioavailability as potassium chloride, similar magnesium 
bioavailability as magnesium citrate, and greater alkali load than potassium 
citrate (Koenig, 1991). In patients with calcium nephrolithiasis, KMgCit 
significantly increased urinary pH and citrate compared to placebo. It was more 
effective than potassium citrate in inhibiting the crystallization of uric acid and 
calcium oxalate in urine (Pak, 1992). 
  
Some of the orally administered citrate may appear in urine by escaping 
hepatic metabolism in vivo. Serum citrate concentration increased significantly 
within 30 minutes after a single oral dose of citric acid and remained significantly 
elevated for 3 hours after citric acid load. Commensurate with this change, 
urinary citrate excretion peaked at 2 hours and gradually decreased during the 
next 2 hours after a citric acid load (Sakhaee, 1992).  
  
KMgCit was equally effective as potassium chloride in correcting HCTZ-
induced hypokalemia. In addition, KMgCit, but not KCl, produced a small but 
significant increase in serum magnesium concentration by delivering a 
magnesium load, and it conferred alkalinizing and citraturic actions (Pak, 2000).  
  
The above actions of KMgCit – potassium and magnesium load, citraturic 
action, and alkali load – might have a role in mitigating metabolic disturbances 
of CTD, as discussed below.   
  
Prevention of TZ-induced hypokalemia by KMgCit from provision of K and 
Mg load. In healthy subjects taking HCTZ, the addition of KMgCit 
corrected/prevented hypokalemia (Ruml, 1999; Wuermser, 2000), without 
producing metabolic alkalosis (Odvina, 2006).  
  
Potential inhibition of RAA-SNS activation by KMgCit powder from provision 
of Mg.  Pilot data from our laboratory indicated that magnesium supplementation 
attenuated sympathetic mediated vasoconstriction during muscle contraction in 
spontaneously hypertensive rats. Normally, exercise triggers parallel increases 
in sympathetic nervous system to the resting and exercising skeletal muscle. In 
the 
resting 
muscle, 
sympathetic 
activation 
triggers 
alpha-adrenergic 
vasoconstriction, thereby redirecting blood flow to the metabolically active 
muscles. In the working muscles, sympathetic vasoconstriction is markedly 
blunted by local vasodilator metabolites, particularly nitric oxide. This 
phenomenon, known as functional sympatholysis, is thought to be a protective 
mechanism to optimize blood flow to the working muscle (Remensnyder JP, 
1962). Our study indicated that functional sympatholysis is impaired in 
hypertensive 
patients, 
which 
may 
contribute 
to 
exercise 
intolerance 
(Vongpatanasin 2011). The impairment in functional sympatholysis in 


5 
 
hypertension was shown to be related to increased skeletal muscle oxidative 
stress that inactivates NO (Zhoa 2006).  
In 
our 
study 
in 
spontaneously 
hypertensive 
rats, 
dietary 
Mg 
supplementation blunted sympathetic mediated vasoconstriction (A, right) 
compared with Mg deficient diet (A, left), and reduced muscle oxidative stress 
both in contracting muscle and resting muscle (B) (Fig. 1). 
A. 
 
 
 
 
 
 
 
B. 
 
 
 
 
  
 
 
 
 
 
Fig. 1: A. percent change in vascular conductance (VC) in the femoral artery in response 
to lumbar sympathetic nerve stimulation (1, 2.5, and 5 Hz) at rest (white bars) and 
during muscle contraction (grey bars) in spontaneously hypertensive rats (SHRs) treated 
with Mg deficient diet (left, 30 mg/kg) vs. high Mg diet (4.8 grams/kg, right) for 12 weeks. 
Sympathetic mediated reduction in vascular conductance is attenuated in the SHRs 
treated with high Mg diet compared to Mg deficient diet, B. Summary data showing 
increased oxidative stress as evidenced by increased ethidium fluorescence (DHE/DAPI 
ratio) in resting and contracting muscles of SHRs treated with Mg deficient diet 
compared to high Mg diet.  
   
Potential inhibition of oxidative stress by KMgCit powder from provision of 
citric acid, alkali and magnesium. A high dose of citric acid (1–2 g/kg) reduced 
brain lipid peroxidation and inflammation, liver damage, and DNA fragmentation 
in mice exposed to lipopolysaccharide, suggesting a protective role of citric acid 
in endotoxin-induced oxidative stress (Abdel-Salam, 2014).  
Supporting an inhibitory role of alkali, a calcium/potassium salt of 
hydroxycitric acid (rich in alkali) extracted from the dried fruit rind of the plant 
Garcinia cambogia reduced inflammation, oxidative stress, and insulin 
resistance in obese Zucker rats (Asghar, 2007). In the Dietary Approaches to 
Stop Hypertension (DASH/SRD) trial, a diet rich in alkali and magnesium and 
low in sodium was shown to reduce urinary F2-isoprostanes by 31% in 
hypertensive patients with heart failure with preserved ejection fraction, 
suggesting decreased oxidative stress (Hummel, 2012). Consumption of black 
currant juice was shown to reduce plasma F2-isoprostanes and improve 
endothelial function in individuals with habitually low dietary intake of fruits 


6 
 
and vegetables (Khan, 2014). Induction of metabolic acidosis with oral 
ammonium chloride for 5 days in normal volunteers increased leucine 
appearance from body protein and led to leucine oxidation, suggesting increased 
protein degradation and amino acid oxidation (Reaich, 1992). It can be inferred 
that alkali load by KMgCit powder would have an opposite effect.  
As evidence of its protective role, Mg was shown to ameliorate creatine 
kinase-MB elevation, oxidative stress, lactate accumulation, and pyruvate 
reduction, as well as preserve creatinine phosphate, adenine nucleotides and 
Na(+),K(+)-ATPase 
activity, 
in 
mice 
with 
lipopolysaccharide-induced 
cardiotoxicity (Ahmed, 2012). Dietary magnesium restriction increased 
ischemic/reperfusion injury in the isolated rat hearts. Dietary Mg deficiency was 
shown to promote cardiomyopathy, in situ cardiac dysfunction, and myocardial 
intolerance to secondary stresses. 
Significant protection against most of 
these Mg deficiency-mediated events 
has been observed with interventions 
that modulate neuronal substance P 
release or its bioactivity, and with 
several 
antioxidants 
(vitamin 
E, 
probucol, epicaptopril, d-propranolol) 
(Kramer, 2009). 
 
We obtained the most direct 
evidence 
of 
KMgCit 
powder’s 
inhibition of oxidative stress in a just 
completed 
trial 
(original 
IND 
116,208). Thirty patients with pre- or 
Stage I hypertension underwent a 
crossover trial, whereby they took 
KMgCit powder, KCit powder, KCl 
powder or placebo for 4 weeks. The 
potassium content during the K salt 
phases was 20 meq bid. In the KMgCit powder phase, patients also took 10 meq 
Mg bid. A spot urine sample was obtained at the end of 4 weeks of treatment of 
each phase. Urinary 8-isoprostane was significantly lower during the KMgCit 
powder phase than during other phases (Fig. 2).  
  
