Chlorthalidone in Chronic Kidney Disease
Phase: PHASE2
Conditions: Renal Insufficiency, Chronic, Hypertension
Sponsor: Indiana University

1 | F i n a l  P r o t o c o l
NCT number: 02841280
Last updates 14 Dec 2019
Chlorthalidone for Hypertension in Advanced
Chronic Kidney Disease (CLICK): A Randomized Control Trial 
Final Protocol 
Statistical Analysis Plan 
Listing of Significant Amendments to Protocol 

2 | F i n a l  P r o t o c o l
TABLE OF CONTENTS 
INTRODUCTION ....................................................................................................................... 5 
OBJECTIVES AND HYPOTHESIS ............................................................................................ 5 
Objectives .............................................................................................................................. 5 
Primary Objective ............................................................................................................... 5 
Secondary Objective .......................................................................................................... 6 
Hypothesis ............................................................................................................................. 6 
BACKGROUND ......................................................................................................................... 7 
The burden of CKD is high; hypertension is common in CKD ................................................. 7 
Dietary excess of sodium (Na) is an important cause of hypertension .................................... 7 
Na overload and extracellular volume expansion is common in CKD and leads to 
hypertension .......................................................................................................................... 7 
Recommendations of the Guidelines on the use of diuretics in CKD ...................................... 8 
Small studies in CKD suggest that thiazide diuretics can cause natriuresis and BP lowering . 9 
Randomized controlled trials on the of use of thiazides in CKD .............................................10 
Risks and benefits of thiazides in CKD ..................................................................................11 
Preferred thiazide diuretic use in CKD ...................................................................................11 
A reduced intake of dietary Na, diuretic use, or both may protect the kidney .........................12 
Pilot Study .............................................................................................................................13 
RESEARCH PROTOCOL AND TRIAL DESIGN .......................................................................15 
Overall Trial Design and Plan ................................................................................................16 
Study Intervention .................................................................................................................17 
Treatment Compliance ..........................................................................................................17 

3 | F i n a l  P r o t o c o l  
 
Protocol for managing blood pressure ...................................................................................17 
Stop points ............................................................................................................................18 
Outcome Variables ................................................................................................................18 
Primary outcome: ..............................................................................................................18 
Secondary outcomes: ........................................................................................................18 
Safety Assessments and Variables .......................................................................................19 
Subjects ................................................................................................................................19 
Inclusion and exclusion criteria ..........................................................................................19 
Retention of Subjects ........................................................................................................20 
Optional Annual Follow Up ....................................................................................................20 
Methods ................................................................................................................................20 
Method of Randomization ..................................................................................................20 
Measurement of clinic BP ..................................................................................................20 
Measurement of 24-hour Ambulatory BP ...........................................................................21 
Measurement of home BP .................................................................................................21 
Chemical Determinations ..................................................................................................21 
Air displacement plethysmography ....................................................................................21 
STATISTICAL METHODS.........................................................................................................22 
Sample Size ..........................................................................................................................22 
Analyses ...............................................................................................................................23 
Primary Analysis ...............................................................................................................23 
Pre-specified sub-group analysis for BP response ............................................................25 
Safety analysis ..................................................................................................................25 
Secondary analysis ...........................................................................................................25 
Alternative study design considerations and clarifications .....................................................26 
TIMETABLE/MILESTONES ......................................................................................................27 

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DATA SAFETY MONITORING BOARD (DSMB) ......................................................................27 
HUMAN SUBJECTS .................................................................................................................27 
Protection of Human Subjects ...............................................................................................27 
Risks .....................................................................................................................................27 
Protection against risks and reporting of adverse events .......................................................27 
Adverse events of special interest .........................................................................................28 
SIGNIFICANT PROTOCOL AMENDMENTS ............................................................................29 
REFERENCE LIST ...................................................................................................................31 
 
 
 

5 | F i n a l  P r o t o c o l  
 
INTRODUCTION 
It is estimated that in the United States there are approximately 8 million individuals who 
have moderate to severe chronic kidney disease (CKD) 1. Among them, hypertension is 
common and is often poorly controlled due to an expanded volume state; diuretics are 
frequently prescribed. Loop diuretics are potent and effective in lowering blood pressure (BP), 
however, their use is associated with acute kidney injury. Thiazide diuretics, on the other hand, 
are less potent and their use may be associated with less acute kidney injury. As of yet there is 
no firm data to support that thiazide diuretic therapy can improve BP in advanced CKD. In a 
review that we recently published, we found 13 studies on the use of thiazide diuretics in 
advanced CKD either alone or in combination with loop diuretics 2. Of these, 9 studies were 
observational and only 4 were randomized clinical trials. Our review suggests that thiazides may 
be useful even among people with advanced CKD. Observational data show that thiazides lead 
to an improvement in seated clinic BP of about 10-15 mmHg systolic and 5-10 mmHg diastolic 
whereas randomized trials show about a 15-mmHg reduction in mean arterial pressure.  
Randomized trials had small sample sizes (7-23 subjects); accordingly, better studies are 
needed to evaluate the safety and efficacy of thiazide diuretics in moderate to advanced CKD. 
We choose chlorthalidone because it is three times more potent as a diuretic compared to 
hydrochlorothiazide, but it is about a tenth of the price of metolazone. Our preliminary studies 
that support its use in advanced CKD is further explained later in the protocol.  
Our study focused on the potential mechanisms by which thiazides may reduce BP and 
offer target organ protection. These effects have not been evaluated so far. This randomized 
controlled trial, addresses a simple, inexpensive, yet an effective way to treating people with 
CKD who have poorly controlled hypertension. We use state-of-the-art methods such as body 
volume measurements (BodPod) and ambulatory BP monitoring for evaluations.  
 
OBJECTIVES AND HYPOTHESIS 
Objectives 
Primary Objective 
To test the hypothesis that CTD will improve BP, we will perform a double-blind, 
placebo-controlled, randomized trial among subjects with CKD and poorly controlled 
hypertension. After a two-week, single-blind placebo run-in, we will randomize 160 hypertensive 
patients confirmed by 24h ambulatory BP monitoring to either placebo or 12.5 mg CTD once 
daily.  We will monitor BP at home twice daily for one week before each of their 4 weekly visits 
and titrate the dose of the drug based on the home BP. We will double the dose of the diuretic 
(up to a maximum CTD dose of 50 mg/d) or placebo every 4 weeks if home BP remains 
≥135/85 mmHg (which is ~140/90 mmHg in the clinic). The primary endpoint will be assessed 
by change from baseline at 12 weeks in 24h ambulatory systolic BP.   
 