Potential amelioration of dyslipidemia by KMgCit powder via Mg load. Mg 
supplementation with bittern, a natural MgCl2 solution from sea or salt lake 
water, reduced the appearance in serum of lipid components after a fat load in 
normal volunteers (Kishimoto, 2010). The concentrations of apo-B48, remnant-
like particle cholesterol, and nonesterified fatty acid were significantly lower at 2 
hours after the fat-with-Mg meal compared with the fat-only meal.  Thus, Mg 
supplementation by KMgCit powder could inhibit fat absorption and improve 
postprandial hyperlipidemia.   
Fig. 
2. 
Spot 
urinary 
8-isoprostane 
following 4 weeks of treatment with 
KMgCit powder, KCit powder, KCl powder 
or placebo. ** p < 0.05 and † < 0.001 from 
the KMgCit powder. p = 0.11 between KCit 
powder and placebo.   


7 
 
  
In rabbits fed a high cholesterol diet (1% or 2%), oral magnesium aspartate 
hydrochloride: (i) lowered serum cholesterol and triglyceride in normal (25-35%) 
as well as atherosclerotic (20-40%) animals, and (ii) attenuated the 
atherosclerotic process markedly. In addition, dietary deficiency of Mg 
augmented atherogenesis markedly and stimulated (or activated) macrophages 
in the reticuloendothelial system (Altura, 1990; Smith 2013). In rats, Mg 
deficient diet reduced post-heparin lipase activity and hepatic lipase, resulting 
in increased serum triglycerides and triglyceride content of chylomicrons, very 
low density lipoproteins, low density lipoproteins and high density lipoproteins 
(Rayssiguier, 1991).  
  
Potential suppression of FGF23 synthesis by KMgCit powder from alkali and 
Mg load.  In mouse calvarial and osteoblast preparations, a culture medium 
mimicking metabolic alkalosis inhibited FGF23 protein and mRNA (Krieger, 
2012). Mice exposed to Mg-deficient diet showed a marked increase in serum 
FGF23 (van Angelen, 2013).  
  
Potential amelioration of insulin resistance and type II diabetes by KMgCit 
powder from alkali and Mg load. In a randomized crossover study in normal 
volunteers, Mg deficient diet reduced insulin sensitivity (estimated from 
intravenous glucose tolerance test), compared to Mg repleted diet (Nadler 1993). 
In a double-blind, placebo-controlled study in prediabetic subjects, KCit 
(delivering alkali load) but not KCl reduced insulin resistance as revealed by 
HOMA-IR (Conen, 2015). In a cross-sectional study, Type 2 diabetes mellitus was 
associated with lower urinary pH and higher net acid excretion, independent of 
age, body weight, creatinine clearance, and dietary factors (Cameron 2006). 
Several populational studies have shown an association between dietary acid 
load and insulin resistance as well as the risk of type 2 diabetes mellitus (Akter 
2015 and Fagherazzi 2014). In the National Health and Nutrition Examination 
Surveys involving healthy US population, low serum bicarbonate and high anion 
gap were independently associated with increased plasma fasting insulin and 
triglyceride, suggesting increased risk of insulin resistance (Farwell 2008). These 
studies inferred potential protective action of KMgCit powder from alkali load.  
  
Several studies suggested a protective role of Mg. In a case control study 
of 163 women and 131 men, hypomagnesemia (serum magnesium ≤1.8 mg/dL) 
was independently associated with incident metabolic syndrome. Additional 
adjustment by serum C-reactive protein showed that metabolic syndrome 
remained associated with hypomagnesemia (OR 1.4; 95% CI 1.1-5.9) but not 
with oxidative stress determined by serum malondialdehyde concentration (OR 
1.1; 95% CI 0.9-5.9) (Guerrero-Romero, 2006). In a prospective observational 
study with median follow up of 16 years, high magnesium intake was a 
significant protective factor for the incidence of Type 2 diabetes, especially among 
subjects with insulin resistance, low-grade inflammation and a drinking habit 
(Hata, 2013).  


8 
 
  
In rats subjected to magnesium-deficient diet, hypomagnesemia had a 
deleterious effect on glucose metabolism by impairing both insulin secretion and 
action. Mg deficient rats displayed 45% reduction in the glucose-stimulated 
insulin secretion. Mg restriction produced defective tyrosine kinase activity of 
insulin receptors, leading to decreased phosphorylation of the beta-subunit of 
the insulin receptor (Suarez, 1995). 
  
Potential 
Mg 
repletion 
by 
KMgCit 
powder from provision of 
bioavailable 
Mg. 
By 
providing bioavailable Mg, 
KMgCit 
powder 
should 
prevent/ameliorate CTD-
induced hypomagnesemia 
or Mg depletion. In prior 
studies 
with 
a 
tablet 
formulation of KMgCit, 30 
healthy 
subjects 
developed 
hypomagnesemia (serum 
Mg < 1.8 mg/dL) on HCTZ 
50 mg/day alone for 2-3 
weeks (Pak, 2000). When 
KMgCit 
was 
added 
to 
HCTZ treatment at a dose 
of 42 meq K and 21 meq 
Mg/day, 
serum 
Mg 
increased to the normal 
range 
(Fig. 
3).   
 
 
 
 
 
 
Among 131 subjects who took HCTZ, the percentage of subjects with 
hypomagnesemia progressively declined when KMgCit was added (Fig. 4, closed 
circles). However, the percentage of subjects with hypomagnesemia increased 
when KCl or potassium citrate was added to HCTZ treatment (open circles).   
Fig. 3. Effect of KMgCit on serum Mg concentration 
among 30 subjects who developed hypomagnesemia 
alone 
on 
HCTZ. 
KMgCit 
was 
added 
to 
hydrochlorothiazide (TZ) therapy for three weeks. † = p 
< 0.001.  


9 
 
 
Fig. 4. The percentage of subjects 
with 
hypomagnesemia 
during 
addition of KMgCit or KCit/KCl to 
ongoing HCTZ therapy. * p < 0.05, 
** p < 0.01 and † p< 0.001. Open 
symbols indicate within group 
comparisons, 
and 
symbols 
enclosed in parenthesis indicate 
between group comparisons. M1, 
M2 and M3 indicate 1, 2 or 3 
weeks of combined treatment.  
Summary 
  In 
summary, 
CTD 
may 
produce various metabolic disturbances, including hypokalemia, activation of 
RAA-SNS, oxidative stress, dyslipidemia, FGF23 synthesis, insulin resistance, 
and magnesium depletion (Fig. 5). These factors act solely or interact with each 
other to contribute to the development of Type II diabetes and metabolic 
syndrome. KMgCit powder can potentially overcome all of these metabolic 
disturbances. On the other hand, the action of KCl powder might be limited to 
correction of hypokalemia. 
 
Fig. 5. Scheme for CTD-induced metabolic disturbances that could lead to Type II 
diabetes and metabolic syndrome. These disturbances might be blocked by KMgCit 
powder.   
A special focus of this protocol will be on the CTD-induced Mg depletion 
(Fig. 6). CTD is well known to cause Mg depletion, hepatic steatosis and Type II 
diabetes-metabolic syndrome. We speculate that Mg depletion is responsible for 
hepatic fat deposition, which then produces insulin resistance. Co-
administration of KMgCit powder would avert Mg depletion, block hepatic fat 
deposition by restoring normal Mg status and direct intestinal binding of fat, 
thereby ameliorating insulin resistance. To test this hypothesis, we shall 
quantitate muscle Mg status and hepatic fat content by MRS.  
CTD
Type II Diabetes &
Metabolic Syndrome
Metabolic Disturbances
• Hypokalemia
• RAA-SNS activation
• Oxidative stress
• Dyslipidemia
• FGF23 synthesis
• Insulin resistance
• Mg depletion
KMgCit
Powder
Pre
TZ
M1
M2
M3
Percentage of Patients
with Hypomagnesemia
0
5
10
15
20
25
30
KMgCit
KCit or KCl
†
†
†
(*)
(**)
(**)


10 
 
 
Fig. 6. Hypothesis for the central role of Mg depletion and hepatic fat deposition in the 
development of CTD-induced metabolic disturbances.  
 