6 | F i n a l  P r o t o c o l  
 
Secondary Objective 
To test the hypothesis that CTD will result in target organ protection, we will evaluate 
changes in albuminuria. Albuminuria will be assessed using overnight urine collections at 
baseline and every 4 weeks. 
To test the hypothesis that CTD causes improvement in BP via a reduction in 
extracellular fluid volume, we will evaluate changes from baseline in the following extracellular 
fluid volume markers: N-terminal pro B-type natriuretic peptide (NT-proBNP), seated plasma 
renin, and plasma aldosterone. We will use the gold-standard for measuring body volume which 
is air displacement plethysmography. We predict that CTD use will be associated with loss of 
fluid weight and therefore a change in body volume. Our preliminary data show changes in each 
of these markers within 4 weeks. 
Hypothesis 
We hypothesize that among subjects with advanced CKD, chlorthalidone (CTD) will 
result in improved 24-hour ambulatory BP. Furthermore, CTD will improve albuminuria over 12 
weeks providing evidence for target organ protection. CTD will produce these effects by 
shrinking the extracellular fluid volume (Figure 1).  
 
 
 
 
 
 
 
 
TARGET ORGAN PROTECTION
MECHANISM OF ACTION
SAFETY/EFFICACY
Aim 2
Loop diuretics
Problems
Urine albumin/creatinine ratio
Renin, Aldosterone
N-terminal B-type natriuretic 
peptide (NTproBNP)
Body volume (BODPOD)
RCT of thiazide diuretics
Acute Kidney Injury
Volume depletion
Hypokalemia
Hyponatremia
Assess safety
at each visit
TRIAL CONCEPT: Diuretics are needed to treat hypertension but in those 
with more severe CKD, thiazides are considered ineffective
Figure 1
↓24-h ambulatory
BP in 12 weeks
Chronic Kidney
Disease (CKD)

7 | F i n a l  P r o t o c o l  
 
BACKGROUND 
The burden of CKD is high; hypertension is common in CKD 
It is estimated that in the United States approximately 7.7% of the population has 
moderate (Stage 3) and 0.35% severe (Stage 4) chronic kidney disease (CKD) 3. The 
prevalence of hypertension in CKD is high. For example, a survey of >10,000 individuals at high 
risk for kidney disease screened in every state in the United States, revealed that 86% of the 
subjects had hypertension and 70% were treated. The control of hypertension to recommended 
levels was dismal; adequate control was present in only 13% 4. In the US adult population the 
prevalence of hypertension is 31%; 70% are treated and 46% are controlled 5. Although BP was 
controlled to <130/80 mmHg in 48% of those with hypertension but without CKD, among those 
with CKD and hypertension, the control rate was only 31% 6. Thus, compared to those without 
CKD, among people with CKD, hypertension is more prevalent and more often treated but less 
often controlled. 
Dietary excess of sodium (Na) is an important cause of hypertension 
Increased dietary Na intake in modern societies is an important and treatable cause of 
hypertension. A meta-analysis combining results of 50 studies shows that 78 mmol/d (1.8 g) 
reduction of dietary Na is associated with a reduction in BP among hypertensive people of 
5.0/2.7 mmHg 7; among non-hypertensives, BP is reduced by 2.0/1.0 mmHg 7. The Dietary 
Approaches to Stop Hypertension (DASH) randomized controlled trial 8 showed that compared 
to the highest Na intake (150 mEq/d), BP was reduced 2.1 mmHg systolic with moderate Na 
restriction (100 mEq/d). Compared to the highest Na intake, BP was reduced 6.7 mmHg systolic 
with greater (65 mEq/d) Na restriction. The greatest reductions in BP were seen among blacks, 
women, and those with hypertension. 
To lower the incidence of hypertension, the Institute of Medicine has recommended that 
dietary Na should be restricted to <1500 mg/d (65 mmol/d) 9. However, recent estimates (2005-
2006) suggest that the average man in the US consumed 4 g Na; the average woman 2.8 g/d 10.  
Dietary Na restriction is also recommended as an initial step to treat pre-hypertension and stage 
I hypertension. Data is now emerging that even people with later stage hypertension including 
those being treated with multiple antihypertensive agents such as those with resistant 
hypertension can benefit with this strategy 11. Although dietary Na restriction is important in 
controlling hypertension, in our salt-rich society, long-term adherence to this life-style change is 
challenging.   
Na overload and extracellular volume expansion is common in CKD and leads to 
hypertension 
Progressive loss of renal function leads to both a reduction in glomerular filtration rate 
(GFR) and tubular mass. Reduced GFR results in reduced filtered Na load and volume 
expansion. Volume expansion provokes reduced renal tubular Na absorption, but failure to fully 
suppress Na reabsorption increases extracellular fluid (ECF) volume. In some CKD states, such 
as the nephrotic syndrome, an increase in tubular Na reabsorption may be the primary 

8 | F i n a l  P r o t o c o l  
 
abnormality causing ECF excess. Indeed, epidemiological studies suggest greater association 
of hypertension with proteinuria than reduced GFR 12-14.   
Among patients with end-stage renal disease, both dietary and dialysate Na restriction 
are the cornerstones for treating resistant hypertension 15. More important, volume reduction 
through ultrafiltration in patients consuming recommended intake of Na is an effective way to 
lower BP. Since these patients are treated with multiple drugs, this is an effective strategy of 
controlling poorly controlled hypertension. The volume control strategy has been tested in one 
randomized controlled trial 16. In the Dry-weight Reduction In hypertensive hemodialysis 
Patients (DRIP) trial we randomized 150 patients in 2:1 ratio to either aggressive volume 
reduction or a control group 16. Within 4 weeks, BP reduction assessed by interdialytic 
ambulatory BP monitoring of about 7/3 mmHg was achieved; this effect persisted through the 8-
week duration of the trial. Despite the intake of an average of 2.5 antihypertensive drugs, this 
reduction in BP suggests that in this difficult to treat group, volume control was effective in 
providing additional antihypertensive effect. 
Recommendations of the Guidelines on the use of diuretics in CKD  
For the treatment of hypertension in CKD, the Seventh Report of the Joint National 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 
7) recommends that those with advanced renal disease (estimated GFR <30 ml/min 1.73 m2), 
should increase doses of loop diuretics and be used in combination with other drug classes 17 . 
The JNC 8 has no statement in this group of patients.  
According to the National Kidney Foundation (NKF), Kidney Disease Outcomes Quality 
Initiative (KDOQI) diuretics should be used to treat hypertension in most patients with CKD 18.  
For those with estimated GFR ≥30 mL/min/1.73 m2 thiazide diuretics given once daily are 
recommended. However, loop diuretics are recommended for those with estimated GFR <30 
mL/min/1.73 m2.  Loop diuretics given once or twice daily, in combination with thiazide diuretics 
can be used for patients with ECF volume expansion and edema.  All these recommendations 
have an evidence level of A. 
The Caring for Australasians with Renal Impairment (CARI) guidelines 19 and the UK 
National Institute of Health and Clinical Excellence (NICE) guidelines20 are silent on the role of 
thiazides in CKD. The Canadian Hypertension Education Program states that for patients with 
non-diabetic CKD, thiazide diuretics are recommended as additive antihypertensive therapy 
(Grade D) 21. For patients with CKD and volume overload, loop diuretics are an alternative 
(Grade D). The Veterans Administration Department of Defense guidelines state that among 
those with CKD a diuretic should be used when a second BP medication is needed, or if 
hyperkalemia occurs 22. Thiazide diuretics may be used if estimated GFR > 30 ml/min/1.73m2, 
but loop diuretics are usually needed for patients with lower estimated GFR. 
Taken together, the guidelines do not strongly support the use of thiazide diuretics in 
advanced CKD. This is because the evidence base to support this recommendation is weak. 