3. Significance: 
 
  
Thiazide type diuretics are widely used as a first line treatment of 
hypertension in a very large number of subjects (James 2014, Vongpatanasin 
2014). While this class of drugs is effective in lowering blood pressure, its use is 
complicated by various metabolic disturbances, many of which are features of 
metabolic syndrome induced or worsened by CTD. Some of these metabolic 
complications already coexist with hypertension and their exacerbation by TZ 
diuretics may not be readily recognized. KMgCit powder potentially represents a 
novel modality to not only prevent CD/TZ-induced hypokalemia, but also inhibit 
or ameliorate metabolic disturbances. This simple replacement of inorganic 
solutes can potentially allow CTD/TZ to exert its full antihypertensive efficacy 
without the negative drawback of worsening metabolic syndrome counteracting 
the benefits of blood pressure control.  
4. Preliminary Data/Past Work: 
  
This investigative group has already obtained preliminary data or 
published relevant work on all four aims of this proposal. Using a tablet 
formulation of KMgCit, the group has delineated physiological action of this 
compound in detail and some of its clinical effects. Safety of usage was also 
shown. Some data to be shown below were derived from original IND with KMgCit 
powder or in experimental animals.  
  
Effect of CTD on inflammation. In our pilot data in 16 subjects with 
uncomplicated stage I hypertension, serum highly sensitive C-reactive protein 
(hsCRP) rose significantly from 3.2 (1.0 – 4.6; 
median, 25th – 75th percentile) at baseline to 4.8 
(2.6 – 9.8) during CTD (p < 0.05) (Fig. 7).  In 
contrast, spironolactone (Spiro) had no effect on 
hsCRP levels in the same subjects.  
Fig. 7. Summary data showing changes in serum 
hsCRP (mcg/ml) in 16 untreated hypertensive 
subjects at baseline, after chlorthalidone treatment 
for 12 weeks, and after spironolactone treatment for 
12 weeks. 
CTD
Mg Depletion
Hepatic Fat
Deposition
Type II Diabetes &
Metabolic Syndrome
0
2
4
6
8
Baseline
CTD
Spiro
p < 0.05 vs baseline


11 
 
Correction/prevention of TZ-induced hypokalemia (Wuermser, 2000). After 
treatment with HCTZ 50 mg/day alone for 2-3 weeks, 30 patients took KMgCit 
tab 42 meq K and 21 meq 
Mg daily, while 30 subjects 
received KCl 42 meq/day, 
along with HCTZ for 3 
weeks 
(Fig. 
8). 
Serum 
potassium 
declined 
on 
HCTZ alone. It rose to the 
normal 
range 
on 
both 
KMgCit and KCl to an 
equivalent degree.  
 
Fig. 8. Effect of KMgCit and 
KCl on serum potassium. † 
represents p < 0.001 from the 
last week of HCTZ alone. 
 
  Inhibition of RAA-SNS 
activation. In spontaneous hypertensive rats, high Mg diet blunted sympathetic 
mediated vasoconstriction (see Fig. 1).  
Effect of KMgCit powder on oxidative stress. Urinary 8-isoprostane 
significantly declined on KMgCit powder. See Fig. 2.  
 
Effect of KMgCit powder on serum triglyceride. In a retrospective analysis 
of data from a prior study (Odvina, 2006), 8 patients took HCTZ 50 mg/day with 
KMgCit tab 40 meq K and 20 meq Mg/day for 6 months. 10 patients took HCTZ 
50 mg/day with KCl tab 40 meq K/day. Serum triglyceride declined by -32  41 
mg/dL from 1 month to 5 months of treatment in the KMgCit group, and 0  31 
in the KCl group (p = 0.09). Unfortunately, no baseline or 6 month data were 
available. 
 
Effect of KMgCit powder on serum FGF23. In 30 patients with pre- and 
Stage I hypertension participating in a crossover randomized trial, serum FGF23 
was significantly lower when they were taking KMgCit powder than KCl powder 
(46.1 +/- 16.7 Rel U/ml vs. 53.1 +/- 22.2 Rel U/ml, p=0.05).  
  
Prevention or correction of thiazide-induced hypomagnesemia. See Fig. 3 & 
Fig. 4.  
5. Methods of Procedure: 
Patients to be studied 
Serum potassium, mEq/L
2
3
4
5
6
KMgCit
KCl
†
†
†
†
†
†
†
†
Pre-treatment Last week
HCTZ
Week 1
supplement
Week 2
supplement
Week 3
supplement


12 
 
 
Studies will be conducted only in patients with treated or untreated stage 
I hypertension without concomitant cardiovascular diseases, chronic kidney 
diseases, or compelling indication for treatment with ACE inhibitor, beta 
blockers, or ARB. Patients will be adult men or women (> 21 years of age) of any 
ethnicity. Study is planned in 72 patients to account for potential dropout rate 
of 20%. 
Excluded will be patients with  
 diabetes mellitus, 
 Renal impairment (serum creatinine > 1.4 mg/dL), 
 Any heart diseases such as congestive heart failure, sustained arrhythmia, 
or coronary heart disease,  
 Chronic regular NSAID use,  
 Allergy to thiazide diuretics,  
 Gastro-esophageal reflux disease (GERD) requiring treatment with acid 
reducing agents or antacid more than once a week,  
 Esophageal-gastric ulcer or history of gastrointestinal bleeding,  
 Chronic diarrhea, vomiting, 
 Excessive sweating,   
 Unprovoked hypokalemia (serum K < 3.5 mmol/L) or hyperkalemia (serum 
K > 5.3 mmol/L),  
 Abnormal liver function test (AST or ALT above upper limit of normal 
range),  
 Subjects on any potassium supplement on a regular basis for any reason, 
such as patients with primary aldosteronism,  
 Pregnancy,   
 History of major depression, bipolar disorder, or schizophrenia,  
 History of substance abuse, 
 Gout,  
 Metabolic alkalosis, with serum bicarbonate > 32 meq/L,  
 Severe dietary salt restriction, less than1/2 spoonful or 50 meq 
sodium/day.  
 
Study design 
 
The patients will participate in a three-phase study in a parallel design 
(Fig. 9).  
 
 
 
 
  Fig. 9. Study scheme.  
 
 


13 
 
After baseline evaluation (Phase 1, without CTD), patients will take CTD 
alone for 2-3 weeks (Phase 2, CTD alone). They will then be randomized to two 
equal groups to take KMgCit powder or KCl powder along with CTD for 4 months 
(Phase 3).  
Test drugs 
  
KCl powder, made by and purchased from Sterling Pharmaceutical 
Services LLC, will contain 20 meq K as potassium chloride per sachet. KMgCit 
powder, also made by Sterling, will contain 20 meq K, 10 meq Mg, and 30 meq 
citrate, per sachet. These preparations will be prepared by the same method, and 
their composition will be the same, as those used in the completed trial (original 
IND 116,208).   
The sachets of KCl and KMgCit powder will be identical in appearance. 
During Phase 3, patients will dissolve the contents of each sachet of KCl or 
KMgCit powder in 250 ml water and ingest it with breakfast and again with 
dinner, to deliver 40 meq K per day. In the group taking KMgCit powder, patients 
will also receive Mg 20 meq and citrate 60 meq per day.   
  