9 | F i n a l  P r o t o c o l  
 
Small studies in CKD suggest that thiazide diuretics can cause natriuresis and BP 
lowering 
We found 13 studies on the use of thiazide diuretics in advanced CKD either alone or in 
combination with loop diuretics.23 Of these 9 studies were observational and 4 were clinical 
trials. Of the 4 clinical trials, 2 were single-blind, cross-over studies, and 2 were double-blind 
cross-over trials. Each of the observational studies was small and included between 8-20 
participants.  
1. The first study reported in 1972 was conducted in 14 participants with advanced 
CKD (creatinine clearance (Ccr) 1.2 to 12 mL/min); metolazone was administered in 
doses ranging from 20-150 mg per day (equivalent to about 200 mg to 1500 mg 
HCTZ). 24   Urine Na excretion increased >2 times.     
2. Bennett et al reported a study in 20 participants with CKD (Ccr 4-48 mL/min) 25. Over 
3 months of the study the dose of metolazone was titrated from 5 mg to 25 mg 
depending on response. Weight fell by 1.4 kg and diastolic BP fell by 12.5± 11.7 
mmHg among the 12 hypertensive participants Hypokalemia, AKI, and an increase in 
fasting blood glucose were the major complications noted. 
3. Craswell et al reported 12 participants with CKD, and all but one had Ccr of <60 
mL/min 26.  Oral metolazone was given in variable doses for durations lasting from 2-
20 weeks. Weight was reduced 1.4 kg, edema improved, and BP fell by 14.2/3.2 
mmHg from a baseline of 147/92 mmHg. Most participants (67%) required potassium 
supplementation, AKI was noted, and uric acid increased despite no patient 
experiencing an attack of gout. 
4. Dargie et al reported 11 participants with nephrotic syndrome and 6 with CKD (GFR 
was between 1-7 mL/min) treated with metolazone in doses of 5-200 mg for 7-180 
days 27.  Nephrotic participants weighed on average 71.2 kg and lost 5.2 kg weight. 
Those with CKD weighed on average 63.0 kg and lost 3.8 kg weight. Changes in BP 
were not reported. 
5. Paton et al reported a study in 10 participants with CKD and 10 participants with 
nephrotic syndrome 28. Among 10 participants with CKD, BP improved from 173/96 
mmHg at baseline to 158/88 mmHg with metolazone (mean dose 11.0 mg over 56.6 
weeks).  Among 10 participants with nephrotic syndrome, BP improved from 147/97 
mmHg to 137/88 mmHg with metolazone (mean dose 14.9 mg, 114.4 weeks). 
6. Wollam et al studied 8 participants with mean serum creatinine 3.31 mg/dL and 
performed an interventional before-and-after study 29.  Increasing the dose of 
furosemide to between 320 and 480 mg/day had only a modest additional diuretic 
effect; plasma volume and arterial pressure were not significantly changed. Adding 
HCTZ, 25 to 50 mg twice a day, produced a marked diuresis, and a significant 
reduction in weight, plasma volume and mean arterial pressure. Three of the 8 
participants were treated with combined HCTZ-furosemide therapy.  These 
participants had an inadequate response to either diuretic alone but had 34/13 
mmHg reduction in supine BP with the combination.  These data suggest that the 

10 | F i n a l  P r o t o c o l  
 
combination of a loop diuretic with a thiazide may reduce plasma volume and BP 
even in advanced CKD.  
7. Additionally, thiazides (HCTZ 50 mg daily or metolazone 5 mg daily or placebo in 4 
week periods in a cross-over study lasting 6 months) have been used among dialysis 
participants making <100 mL urine per day. There was no effect on pre and post-
dialysis BP, body weight, plasma volume, and plasma renin30. 
8. Cirillo et al compared effect of fixed dose CTD 25 mg QD among people with 
estimated GFR < 60 mL/min/1.73 m2 and poorly controlled hypertension to those 
with eGFR >60 (n=60) 31. At 8 weeks, office systolic BP and body weight were both 
significantly reduced from baseline by 19 mmHg and 0.88 kg respectively. 
Importantly, both the subgroups of 28 subjects with eGFR 30-44 and 9 subjects with 
eGFR 15-29 had similar reductions in systolic BP at 19 and 20 mmHg respectively. 
BP reductions were similar in those with eGFR >60. Laboratory abnormalities and 
adverse events occurred in 15% of patients; these included hypokalemia, 
hyponatremia, and hyperuricemia. 
9. The last study is ours and is discussed in preliminary data. 
Randomized controlled trials on the of use of thiazides in CKD 
Literature search revealed only 4 randomized controlled trials (RCTs) evaluating the 
response to thiazides among participants with CKD. All were small; the largest being of 23 
participants. 
1. Fliser et al reported the first single-blind, cross-over RCT in 10 participants with 
advanced CKD; natriuresis was the end-point 32. Inulin clearance averaged 13.1 
mL/min/1.73 m2.  After a low Na diet (150 mmol/d) a sham infusion of 50 ml 5% 
dextrose was given on Day 6 and Day 13. On the days following the sham infusion 
(days 7 and 14), participants received either torsemide 50 mg IV alone or torsemide 
50 mg in combination with butizid 20 mg IV (equal to ~30 mg of HCTZ) in a cross-
over fashion.  With torsemide alone, Na excretion rate increased from 154 mEq/d to 
232 mEq/d. With torsemide + thiazide, Na excretion rate increased significantly more 
from 156 mEq/d to 290 mEq/d.  
2. Knauf and Mutschler performed a single-blind RCT (n=19) of loop diuretic or a 
combination of loop diuretic plus a thiazide in participants with moderately severe 
renal failure (Ccr 39.5 mL/min) 33. After establishment of a steady state of urinary 
electrolyte excretion, a single oral dose of HCTZ (25 mg) induced an increase in the 
urinary excretion of Na, K, Cl, Ca, and Mg over the subsequent 12 h, which was 
significantly and inversely related to the GFR for each electrolyte. Doubling the dose 
of either HCTZ or furosemide produced statistically insignificant increases in Na 
excretion. In contrast, when the lower doses of each (25 mg HCTZ + 40 mg 
furosemide) were co-administered, there was a substantial and a statistically 
significant increase in Na excretion. Thus, a combination of low doses of diuretics 
acting at different functional sites of electrolyte reabsorption in the nephron may be 
superior in natriuretic potency to increasing the dose of either diuretic alone. 

11 | F i n a l  P r o t o c o l  
 
3. Dussol et al, reported the first double-blind, RCT of furosemide and HCTZ in 2005 
(n=7, Ccr <40 mL/min) 34. Long-acting furosemide (60 mg/d) or HCTZ (25 mg/d) was 
given in a cross over manner for 30 days with a washout of 1 month. Both diuretics 
were equally effective in reducing clinic oscillometric supine mean arterial BP. 
Somewhat surprisingly, HCTZ was more effective than furosemide in causing 
natriuresis. Perhaps, this was because once daily dosing of furosemide may not elicit 
persistent natriuresis and therefore may appear to be weaker than HCTZ.  The 
combination of the two drugs was more effective than either therapy given alone. 
4. Dussol et al, in 2012 reported the second double-blind, cross-over RCT of 
furosemide and HCTZ among 23 participants with stage 4 and 5 CKD 35. They found 
that both the natriuretic and the antihypertensive response to the standard dose of 
furosemide and HCTZ were similar. But the combination of furosemide and HCTZ 
had an additive effect on both natriuresis and BP.  
Taken together, the above studies, although small, demonstrate the potential for the use 
of thiazide-like diuretics in patients with CKD. A functioning kidney and a negative Na balance 
are both needed to produce an antihypertensive effect. There does not appear to be an 
independent effect of thiazides on vasculature and peripheral vascular resistance. None of the 
above studies, even when considered collectively, provide enough support to firmly recommend 
the routine use of these drugs in advanced CKD.   
Risks and benefits of thiazides in CKD 
There are several problems that may be associated with thiazide use in CKD. These 
include volume depletion, hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia, 
hyperglycemia, dyslipidemia, and idiosyncratic events (e.g., rash, pancreatitis etc.). Like with 
other BP lowering agents, transient creatinine elevation and orthostatic hypotension may be 
seen. Thus, the use of these agents requires close monitoring, especially when initially 
prescribed or when their dose is increased. These risks can be assessed only in larger and 
longer studies. 
Thiazides may augment the natriuretic effect of loop diuretics and in doing so may 
improve the control of BP. This may be especially true among individuals who may have been 
on diuretics for a long time and consequently developed a hypertrophied distal nephron. By 
increasing K excretion, thiazides may be valuable in the setting of hyperkalemia such as people 
with diabetic nephropathy and Type IV renal tubular acidosis. 
Preferred thiazide diuretic use in CKD 
There are important differences between thiazide diuretics in potency, duration of action, 
side effects, and costs. In a recent meta-analysis of trials comparing the antihypertensive effects 
of thiazides among patients with hypertension, Peterzan et al reported markedly different 
potencies of hydrochlorothiazide, chlorthalidone (CTD), and Bendroflumethiazide 36. Potency 
followed a log-linear relationship Bendroflumethiazide > CTD > HCTZ. The estimated dose of 
each drug predicted to reduce systolic BP by 10 mm Hg was 1.4, 8.6, and 26.4 mg, 
respectively. Thus, CTD has nearly three times the potency compared to the commonly used 

12 | F i n a l  P r o t o c o l  
 
HCTZ. However, at ceiling doses of different thiazides, the maximum reduction in systolic BP 
was similar. Given the higher potency, a longer duration of action, and a lower cost, CTD may 
be preferred to other thiazides. In studies that have compared ambulatory BP with HCTZ or 
CTD, the latter appears to provide a more consistent reduction in 24-hour BP i.e., both during 
the day and during the night. For example, in a cross-over study of 30 participants, of which 24 
completed 8 weeks of treatment with both agents, 50 mg HCTZ produced 7.4 mmHg reduction 
in 24-hour systolic BP, whereas 25 mg CTD produced 12.4 mmHg decline (p=0.054) 37. More 
significant were the differences in nighttime BP; 50 mg HCTZ produced a 6.4 mmHg reduction 
whereas 25 mg CTD produced 13.5 mmHg reduction (p=0.009). Reductions in clinic BP were 
similar between agents. Post-hoc analysis of the Multiple Risk Factor Intervention Trial suggests 
that compared to HCTZ, CTD may more effectively cause regression of left ventricular 
hypertrophy 38 and fewer cardiovascular events 39. However, CTD is also most likely to cause 
hypokalemia. For example, in the Multiple Risk Factor Intervention Trial when compared to 
HCTZ, CTD use was associated with lower serum potassium and a higher serum uric acid 39. 
Additionally, metolazone is also effective in CKD, but it costs nearly ten times that of 
generic thiazides. Also, the bioavailability of metolazone depends on the formulation. Thus, in 
comparison to others, it appears that CTD would be the preferred thiazide. 
A reduced intake of dietary Na, diuretic use, or both may protect the kidney 
In a cross-sectional study, the Reasons for Geographic and Racial Differences in Stroke 
(REGARDS) Study, the interactive relationship between dietary Na and body mass index on 
albuminuria was evaluated 40. In 30,239 adults aged ≥45 years and among obese participants, a 
higher dietary Na intake or a higher urinary Na/K ratio was associated with albuminuria. Among 
3,680 participants in the Chronic Renal Insufficiency Cohort study, the relationship between 24-
hour urinary sodium or potassium on 24-hour urine protein excretion was examined 41. Urinary 
sodium excretion was associated with increasing proteinuria even after and adjustment for 
demographic and clinical factors, including 24-hour urinary potassium. 
A high dietary salt intake may accelerate the progression of CKD independent of 
angiotensin II and systemic blood pressure. A high dietary salt intake activates the vascular 
endothelium and provokes the release of transforming growth factor-beta1 (TGF-β1) 42. 
Additionally, a high dietary salt intake provokes nitric oxide production, which attenuates TGF-
β1. In this model, the overproduction of TGF-β1 permits excess biological activity of this 
important fibrogenic growth factor with subsequent development or acceleration of vascular and 
kidney damage. In patients with diseases whose pathogenesis is related to excess production of 
TGF-β1, such as chronic allograft nephropathy and diabetic nephropathy, increased salt intake 
may hasten loss of function, particularly if nitric oxide production does not increase.  
The effects of modest salt restriction on BP and urine protein excretion in nondiabetic 
black hypertensive participants were examined in a randomized, double blind, and placebo-
controlled, cross-over study 43. After the run-in period, on their usual diet and on reduced salt, 
participants continued to restrict their salt intake and then received either “slow Na” tablets, 
designed to bring their salt intake back to normal, or placebo tablets for 4 weeks. In the 40 who 
completed the study, switching “slow Na” to placebo caused urinary Na excretion to fall from 
169 to 89 mmol/d. BP fell from 159/101 to 151/98 mm Hg (P<0.01). Protein excretion fell from 