A taste enhancer and sucralose will be added to improve tolerance of the 
test medications. Each sachet will be marked by a code, the identity of which 
will be known only to an independent study monitor. Each sachet will be labeled: 
Study drug # --; CTD-Induced Hypokalemia; Investigator: W. Vongpatanasin, 
M.D.  
 
Chlorthalidone, 25 mg generic tablets, will be purchased from a local 
pharmacy.   
Conflict of interest statement 
  
UT Southwestern had licensed KMgCit powder to Althos Pharma. 
Unfortunately, Althos Pharma is no longer operational due to financial 
difficulties. Accordingly, all the licensing agreements between UTSW and Althos 
Pharma, including one for KMgCit powder, have been terminated. (Tracy 
Roberson, licensing officer of UTSW’s Office of Technology Development, can be 
consulted for verification.) No relationship now exists between Althos Pharma 
and UTSW or investigators. 
 
Despite lack of industrial sponsorship, the investigators are convinced that 
the high scientific merit of the proposal mandates its pursuit. Thus, this protocol 
is investigator-initiated and research-driven, and not industry-sponsored. The 
initial costs of the study will be borne by the biotechnology program of CMMCR. 
CMMCR will purchase test medications from Sterling Pharmaceutical Services.  
 
Outline of the study (Table 1) 


14 
 
 
Baseline (Phase 1, time zero). At enrollment, various tests/procedures as 
outlined in Table 1 will be obtained. Patients who are on antihypertensive 
medications will be asked to stop them. 
CTD Alone (Phase 2). Patients will take CTD 25 mg/day. Two weeks later, 
they will return with a 24-h urine collection. Venipuncture and other procedures 
as outlined in Table 1 will be performed. Subjects who develop hypokalemia 
(serum K < 3.5 mEq/L) will immediately enter Phase 2. The remaining patients 
will continue on CTD for another week. On return at 3 weeks, all the 
tests/procedures will be performed in all patients.  
Table 1. Study Outline 
Weeks /months 
 
0 
2/3w   Rx 
1m 
2m 
3m 
4m 
 
Treatment 
 
 
 
   CTD  
 
 
   --------------------------------------------------- 
   KMgCit/KCl 
 
 
 
 ----------------------------------- 
Office blood pressure 
 
 
 
 
 
 
 
 
Serum tests  
 
 
 
 
 
 
 
 
 
 
Urine tests 
 
 
 
 
 
 
 
 
 
 
 
Side effects QN 
 
 
 
 
 
 
 
 
 
Diet history & BWt  
 
 
 
 
 
 
 
 
Sachet count  
 
 
 
 
 
 
 
 
 
CTD pill count 
 
 
 
 
 
 
 
 
 
Fecal occult blood  
 
 
 
 
 
 
 
 
 
Muscle Mg MRS 
 
 
 
 
 
 
 
 
 
Hepatic fat MRS 
 
 
 
 
 
 
 
 
_________________________________________________________________________________ 
Some patients may require only 2 weeks of CTD, instead of 3 weeks. Thus, the complete 
study duration might be shorter by 1 week. 
 
If patients develop symptomatic hypotension (blood pressure ≤ 90/60 
mmHg) after CTD treatment for 2 weeks, the dose of CTD will be reduced to 12.5 
mg daily temporarily. Blood pressure will be repeated 1 week after dose 
reduction. If BP is increased above 120/80 mmHg, the dose of CTD will be 
increased to 25 mg daily. Few patients who cannot later tolerate a higher dose 
of 25 mg/day will be withdrawn from the trial. If patients develop (BP ≥ 
130/80mmHg) after CTD treatment for 2 weeks, amlodipine 5 mg daily will be 
added to the regimen for blood pressure control. Blood pressure will be repeated 
in 1 week.  
 
 
 
CTD + KMgCit/KCl (Phase 3). Patients who developed hypokalemia at 2 
weeks of CTD will enter Phase 3. Those who completed three weeks of treatment 
with CTD alone will enter Phase 3 whether or not they develop hypokalemia. All 
patients will continue to take CTD 25 mg/day. All subjects will be randomized 
to receive KMgCit powder or KCl powder at a dose of 40 meq of K daily for 4 
months. Various tests will be performed at times indicated in Table 1.  


15 
 
 
Tests 
  
Office blood pressure. During clinic visits at baseline, at 2 and/or 3 weeks 
of CTD alone, at monthly intervals during combined treatment with CTD and 
KMgCit or KCl powder, the research nurse will obtain blood pressure by using 
the clinic’s oscillometric device (Welch Allyn, Vital Signs, WA). At each visit, three 
blood pressure measurements will be made after subjects sit quietly for at least 
10 minutes. The first reading will be discarded. The 2nd and 3rd measurements 
will be averaged.  
Serum tests. At baseline, 2 and/or 3 weeks after CTD alone, and at 2 and  
4 months of combined CTD and K salt treatment, a fasting venous blood sample 
will be obtained for electrolytes (potassium, sodium, chloride and carbon 
dioxide), magnesium, creatinine, calcium, phosphorus, albumin, triglyceride, 
cholesterol, LDL, HDL, and glucose (by Quest Laboratory). Serum PTH, insulin, 
8-isoprotanes, hsCRP, FGF23 and Klotho will be measured (by the Mineral 
Metabolism Laboratory, Moe’s Laboratory or O’Brien Center). At same times, a 
sample will be frozen for aldosterone (to be determined later when warranted by 
the results). Lymphocytes will be harvested from EDTA-treated blood sample and 
stored in RNALater for WNK1 mRNA (to be determined later when warranted in 
the laboratory of C.-L. Huang).   
 
Urine Tests. A 24-h urine sample will be collected under oil at baseline, 2 
and/or 3 weeks of CTD alone, 2 months and 4 months of combined treatment. 
Samples will be analyzed for stone risk factors (including potassium, pH, citrate, 
magnesium, sodium, calcium, phosphorus, sulfate, chloride, creatinine, and 
total volume), and net acid excretion by the Mineral Metabolism Laboratory. 
Samples will also be analyzed for 8-isoprostanes (by Moe’s laboratory) and frozen 
for aldosterone (to be determined later).   
 
At same times, a fresh spot urine sample will be obtained for creatinine 
(by Mineral Metabolism Laboratory), and frozen for WNK1 protein and mRNA, 
and exosomes (to be determined in the laboratories of Huang and Moe if 
warranted). WNK1 might be a mediator of changes in renal (sodium handling) 
and vascular (resistance) determinants of blood pressure that might ensue from 
varying potassium intake. Exosomes are shed membranes enclosing cytoplasm 
from the kidney shown to contain mRNA The measurement will allow us to 
assess levels of proteins and signaling molecules involved in the renal mineral 
transport.  
 
 Side effect questionnaire. At baseline, 2 and/or 3 weeks after CTD, and at 
monthly visits of combined treatments, the research nurse will complete the side 
effect questionnaire by interviewing the patients (Table 2). This history permits 
computation of “gastrointestinal symptom score”, a quantitative estimate of 
frequency and severity of gastrointestinal side effects (Ruml, 1999). 


16 
 
Other tests. At each follow-up visit, the research nurse (D. Arbique) will 
collect the test medications and count the number of unused packets or pills, in 
order to estimate compliance of patients in taking medications. At each visit, the 
research nurse will obtain history of unusual dietary intakes. Body weight will 
be measured. Smear of stool brought in by patients will be tested for occult blood.  
 
Muscle Mg by MRS. Intracellular muscle Mg will be obtained by magnetic 
resonance spectroscopy in the Department of Radiology.  
 
 
Hepatic fat by MRS. Hepatic TG content will be evaluated using a1.5 Tesla 
Gyroscan Achieva whole body clinical system (Philips Medical Systems, 
Cleveland, USA) equipped with software for localized spectroscopy as described 
(Price, 2013). In short, high-resolution morphological images are collected to 
serve as a “roadmap” for selection of a testing volume of 27 cc within the upper 
right hepatic lobe. All spectra are collected using PRESS sequence (Point 
RESolved Spectroscopy) for spatial localization and the signal acquisition with 
the following data acquisition parameters: Te = 27 ms, Tr = 3 s. All data are 
collected without water suppression. Areas of resonances from protons in water 
molecules and in methylenes of fatty acid chains will be evaluated with line-fit 
procedure using a commercial software (NUTS-ACORNNMR, Freemont, CA). 
 
Subjects with claustrophobia or metal devices precluding MRI, will not have MRI 
completed as part of this study. 
 
Table 2. Side Effect Questionnaire 
 
 
 


17 
 
6. Statistical Analysis 
Expectations (Table 3) 
 
 
 
 
Table 3. Anticipated Findings 
 
CTD CTD + KMgCit CTD + KCl 
Ks 
↓ 
= 
= 
Isoprostanes 
↑ 
↓ 
↑ 
Serum FGF23 = 
↓ 
= 
HOMA-IR 
↑ 
↓ 
↑ 
Aldosterone 
 
 
 
Muscle Mg 
 
 
 
Hepatic fat 
 
 
 
 
- 
On CTD alone, serum K would decline, reaching below normal in most 
patients. On both KMgCit powder and KCl powder along with CTD, serum 
K would increase to the normal limits. Similar levels of serum K would be 
observed during KMgCit powder vs. KCl powder.  
- 
Office blood pressure would decline during CTD alone. It would remain low 
on combined KMgCit powder or KCl powder with CTD.   
- 
It is expected that serum and urinary isoprostanes (marker of oxidative 
stress) would increase on CTD alone, decrease on combined KMgCit 
powder + CTD and remain unchanged on KCl powder + CTD.  
- 
We anticipate that serum FGF23 would increase on CTD alone, decrease 
on addition of KMgCit powder but not KCl powder.  
- 
Fasting plasma glucose and insulin would be higher during CTD when 
compared to baseline. KMgCit powder would attenuate the increase in 
plasma glucose and insulin, whereas KCl powder would not. HOMA-IR 
would show changes in the same direction.  
- 
Serum aldosterone (marker of renin-angiotensin system) would increase 
on CTD; the addition of KMgCit powder would attenuate this rise, but KCl 
powder would not.   
- 
The gastrointestinal symptom score during CTD alone will be similar to 
baseline. On combined treatment, gastrointestinal symptom score would 
be higher for KCl powder than KCit powder, with a larger percentage of 
patients complaining of dysgeusia on KCl powder.  
- 
At 3 weeks, 24-hour urinary potassium on KMgCit powder and KCl powder 
would be higher than CTD alone by about 35-40 meq/day. Urinary pH and 
citrate would be higher on KMgCit powder than CTD alone or KCl powder.  
- 
Free muscle Mg would increase on KMgCit powder but decline on KCl 
powder.  
- 
Hepatic fat would increase on KCl powder + CTD, but decline or remain 
unchanged on KMgCit + CTD.  
 
Sample Size Calculations 


18 
 
  
From our previous CTD studies, the mean increase in fasting serum  
glucose at CTD dose of 25 mg/day plus KCl supplementation to keep serum K 
constant was 10 mg/dL. The within subject SD of serum glucose was between 
2.0-8.5. Assuming SD = 8.5, power of 0.8 and  of 0.05, 60 patients (30 
randomized to KCl powder and 30 to KMgCit powder) would be needed to detect 
a potential reduction in serum glucose of 6 mg/dL by KMgCit. Assuming SD of 
5, power of 0.80 and  of 0.05, 60 patients would be needed to detect a potential 
reduction in serum glucose of 4 mg/dL by KMgCit. To account for a dropout of 
20%, we plan to recruit 72 subjects for the study. 
 
Statistical Methods 
  
Descriptive statistics and 95% confidence intervals will be used to 
summarize blood pressure and other responses for the three phases. Data from 
the three phases will be compared by using the repeated measures analysis of 
variance models. Significant differences between the three phases will be further 
analyzed by comparison of pairs of phases using contrasts constructed from the 
ANOVA models. By employing Bonferroni inequality to adjust for multiple 
testing, various comparisons between phases will be made. In addition, the 
existence of a trend in the differences of various parameters between phases will 
be sought (Perlman, 2002). Interim analysis will be performed at 50% completion 
of the trial. 
 
 


19 
 
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ICF_001.pdf: 
STU092015-058, Vongpatanasin, FormE-Consent, Mod_15, 07-23-20 
 
The University of Texas Southwestern Medical Center  
Parkland Health & Hospital System 
Children’s Medical Center 
Retina Foundation of the Southwest 
Texas Scottish Rite Hospital for Children 
Texas Health Presbyterian Hospital Dallas 
 
 
CONSENT TO PARTICIPATE IN RESEARCH 
 
 
Title of Research: 
Preventing metabolic side effects of thiazide diuretics 
with KMgCitrate 
 
Funding: 
Center for Mineral Metabolism and Clinical Research 
 
Study Doctors:  
Wanpen Vongpatanasin 
 
 
 
 
You may call these study doctors or research personnel during regular office hours at 
214-648-2968. At other times, you may call them at 214-645-8424. 
 
Instructions: 
Please read this consent form carefully and take your time making a decision about 
whether to participate.  As the researchers discuss this consent form with you, please ask 
him/her to explain any words or information that you do not clearly understand.  The 
purpose of the study, risks, inconveniences, discomforts, and other important information 
about the study are listed below.  If you decide to participate, you will be given a copy of 
this form to keep. 
 
Why is this study being done? 
This study is being done to test if potassium magnesium citrate powder (KMgCit) is 
more effective than potassium chloride (KCl) in preventing increases in blood sugar and 
insulin levels which are side effects of Chlorthalidone. Chlorthalidone is a commonly 
used diuretic approved for the treatment of high blood pressure.  
 
Why is this considered research?  
This is a research study because potassium or magnesium supplements are not 
approved preventing the increase in blood sugar and insulin caused by Chlorthalidone.  
 