13 | F i n a l  P r o t o c o l  
 
93 mg to 75 mg per 24 hours (P<0.008). Therefore, reducing salt intake from approximately 10 
to 5 g per day reduced both BP and urine protein excretion among black hypertensives. 
Furthermore, this reduction in urine protein was seen within a few weeks.  
Vogt et al performed a randomized, double-blind, placebo-controlled trial to determine 
the separate and combined effects of a low-Na diet and hydrochlorothiazide (HCTZ) on 
proteinuria and BP 44. In 34 proteinuric patients, without diabetes, mean baseline proteinuria 
was 3.8 g/d, and this was reduced by 22% with a low-Na diet alone. Losartan monotherapy 
reduced proteinuria by 30%, and the addition of a low-Na diet led to a total reduction by 55% 
and the addition of HCTZ to 56%. The combined addition of HCTZ and a low-Na diet reduced 
proteinuria by 70% from baseline (all P < 0.05). The reduction in urine protein was seen within a 
few weeks. Reductions in mean arterial pressure showed a similar pattern (all P < 0.05).  
Thus, the benefits of reducing dietary Na intake, diuretics, or both may extend to 
protecting the kidney, above and beyond reducing BP. 
Pilot Study 
To gauge the feasibility of this protocol we implemented a pilot, open-label study of CTD 64. To 
test the hypothesis that CTD effectively lowers BP in moderate to advanced CKD after 
confirming poorly controlled hypertension with 24-hour ambulatory BP monitoring in 14 men 
(age 67.5 y, diabetes mellitus in 12, median number of antihypertensive drugs 4), with stage 3B 
(n=4) or 4 CKD (n=10) (eGFR 26.8 ± 8.8 mL/min/1.73m2) we added CTD in a dose of 25 mg/d 
and doubled its dose every 4 weeks if BP remained elevated. Mixed modeled mean prescribed 
CTD dose at 4 weeks was 34 mg, at 8 weeks 55 mg, and at final visit 51 mg/d. Over 12 weeks 
of treatment 24-hour BP which was 143.1/75.1 mmHg at baseline was reduced by 10.5/3.1 
mmHg (p = 0.01/p=0.17, Figure 2). Home BP at baseline was 152.4/82.6 mmHg and fell at 4, 8, 
and 12 weeks by 10.2/4.8, 13.4/6.0, and 9.4/3.7 mmHg (all p<0.05, Figure 3). Clinic BP was 
137.7/65.4 mmHg and was significantly reduced only at 8 weeks. Maximal reduction in body 
weight and total body volume was seen at 8 weeks concurrent with the maximal elevation in 
serum creatinine concentration and plasma renin activity (Figure 4). Albuminuria was 
significantly reduced by 40-45% from baseline. Adverse events following CTD therapy occurred 
in 7 participants: hypokalemia (n=4), hyperuricemia (4), hyponatremia (3), transient creatinine 
changes (3), dizziness (2), hyperglycemia (1), and constipation (1). One subject had ischemic 
stroke during the study. In conclusion, in advanced CKD, CTD has the potential to control 
hypertension; an RCT is now needed.  
 

14 | F i n a l  P r o t o c o l  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n
Durtn
Hrs
SBP
CFB
CFB(p)
14
1370 ± 35
23 ± 1
143.1 ± 2.9
12
1279 ± 38
22 ± 1
132.6 ± 3.1
-10.5 ± 4.2
0.01
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
143.1
132.6
125
135
145
155
165
120
130
140
150
160
170
Systolic 24h ambulatory BP (mmHg)
wk 4
wk 12
Week of  study
14
1370 ± 35
23 ± 1
75.1 ± 2.4
12
1279 ± 38
22 ± 1
72 ± 2.6
-3.1 ± 2.3
0.17
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
75.1
72.0
55
65
75
85
95
105
50
60
70
80
90
100
110
Diastolic 24h ambulatory BP (mmHg)
wk 4
wk 12
Week of  study
n
Durtn
Hrs
DBP
CFB
CFB(p)
Figure 2
n
CFB (±SE)
CFB (p)
CAD (±SE)
CAD (p)
14
0
0
14
-10.0± 2.8
<0.001
0
11
-20.2± 3.1
<0.0001
-10.2± 3.1
<0.001
10
-23.3± 3.2
<0.0001
-13.4± 3.2
<0.0001
11
-19.3± 3.1
<0.0001
-9.4 ± 3.1
<0.01
162.4
152.4
142.2
139.0
143.0
135
145
155
165
140
150
160
170
Systolic home BP (mmHg)
-2
0
4
8
12
Week of study
Baseline
CTD start
Figure 3
CFB = Change from baseline (week - 2)
CAD = Change after drug (week 0)
CTD = Chlorthalidone
SE = Standard error of mean
n = number of subjects with BP

15 | F i n a l  P r o t o c o l  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH PROTOCOL 
AND TRIAL 
DESIGN 
 CLICK will provide evidence for the specific role of thiazide diuretics in the management 
of hypertension in those with advanced CKD. BP control is the backbone of renal and 
cardiovascular protection, yet control rates are dismal. Furthermore, the use of CTD has 
increased after publication of ALLHAT. This study will examine the benefits of CTD in a 
vulnerable group of patients including albuminuria and providing surrogate evidence for target-
organ protection. The wider use of this specific thiazide diuretic may also improve CV outcomes 
in CKD. The results will help support the use of a low-cost, but potentially effective, 
antihypertensive drug in this high-risk group.  
n
Mean (± SE)
CFB (± SE)
CFB (p)
14
91.5 ± 3.5
0
12
91.0 ± 3.5
-0.5 ± 0.8
0.57
12
89.8 ± 3.5
-1.7 ± 0.8
0.05
12
90.3 ± 3.5
-1.2 ± 0.9
0.18
91.5
91.0
89.8
90.3
87
89
91
93
85
90
95
Weight (kg)
-2
0
4
8
12
Week of  study
n
Mean (± SE)
CFB (± SE)
CFB (p)
14
89.6 ± 3.5
0
12
88.8 ± 3.5
-0.8 ± 0.7
0.24
12
87.8 ± 3.5
-1.9 ± 0.7
<0.01
12
88.1 ± 3.5
-1.5 ± 0.7
0.03
89.6
88.8
87.8
88.1
87
89
91
93
85
90
95
volume (L)
-2
0
4
8
12
Week of  study
n
Mean (CI)
CFB fold change  (CI)
CFB (p)
14
0.8 (0.4,1.7 )
12
2.1 (1.0,4.6 )
2.7 (1.9,3.9 )
<0.0001
10
2.7 (1.3,6.0 )
3.5 (2.4,5.2 )
<0.0001
12
1.9 (0.9,4.0 )
2.4 (1.7,3.5 )
<0.0001
0.8
2.1
2.7
1.9
0.5
1.5
2.5
3.5
4.5
5.5
0
1
2
3
4
5
6
Plasma renin activity (ng/mL/h)
-2
0
4
8
12
Week of  study
n
Mean (CI)
CFB fold change  (CI)
CFB (p)
14
3.7 (2.1,6.7 )
12
6.9 (3.8,12.6 )
1.8 (1.2,2.9 )
<0.01
10
6.3 (3.4,11.7 )
1.7 (1.0,2.7 )
0.03
12
4.5 (2.4,8.1 )
1.2 (0.8,1.9 )
0.44
3.7
6.9
6.3
4.5
3.0
5.0
7.0
9.0
11.0
2
4
6
8
10
12
Plasma aldosterone (ng/dL)
-2
0
4
8
12
Week of  study
n
Mean (CI)
CFB fold change  (CI)
CFB (p)
14
73 (42,125 )
12
35 (20,62 )
0.5 (0.3,0.8 )
<0.01
12
51 (29,91 )
0.7 (0.4,1.1 )
0.14
12
61 (35,108 )
0.8 (0.5,1.3 )
0.48
72.5
35.1
51.4
61.4
30
50
70
90
110
20
40
60
80
100
120
Plasma BNP (pg/dL)
-2
0
4
8
12
Week of  study
n
Mean (± SE)
CFB (± SE)
CFB (p)
14
2.87 ± 0.24
12
3.04 ± 0.25
0.17 ± 0.14
0.21
12
3.12 ± 0.25
0.24 ± 0.14
0.07
12
2.92 ± 0.25
0.04 ± 0.14
0.74
2.87
3.04
3.12
2.92
2.80
3.20
2.6
3.0
3.4
Plasma creatinine (mg/dL)
-2
0
4
8
12
Week of  study
Figure 4