The following definitions may help you understand this study:  
 Double-blind means neither you nor the researchers will know which drug you 
are receiving.  
 Randomization means you will be placed by chance (like a flip of a coin) in one of 
the study groups.   
IRB Approved Date: 7/23/2020


STU092015-058, Vongpatanasin, FormE-Consent, Mod_15, 07-23-20 
 
 Standard medical care means the regular care you would receive from your 
personal doctor if you choose not to participate in this research 
 MAGNETIC RESONANCE IMAGING OR MRI: A method to take pictures or 
measure metabolism of the inside of the body. The MRI exam in this research is 
investigational. 
 TESLA: is the unit for magnetic field strength. Standard clinical MRI scans are 
typically performed between 1 and 3 Tesla. We will use 3 Tesla to measure fat in 
your liver and 7 Tesla to measure your muscle magnesium. The 7 Tesla MRI 
procedures for this study will be done on a research scanner.  
 Researchers means the study doctor and research personnel at the University of 
 Texas Southwestern Medical Center in Dallas and its affiliated hospitals. 
 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you have high blood pressure 
(blood pressure on or off treatment is between 130/80and 160/100). 
 
Do I have to take part in this research study? 
No. You have the right to choose whether you want to take part in this research study.  
If you decide to participate and later change your mind, you are free to stop participation 
at any time. 
 
If you decide not to take part in this research study it will not change your legal rights or 
the quality of health care that you receive at this center. 
 
How many people will take part in this study? 
About 72 people will take part in this study at UT Southwestern.   
 
What is involved in the study? 
If you volunteer to take part in this research study, you will be asked to sign this consent 
form and will have the following tests and procedures.  Some of the procedures may be 
part of your standard medical care, but others are being done solely for the purpose of 
this study. 
 
Screening Procedures 
To help decide if you qualify to be in this study, you will have the following tests 
and/or evaluations. 
 Physical exam, medical and surgical history, history of mental illness, and 
substance abuse, 
 Vital signs, 
 Demographic information (age, sex, ethnic origin), 
 If you are taking medications for high blood pressure, you will be asked to 
stop taking your current medications.  
 
Group Assignment  
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If the researchers believe you can take part in this study, you will be given 
chlorthalidone for 2 or 3 weeks. Then you will be asked to take either potassium 
magnesium citrate or potassium chloride supplement twice a day for 4 months.    
The supplement will be provided in the powder form and you will need to dissolve 
each packet in the drinking water before taking it. You have a 1 in 2 chance of 
receiving either of the potassium supplements. 
 
Neither you nor the researchers will be allowed to choose which group you are 
placed into.  
 
Neither you nor the researchers will know which group you are in.  However, the 
sponsor will release the information about your assignment to the researchers if it is 
needed for your safety. 
 
Study Medication/Intervention 
If you decide to participate in this study, you will be asked to 
 Stop current medications (if taken) for hypertension for 3 weeks  
 Take Chlorthalidone daily alone for 2 or 3 weeks. Then you will; 
 Take Chlorthalidone daily AND 
 Take 1 package of Potassium Chloride powder, dissolved in water twice a 
day(with breakfast and dinner) for 4 months  
                                                   or  
 Take 1 package of Potassium Magnesium Citrate powder, dissolved in water 
twice a day (with breakfast and dinner)  for 4 months 
 
The blood, urine, and imaging tests in this study are designed for research and not 
for medical purposes.  These tests are not useful for finding problems or diseases.  
Even though the researchers are not looking at your blood or urine tests to find or 
treat a medical problem, you will be told if they notice something unusual.  You and 
your regular doctor can decide together whether to follow up with more tests or 
treatment.  Because the blood and urine tests done in this study are not for medical 
purposes, the research results will not be sent to you or to your regular doctor.  
 
Procedures and Evaluations during the Research  
You will be asked to come in for 6 visits. All Procedures during this study are for 
experimental purposes. If you have a history of claustrophobia or a metal 
device that precludes MRI, you will not have an MRI done as a part of the 
study. 
 
Visit 1: (At 0 week) 
 Research personnel will check your blood pressure and your weight.  
 You will be asked to collect urine for 24 hour urine  
 Urine pregnancy test will be done for women of child bearing age  
 Research personnel will collect three tablespoons of blood from the tube in 
your arm for the research purpose. 
 You will be asked about any symptoms of stomach or intestinal discomfort, 
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nausea, or heartburn, you might have before taking study medications. 
 You will be given a stool card kit which you will need to return prior to your 
next visit. 
 If you were taking blood pressure medication, you will be asked to stop your 
blood pressure medications for 3 weeks. 
 Research personnel will provide counseling regarding low sodium diet and 
diet rich in fruits and vegetables or DASH diet to control blood pressure 
 If you were not taking blood pressure medication, you will have MRI 
(Magnetic Resonance Imaging) of right calf for measurement of magnesium 
content and MRI of your liver to measure fat content for research purposes 
 Women of child bearing age will have a urine pregnancy test 
 You will then start taking Chlorthalidone 25mg daily if you were not on blood 
pressure medications before the study  
 
 
Visit 2 (1 week after drug washout) 
 Research personnel will check your blood pressure.  
 If blood pressure is 160/100 or above, we will start Chlorthalidone 25 mg 
without delay. If your blood pressure is under 160/100 mmHg, you will return 
in one week.  
 Research personnel will provide counseling regarding low sodium diet and 
diet rich in fruits and vegetables or DASH diet to control blood pressure 
 
 
Visit 3 (2 weeks after drug washout) 
 Research personnel will check your blood pressure.  
 If blood pressure is 160/100 or above, we will start Chlorthalidone 25 mg 
without delay. Patient with blood pressure under 160/100 mmHg will return in 
one week.  
 
 
Visit 4: (3 weeks after drug washout) 
 Research personnel will check your blood pressure.  
 You will have MRI (Magnetic Resonance Imaging) of right calf for 
measurement of magnesium content and MRI of your liver to measure fat 
content for research purposes 
 You will start taking Chlorthalidone 25 mg daily 
 
Visit 5: (2 weeks after the first study medication) 
 
 Research personnel will check your blood pressure and your weight and 
count your pills. If your blood pressure is less than 90/60 dose of 
chlorthalidone will be reduced by half and blood pressure will be checked in 1 
week. If your blood pressure is greater than130/80, you will be asked to take 
amlodipine 5mg daily 
 Research personnel will collect three tablespoons of blood from the tube in 
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your arm for the research purpose. 
 You will be asked to collect urine for 24 hour urine  
 You will be asked about any symptoms of stomach or intestinal discomfort, 
nausea, or heartburn, you might have after taking study medications.   
 If your potassium level is less than 3.5 mEq/L, you will go directly to visit 4 
and skip visit 3.  
 
 
   
Visit 6: (those on Chlorthalidone for 3 weeks) 
 When you return urine sample, research personnel will check your blood 
pressure and your weight. If your blood pressure is below 120/80, you will be 
excluded from the study. If your blood pressure is above or equal to 120/80, 
you will be able asked to take 25mg of chlorthalidone daily. 
 Research Personnel will count Chlorthlidone pills 
 You will be asked about any symptoms of stomach or intestinal discomfort, 
nausea, or heartburn, you might have before taking study medications. 
 You will be given either potassium magnesium citrate OR potassium chloride  
 
 
Visit 7: (1 month on Chlorthalidone plus KMgCit OR KCl) 
 Research personnel will check your blood pressure and your weight and 
count your medication packages and pills  
 If your blood pressure is greater than130/80, you will be asked to take 
amlodipine 10mg daily 
 Research personnel will check fasting glucose level for research purpose. 
 You will be asked about any symptoms of stomach or intestinal discomfort, 
nausea, or heartburn, you might have after taking study medications. 
 
Visit 8: (2 months on Chlorthalidone plus KMgCit OR KCl) 
 Research personnel will check your blood pressure and your weight and 
count your medication packages.  
 If your blood pressure is greater than130/80, you will be asked to take 
doxazosin 2mg daily 
 Research personnel will collect three tablespoons of blood from the tube in 
your arm for the research purpose. 
 You will be asked to collect urine for 24 hour urine  
 You will be asked about any symptoms of stomach or intestinal discomfort, 
nausea, or heartburn, you might have after taking study medications.    
 You will be given a stool card kit which you will need to return prior to your 
next visit. 
  
   
 
 
 Visit 9: (3 months on Chlorthalidone plus KMgCit OR KCl) 
 Research personnel will check your blood pressure and your weight and 
count your medication packages  
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 If your blood pressure is greater than130/80, you will be asked to take 
doxazosin 4mg daily 
 Research personnel will check fasting glucose level for research purpose. 
 You will be asked about any symptoms of stomach or intestinal discomfort, 
nausea, or heartburn, you might have before taking study medications. 
 
 
Visit 10: (4 month on Chlorthalidone plus KMgCit OR KCl) 
 Research personnel will check your blood pressure and your weight and 
count your medication packages and pills 
 You will be asked to collect urine for 24 hour urine  
 Research personnel will collect three tablespoons of blood from the tube in 
your arm for the research purpose. 
 You will be asked about any symptoms of stomach or intestinal discomfort, 
nausea, or heartburn, you might have before taking study medications. 
 You will be given a stool card kit which you will need to return to us 
 You will have MRI of right calf and MRI of your liver for research purposes. 
End of study 
 
You will have magnetic resonance imaging (MRI) of your liver and calf. For this 
procedure, you will lie quietly inside a large, doughnut-shaped magnet for about 30 
minutes. 
 
How long can I expect to be in this study? 
The study will last for approximately 18-19 weeks. Follow up visits with MRI will take 
about 3 hours. Visits without imaging will take about 60 minutes 
 
You can choose to stop participating for any reason at any time.  However, if you decide 
to stop participating in the study, we encourage you to tell the researchers.  You may be 
asked if you are willing to complete some study termination tests. 
 
What are the risks of the study? 
 
Study Procedure/Intervention 
Because of your participation in this study, you are at risk for the following side effects. 
You should discuss these with the researchers and your regular health care provider. 
  
a) Chlorthalidone: Information about known problems is based upon the experiences of 
hypertensive patients on treatment for 4-5 years. 
• In past research, 12 out of 100 users of chlorthalidone had diabetes mellitus, whereas 
8-10 out of 100 users of other blood pressure medications had diabetes mellitus 
• 9 out of 100 had low potassium 
• 1 out of 100 had gout 
• Risk of kidney failure is not increased compared to other blood pressure medication. 
However, patients who cannot drink normal amount of fluid or maintain normal amount 
of salt intake may have low blood pressure, dehydration, and kidney problem 
 
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b) Potassium Chloride powder and Potassium Magnesium Citrate powder: may cause 
some, all or none of the side-effects listed below.  
 
 
 
Frequent 
30% of subjects 
Occasional 
15% of subjects 
Rare 
Less than 1% of subjects 
Serious 
 
 
High potassium levels 
in your blood 
Less Serious 
 
Stomach upset, 
vomiting, nausea, 
belching, diarrhea, 
loose bowel, stomach 
or intestinal pain, loss 
of appetite, pain with 
swallowing,  
 
 
Minor 
 
 
Fatigue 
 
c) Amlodipine may cause some, all or none of the side-effects listed below;  
 
 
 
 
Frequent 
30% of subjects 
Occasional 
15% of subjects 
Rare 
Less than 1% of subjects 
Serious 
 
 
Allergic reaction 
Less Serious 
 
Swelling of the feet, 
constipation, 
headache, elevated 
heart rate, heart 
pounding 
 
Low blood pressure, 
dizziness 
Minor 
 
 
Increase in size of 
gums 
 
d) Doxazosin may cause some, all or none of the side-effects listed below  
 
Frequent 
30% of subjects 
Occasional 
15% of subjects 
Rare 
Less than 1% of subjects 
Serious 
 
 
Allergic reaction 
Less Serious 
Headache 
Confusion, dizziness, 
faintness when 
getting up from a 
lying or sitting 
position, sweating, 
swelling in legs, 
 
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elevated heart rate, 
heart pounding 
 
Minor 
 
 
Frequent urge to 
urinate 
 
 
e) MRI: There are no known risks from exposure to magnetic fields. You may 
experience nervousness and/or anxiety due to the loud banging made by the machine 
while it is taking pictures and from confinement in a tight space (claustrophobia). If you 
become anxious, you can stop the procedure at any time .You may also experience 
some discomfort and fatigue from lying still during imaging. If you have any metal clips 
or plates in your body, you should tell the investigator. MRI may not be appropriate if 
you are pregnant or are trying to become pregnant. MRI may not be appropriate if you 
have permanent eyeliner or eyebrows or any pieces of metal in your body, such as the 
following:  
• Heart pacemaker, heart valve replacement, or aortic clips 
• Metal fragments in your eyes, skin, or elsewhere in your body 
• Brain clips or pieces of metal used in aneurysm surgery or intracranial bypass 
• Venous umbrella  
• Pieces of metal in the body resulting from work as a sheet-metal worker or welder  
• Clips placed in an internal organ  
• Prosthetic devices, such as middle ear, eye, joint, or penile implants  
• Joint replacement.  
• Hearing aid that cannot be removed  
• Neurostimulator  
• Insulin pump 
• Intrauterine device (IUD)  
• Shunts or stents 
• Metal mesh or coil implants  
• Metal plate, pin, screws, or wires, or any other metal implants 
 
Please tell the researchers if you have any metal in your body as this will exclude you 
from completing the MRI portion of the study  
 
Risk of High Field MRI 
7T MRI Scanner: 7T scanners are solely for research purposes for measuring 
magnesium in your muscle and are considered experimental (i.e not used for clinical 
diagnosis). The FDA has concluded that MRI systems operating at 7 Tesla do not 
represent significant risk. However, this research study will expose you to strong 
magnetic fields and long term safety data is limited. At this time, there are no known 
long-term risks of exposure to 7 Tesla magnetic fields. 
3T MRI Scanner: The 3T scanner used in this study is for measurement of fat in your 
liver. It has been approved and is used in clinical diagnosis.   
 
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-Blood pressure cuff inflation: The blood pressure cuff will squeeze your arm tightly. 
However, any discomfort will stop as soon as the pressure in the cuff is released. 
 
-Blood samples: You may experience discomfort, bleeding, and/or bruising.  You may 
feel dizzy or faint.  On a rare occasion, an infection may develop at the site where the 
blood was collected. 
- Urine Collection:   No known risk associated with urine collection.  
 
 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  
Every effort will be made to keep your information confidential; however, this cannot be 
guaranteed.  
 
Risks Embryo, Fetus or Breast-fed Infant 
If you are part of this study while pregnant or breast-feeding an infant, it is possible that 
you may expose the unborn child or infant to risks.  For that reason, pregnant and 
breast-feeding females cannot participate in the study.  If you can become pregnant, a 
urine pregnancy test will be done, and it must be negative before you participate in this 
study. If you do become or are planning to become pregnant during this study, you must 
tell the researchers immediately 
 
Risks of Blood Drawing 
Risks associated with drawing blood from your arm include minimal discomfort and/or 
bruising.  Infection, excess bleeding, clotting, and/or fainting also are possible, although 
unlikely. 
 