16 | F i n a l  P r o t o c o l  
 
Overall Trial Design and Plan 
To test the notion that CTD added to the regimen of antihypertensive drugs will improve BP in 
those with advanced CKD and uncontrolled hypertension, we propose a placebo-controlled, 
double-blind, randomized controlled trial (Figure 5). This trial will assess the effects of CTD in 
patients with CKD and poorly controlled hypertension. According to the European Society of 
Hypertension (ESH 2013) guidelines, poorly controlled hypertension is defined as the average 
24-hour ambulatory blood pressure of ≥ 130 mmHg systolic or ≥ 80 mmHg diastolic45. During 
the study, doubling the dose of the diuretic or placebo will occur every 4 weeks if home BP 
remains above ≥135/85 mmHg. This level of BP was chosen because it roughly approximates to 
the clinic BP of ≥140/90 mmHg, which is the current target for treatment for people with CKD. 
The effects will be assessed by change in ambulatory BP measured over 24 hours from 
baseline to 12 weeks.  
At baseline and every 4 weeks thereafter, we will also evaluate changes in albuminuria 
and markers of volume (renin, aldosterone, NT-proBNP, and body volume). Home BP will be 
measured prior to each clinic visit for one week, twice daily.  The final visit will be two weeks 
after stopping the study drug to have a proper wash out period. At the post-termination visit, if 
the increase in home BP from drug discontinuation is ≥7/4 mmHg open label CTD of at least 
12.5 mg/d will be administered. Further follow up will be provided by the participant’s physician. 
Placebo run-in
2 weeks
+ Placebo
+ CTD 12.5mg
4w x 3 = 12 weeks
Increase dose q4w if home BP
≥135 systolic or ≥85 diastolic
Lisinopril/Losartan
OR
Atenolol
± Other drugs
No Thiazides
Home BP measured twice daily x 1 week prior to each clinic visit
Baseline
1 week
160 patients with CKD
(eGFR 15-30 mL/min/1.73m2)
Treated, uncontrolled HTN 
(confirmed by 24h -ABPM).
2x Placebo
+ 4x Placebo
R
+ CTD 25mg
+ CTD 50mg
Measurements
Time
Week 0
Week 4
Week 8 
Week 12
Week 14
24h ambulatory BP + 24 h urine
x
x
Home BP (BID x 1w), Clinic BP
x
x
x
x
x
Markers of target organ damage
x
x
x
x
x
Markers of volume
x
x
x
x
x
2 weeks
washout
Figure 5: Trial design and study procedures
4 weeks
4 weeks
4 weeks
R
stratified by prior loop diuretic use

17 | F i n a l  P r o t o c o l
At week 14, we will measure albuminuria and volume markers to provide a stronger mechanistic 
basis for the effect of CTD on these outcomes.  
Study Intervention 
Participants with CKD and poorly controlled hypertension, confirmed by ambulatory BP 
monitoring after the two-week run-in, who meet the inclusion and exclusion criteria will be 
administered the study drugs in increasing doses. There are 9 study related visits at week -3, -2, 
0, 4, 8, 12, and 14. Visits occurring before randomization (week 0) will have a ± 2-day visit 
window. Any visit occurring after randomization will have a ± 3-day window. At both weeks 0 
and 12, visits on two consecutive days are to perform 24h ambulatory BP monitoring and 24-
hour urine collection. Participants will be identified in the renal clinic on the basis of estimated 
GFR and BP. If they are on any antihypertensive medications excluding a thiazide-like diuretic 
in the prior 12 weeks (HCTZ, CTD, or metolazone), they will be sent home with a BP monitor. If 
the average systolic clinic blood pressure is <110 mmHg, they will not be further considered for 
participation. This is based on our prior study that suggests the prevalence of uncontrolled 
hypertension is less than 2% in persons with a clinic systolic blood pressure of 90-110mmHg 46. 
At the beginning of the run-in, all participants will receive a standard regimen of 
antihypertensive medications from various classes of drugs, e.g., ACE inhibitors (lisinopril 20-40 
mg/d), angiotensin receptor blocker (losartan 50-100 mg/d if intolerant to ACE inhibitors), 
dihydropyridine calcium channel blockers (amlodipine 10 mg/d), beta blockers (atenolol 25-100 
mg/d) and/or a loop diuretic (torsemide 10-20 mg/d). The nature of the antihypertensive used 
will depend on their existing regimen. Thus, if they are on a beta-blocker and a diuretic, they will 
receive atenolol and torsemide. Doses will be selected based on what the patient is currently 
prescribed. For those on furosemide, 20 mg of furosemide will be considered equivalent to 10 
mg torsemide. Atenolol is renally cleared and has a long half-life in those with CKD. For those 
on metoprolol, 100 mg atenolol will be considered equivalent to 200 mg metoprolol.  For those 
on clonidine or minoxidil as fifth and sixth drugs, the doses of these drugs will be left 
unchanged. Some participants receive alpha-blockers for prostatic symptoms. The dose of 
alpha-blockers will not be changed to avoid precipitating acute urinary retention. Those on K-
sparing diuretics (e.g., amiloride, spironolactone, or eplerenone) will continue taking the same 
dose with the drug remaining unchanged. The final dose of the standardized medication 
regimen will be determined by the study physician. All participants will be provided written 
instructions to consume a diet containing <100 mEq Na/day. 24-hour urine Na will be measured 
to assess dietary sodium intake. 
Treatment Compliance 
We recognize the limitations of pill count, however, we will assess treatment compliance 
with the study drug by performing pill count at each of the study visits.   
Protocol for managing blood pressure 
This is a forced-titration study, thus the study drug will be increased if goal BP is not 
achieved. Goal BP is defined by home BP monitoring. We will ask participants to provide BP 

18 | F i n a l  P r o t o c o l  
 
readings in triplicate twice a day for one week. The average of these will be used for decision 
making when it comes to medication management. However, if fewer than 3 days of readings 
are available, we will make a decision based on clinic BP. 
The dose of study medication will not be increased if the patient has the following 
symptoms: home BP of <135 mmHg systolic, symptomatic hypotension, hypercalcemia, 
hypomagnesemia, moderate hypokalemia (K<3 meq/L), acute gout, or a recent hospitalization 
for poorly controlled diabetes. In these instances, the dose of the drug will be maintained or 
down-titrated based on investigator’s judgment. 
Stop points 
1. The study medication will be stopped, or the dose reduced, at the discretion of the PI 
if the patient experiences significant acute kidney injury, drug-induced rash, or other 
adverse event attributable to the drug, or in the PI’s judgment the benefits of taking 
the medication outweigh the risks. 
2. If home BP averaged over one week exceeds either 179 mmHg systolic or 109 
mmHg diastolic, the dose of the study drug will be increased, and participant will be 
called in 1 week with home BP recordings. If home BP recording remain ≥180/110 
mmHg, the participant will be withdrawn from the study.  
3. If home BP averaged over one week is 160-179 mmHg systolic or 100-109 mmHg 
diastolic, the dose of the study drug increased, and participant will be called in two 
weeks. If BP is not <160/100 mmHg within 4 weeks, the participant will be withdrawn 
from the trial.   
Outcome Variables 
The outcome variables are as follows.  
Primary outcome:  
The primary outcome variable is the change from baseline to 12 weeks in systolic ambulatory 
BP in the CTD group compared to placebo. 
Secondary outcomes: 
1. Change from baseline at each 4 week visit in the log transformed albumin/creatinine 
ratio in the CTD group compared to placebo.  
2. Change from baseline at each 4 week visit in  
a. log of aldosterone to renin ratio 
b. log of NT-proBNP,  
c. and body volume  
in the CTD group compared to placebo. No adjustments will be made for multiple 
comparisons. 

19 | F i n a l  P r o t o c o l  
 
Safety Assessments and Variables 
Harms will be assessed by monitoring changes in eGFR, potassium, calcium, uric acid 
and hemoglobin A1C. For more definitive assessments, the frequency of acute kidney injury 
(using AKIN definition), symptomatic orthostatic hypotension (fall >20 mmHg within 3 min of 
standing with symptoms), hypokalemia (mild <3.5 mEq/L, moderate to severe <3.0 mEq/L), 
need for K replacement, hypercalcemia (>10.5 mg/dL), hypomagnesemia (<1.8 mg/dL), gout 
(clinical diagnosis), and hospitalization for hyperglycemia will be examined in the two groups. A 
screening 12 lead EKG will be completed for all qualifying patients prior to randomization. A 
pregnancy test will be required for women of childbearing potential. A survey of symptoms 
commonly linked to antihypertensive drug use in general, thiazides in particular, will be 
administered at the time of enrollment and every 4 weeks thereafter. Safety of continued 
participation will be assessed at each study visit. The stop-points will be treatment-emergent 
severe adverse events that precludes further exposure to the drug, such as an allergic drug 
reaction, initiation of renal replacement therapy, or death. If the study drug is stopped, the 
subject will be continued to be studied so as to not violate the intention-to-treat principle. 
Subjects
Inclusion and exclusion criteria 
Inclusion Criteria 
1. Age greater than 18 years. 
2. Calculated GFR by 4-component MDRD formula < 30 ml/min/1.73m2 but ≥15 
mL/min/1.73m2. Our hospital laboratory uses IDMS-calibrated creatinine, and the 
appropriate formula is used to estimate GFR. 
3. Hypertension, which is defined as BP of either ≥130 systolic or ≥80 mmHg by 24-
hour ambulatory BP monitoring. 
4. Treatment with antihypertensive drugs, which requires the use of at least one 
antihypertensive drug. One of the drugs should be either an ACE inhibitor or 
angiotensin receptor blocker. If these are contraindicated, then use of a beta-blocker 
is required prior to randomization. 
Exclusion Criteria 
1. Use of thiazide or thiazide-like drugs in the previous 12 weeks. 
2. Use of furosemide in a dose >200 mg/d. 
3. BP of either ≥160 systolic or ≥100 mmHg by 24-hour ambulatory BP monitoring. 
4. Expected to receive renal replacement therapy within the next 3 months. 
5. Myocardial infarction, heart failure hospitalization, or stroke ≤3 months prior to 
randomization. 
6. Pregnant or breastfeeding women or women who are planning to become pregnant 
or those not using a reliable form of contraception (oral contraceptives, condoms and 
diaphragms will be considered reliable).  
7. Known hypersensitivity to thiazide or sulfa drugs. 
8. Organ transplant recipient or therapy with immunosuppressive agents. 
 

20 | F i n a l  P r o t o c o l
Retention of Subjects 
Nine study related visits are required. We will offer them $150 for participation in the trial. 
This amount will be prorated based on the number of visits performed.  
Optional Annual Follow Up 
Participants who complete all post-randomization visits will be invited to participate in an 
observational cohort sub-study with follow up visits once a year for 3 years. Those who respond 
in the affirmative will be contacted once every 12 months to consent to the follow up visits. The 
follow up sub-study consists of two consecutive visits. At Visit 1, clinic blood pressure and 
anthropometric measurements will be taken, blood and urine specimens will be obtained for 
analysis, concomitant medications and changes in health status will be reviewed, and 
participants will undergo body composition measurement using air displacement 
plethysmography. Participants will then begin 24-hour ambulatory blood pressure monitoring 
and complete an overnight urine collection, returning the following day for Visit 2. At Visit 2, 
clinic blood pressure measurements will again be obtained and the results of the 24-hour 
ambulatory blood pressure monitoring study will be reviewed. These data will provide valuable 
insight into longitudinal outcomes for the randomized cohort. If the participants are unable to 
come for the visits, we will ask for their verbal consent to obtain access to their medical records 
and conduct a health questionnaire over the phone.  
Methods 
Method of Randomization 
Participants will be randomized in a 1:1 ratio to either CTD or placebo with stratification 
for prior loop diuretic use. A random permuted block design will be used to avoid imbalance in 
assignment to the study drugs over time. Random sequence will be generated by the statistician 
and the randomization sequence will be concealed individually in opaque envelopes. The study 
pharmacist, who will not interact with participants and maintain the blind, will dispense 
medication according to the randomization sequence for the appropriate stratum after 
confirming eligibility with the principal investigator.   
Measurement of clinic BP 
At Visit 1, clinic BP measurements will be obtained by a trained observer after 5-minute 
rest in triplicate in both arms after applying an appropriately sized cuff using a digital 
oscillometric sphygmomanometer (Model HEM-907, Omron Healthcare) following the 
recommendation of the European Society of Hypertension 47. The arm and the forearm will be 
supported at the level of the heart (mid-sternal level) and the oscillometric BP averaged over 
three readings will be used as that clinic visit BP. The left arm will be used for all 
measurements, unless between arm reading exceed 5 mmHg systolic. If so, the arm with the 
higher BP will be designated the “BP arm” and will be used for all subsequent clinic BP 
measurements. If subjects have a dialysis access (AV fistula or AV graft), we will use the non-
access arm for clinic blood pressure measurements. 