You will have 12 tablespoons (180 ml) of blood collected over 4.5 months because you 
are in this research study. 
 
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are 
concerned about other, unknown side effects, please discuss this with the researchers. 
 
How will risks be minimized or prevented?   
The research laboratory is fully equipped to handle any untoward side effects. Dr. 
Vongpatanasin is a hypertension specialist and cardiologist with extensive experiences 
in performing the research procedures in this study. Emergency equipment, in the event 
of that your heart stops or you stop breathing, is immediately available with highly 
trained staff. 
 
What will my responsibilities be during the study?   
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While you are part of this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do the 
following: 
 Ask questions about anything you do not understand. 
 Keep your appointments. 
 Follow the researchers’ instructions. 
 Let the researchers know if your telephone number or address changes. 
 Tell the researchers before you take any new medication, even if it is prescribed 
by another doctor for a different medical problem or something purchased over 
the counter. 
 Tell your regular doctor about your participation in this study. 
 Report to the researchers any injury or an illness while you are on study even if 
you do not think it is related.  
 
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study? 
Yes.  You will be told if any new information becomes available during the study that 
could cause you to change your mind about continuing to participate or that is important 
to your health or safety. 
 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the study, 
you should report them to the researchers right away.  Telephone numbers where they 
can be reached are listed on the first page of this consent form. 
 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the 
nearest hospital emergency room, or call 911 (or the correct emergency telephone 
number in your area).  Tell emergency personnel about any medications you are taking, 
including any medications you are taking for this study.   
 
What are the possible benefits of this study? 
 
If you agree to take part in this study, there will not be direct benefits to you.  The 
researchers cannot guarantee that you will benefit from participation in this research. 
 
We hope the information learned from this study will benefit others with high blood 
pressure in the future.  Information gained from this research could lead to better 
treatment of hypertension.   
 
 
What options are available if I decide not to take part in this research study? 
You do not have to participate in this research to receive care for high blood pressure. 
Instead of being in this study, you can receive high blood pressure treatment from your 
regular doctor. 
 
Will I be paid if I take part in this research study? 
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Yes.  You will be issued a UT Southwestern Greenphire ClinCard, which can be used 
as a credit or debit card. You will be paid $1,000 at the end of this 4.5 - 5 month study 
with MRI. You will be paid $800 at the end of this 4.5 – 5 month study if MRI’s are not 
completed.  If you stop taking part in this study or are withdrawn by the research team, 
you will be paid according to the number of weeks you participated in the study at $55 
per week (if you were not on blood pressure medications before the study and complete 
MRI) or $47 per week (if you were on blood pressure medications before the study and 
complete MRI). If you are unable to complete the MRI’s as a part of the study related to 
medical device or claustrophobia, you will be paid according to the number of weeks 
you participated in the study at $44 per week (if you were not on blood pressure 
medications before the study) or $38 per week (if you were on blood pressure 
medications before the study). 
 
There are funds available to pay for parking expenses at the Aston Clinical Building. 
There are no funds available for transportation to and from the research center, lost 
time away from work and other activities, lost wages, or child care expenses. 
 
Your name, address, date of birth and social security number will be shared with a third-
party solely for the purposes of compensation processing. All information will be stored 
in a secure fashion.   
 
Please note that if you are on record as owing money to the State of Texas, such as for 
back child support or a delinquent student loan, the payment may be applied to that 
debt.  
 
An IRS Form 1099 will be sent to you if your total payments are $600 or more in a 
calendar year, unless it’s a reimbursement.  
 
Will my insurance provider or I be charged for the costs of any part of this 
research study? 
No. Neither you, nor your insurance provider, will be charged for anything done only for 
this research study (i.e., the Screening Procedures, Medications, Labs, Experimental 
Procedures, or Monitoring/Follow-up Procedures described above).   
 
 
What will happen if I am harmed as a result of taking part in this study? 
It is important that you report any illness or injury to the research team listed at the top 
of this form immediately. 
 
Compensation for an injury resulting from your participation in this research is not 
available from the University of Texas Southwestern Medical Center at Dallas. 
  
You retain your legal rights during your participation in this research 
 
Can I stop taking part in this research study? 
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Yes.  If you decide to participate and later change your mind, you are free to stop taking 
part in the research study at any time. 
 
If you decide to stop taking part in this research study, it will not affect your relationship 
with the UT Southwestern staff or doctors.  Whether you participate or not will have no 
effect on your legal rights or the quality of your health care. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status 
will not be affected in any way. 
 
Your doctor is a research investigator in this study.  S/he is interested in both your 
medical care and the conduct of this research study.  At any time, you may discuss your 
care with another doctor who is not part of this research study.  You do not have to take 
part in any research study offered by your doctor. 
 
If I agree to take part in this research study, can I be removed from the study 
without my consent? 
Yes.  The researchers may decide to take you off this study if: 
 Your medical problem becomes worse. 
 The researchers believe that participation in the research is no longer safe for 
you. 
 The researchers believe that other treatment may be more helpful. 
 The sponsor or the FDA stops the research for the safety of the participants. 
 The sponsor cancels the research. 
 You are unable to keep appointments or to follow the researcher’s instructions. 
 
Will my information be kept confidential? 
 
Information about you that is collected for this research study will remain confidential 
unless you give your permission to share it with others, or as described below.  You 
should know that certain organizations that may look at and/or copy your medical 
records for research, quality assurance, and data analysis include: 
 
• 
Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA), involved in keeping research safe for people; and 
• 
The UT Southwestern Institutional Review Board.  
• 
Quest Diagnostic and Aston Clinical Laboratory  
In addition to this consent form, you will be asked to sign an "Authorization for Use and 
Disclosure of Protected Health Information."  This authorization will give more details 
about how your information will be used for this research study, and who may see 
and/or get copies of your information. 
 
Whom do I call if I have questions or problems? 
For questions about the study, contact Dr. Vongpatanasin 214-648-3180 during regular 
business hours and at 214-645-8000 after hours and on weekends or holidays.   
 
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For questions about your rights as a research participant, contact the UT Southwestern 
Institutional Review Board (IRB) Office at 214-648-3060. 
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SIGNATURES: 
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
 
Your signature below certifies the following: 
 
 You have read (or been read) the information provided above. 
 You have received answers to all of your questions and have been told who to 
call if you have any more questions. 
 You have freely decided to participate in this research. 
 You understand that you are not giving up any of your legal rights. 
 You understand that a copy of this signed consent document, information about 
this study, and the results of any test or procedure that may affect your medical 
care, may be included in your medical record.  Information in your medical 
record will be available to health care providers and authorized persons 
including your insurance company. 
 
 
 
____________________________________________ 
 
 
Name of Participant (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Participant 
Date 
Time 
 
____________________________________________ 
 
 
Name of Person Obtaining Consent (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Person Obtaining Consent 
Date 
Time 
 
 
 
 
 
 
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Interpreter Statement: 
I have interpreted this consent form into a language understandable to the participant 
and the participant has agreed to participate as indicated by their signature on the 
associated short form. 
____________________________________________ 
 
 
Name of Interpreter (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Interpreter 
Date 
Time 
 
 
 
 
 
 
 
 
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