21 | F i n a l  P r o t o c o l  
 
Measurement of 24-hour Ambulatory BP 
Ambulatory BP monitoring will be performed in all participants at baseline prior to 
randomization and at the end of the 12 weeks of treatment. We will use the Spacelabs 90207 
monitor which has been shown to be accurate by both the British Hypertension Society (BHS) 
and the Association for the Advancement of Medical Instruments (AAMI) 47. Appropriately sized 
cuffs will be used with bladder sizes that encircle 80–100% of arm circumference and widths 
that are at least 40% of arm circumference. We will measure ABP every 20 minutes from 06:00 
– 22:00 and every 30 minutes from 22:00 – 06:00 based upon a prior protocol 48. Participants 
will be asked to record their wake and sleep times into a diary which will be used to calculate 
diurnal ambulatory BP. At least 16 total recordings will be required to call 24h ambulatory BP 
adequate (excluding readings taken for monitor validation during ambulatory dispensing). All 
ambulatory BP measurements taken on subject’s non-dominant arm. If subject has dialysis 
access, all measurements completed on non-access arm. 
Measurement of home BP 
Home BP measurements will be performed with a home digital sphygmomanometer with 
an automatic inflator and printer for recording (Model HEM790IT or the newer model BP791IT, 
Omron Healthcare, Inc, Vernon Hills, IL) with a cuff size appropriate for arm size. This monitor 
stores up to 200 measurements in memory that can be retrieved. A similar device (Omron 
HEM705CP) was used to monitor BP in the large Anglo-Scandinavian Cardiovascular 
Outcomes Trial (ASCOT) for the purposes of BP monitoring 49. At minimum at least three days 
of home BP monitoring is required for valid home BP recordings 50, 51. Thus, participants will be 
asked to record their BP after 5 minutes of seated rest in triplicate twice daily for one week prior 
to clinic visit. All participants will be instructed on how to use the monitor prior to participation in 
the study. All home BP measurements will be taken on subject’s non-dominant arm. If subject 
has dialysis access, all measurements completed on non-access arm. 
Chemical Determinations 
Chemical determinations on research samples will be conducted on those frozen at -80C 
for analysis of NT-proBNP, plasma renin, plasma aldosterone, and urinary albumin and 
creatinine. Routine safety laboratory tests will be done in the hospital laboratory. 
Air displacement plethysmography 
Air displacement plethysmography (ADP) will be measured using the BOD POD Gold 
Standard Body Composition Tracking System (Life Measurement, Inc, Concord, CA).  The ADP 
system consisted of the air plethysmograph, a digital scale, and computer software (BOD POD 
version 4.2+). Each participant will be asked to change into compression shorts (for men) or a 
swimsuit (for women) and a swim cap and to remove any jewelry. Body mass will be measured 
to the nearest 0.001 kg using the electronic scale prior to the body volume measurement.  
Height will be measured using a Seca 222 measuring rod (Seca Group, Hamburg, Germany).  
Manufacture recommended procedures will be used to measure body volume. Body fat percent 

22 | F i n a l  P r o t o c o l  
 
will be calculated using gender and race-specific equations as follows: for non-blacks we will 
use the Siri equation 52, for black men the Schutte equation 53, and for black women the Ortiz 
equation 54. Pilot data (see below) suggest that this method is very sensitive in detecting 
changes in body volume in the time of the study. 
 
STATISTICAL METHODS 
Sample Size 
The primary objective of the study is to assess CTD-induced lowering of systolic BP.  
Sample size estimation was based on our pilot data using change from baseline to 12 weeks in 
average 24-hour ambulatory systolic BP. There was 1 patient who stopped taking his 
medication and suffered a stroke. In contrast to all others, this patient showed an increase in 
SBP of 31 mm Hg. We believe this outlier markedly increases the variability and reduces the 
estimated change in BP. Table 1 below shows the mean changes (standard deviation) and 
estimated sample size based on ambulatory SBP achieved by CTD, with and without this 
person and estimated sample size: 
 
Table 1: Estimates of change in 24-hour ambulatory systolic BP, variability, and sample size 
 
SBP including outlier 
SBP excluding outlier 
Change in average 24-h SBP 
-8.5 
-12 
STD DEV of Change 
16.0 
10.7 
Sample Size to detect this change 
57 
13 
 
We recognize that ignoring the outlier assumes this won’t occur and we do not believe 
that to be a safe assumption. However, the outlier has undue influence in the pilot sample 
especially with respect to the estimation of variability in ambulatory BP monitoring. While we 
don’t expect the impact of such cases in the larger Phase II study planned, we do accept that 
the -12 mm Hg reduction maybe optimistic for two reasons. One is regression toward the mean 
or other placebo effects (the pilot is a single group) and the second is that there will be a few 
outliers that may impact the mean difference.  From an ongoing study of patients with CKD (with 
clinical characteristics similar to one proposed in this trial) who had ABPM performed 4 weeks 
apart, in 63 pairs of recordings with average 24-hour ambulatory BP of 141 mmHg, the SD of 
difference was 10.5 mmHg. We expect the SD at 12 weeks to be larger by about 10% or 12 
mmHg.  With these assumptions, two tailed test and 80% power, the required sample size to 
detect a between group difference of 6 mmHg is 63 subjects completing the study in each 
group.  Assuming 80% of those randomized complete the trial we would need to randomize 
63/0.80 = 79 subjects per group.    
For Aims 2 and 3 we will use similar techniques and evaluated the confidence intervals 
of the changes. For the change in albumin/creatinine ratio from the 24 hours urine collections, 
the observed decline was consistent and between 40-45% regardless of whether daytime or 
nighttime collection of urine was evaluated. Power exceeded 99% for both daytime excretion as 
well as nighttime based on our pilot results with 63 subjects per group based on the observed 

23 | F i n a l  P r o t o c o l  
 
changes on the natural log scale of 0.48 (0.613) nighttime and 0.57 (0.694) daytime from 
baseline to 8 weeks. With 63 completed subjects in each group, we can detect at least 27% 
decline in UACR, which is clinically meaningful and an effect size that is more likely to be seen 
in the larger phase 2 trial. We also note that we will have repeated measures over time and 
using longitudinal data methods will greatly increase our power. 
From the pilot, the mean change between baseline and final visit in Body Volume using 
Air Displacement Plethysmography was 1.234 (sd 2.88) with a similarly small within person 
standard deviation. Repeated measures analyses using Proc Mixed in SAS showed and 
estimated change of 1.54 with a standard error of 0.7375, slightly larger due to the fitting of the 
model to all data points. A repeated measures design with two treatment arms and 4 
assessments over time with 60 subjects per group achieves the following power (computed 
using simulations with PASS) for various differences in the groups:  
 
Table 2: Power to detect minimum detectable difference in body volume with air displacement 
plethysmography  
Minimum 
detectable difference 
0.9 
1.0 
1.1 
1.2 
1.3 
Power 
0.64 
0.73 
0.82 
0.88 
0.92 
 
Each subject is measured 4 times. This design achieves 82% power to test the 
treatment difference in volume is at least 1.54 with a 5% significance level assuming the 
variance of the volume assessments is 6 and the correlation amongst the volume 
measurements is 0.75. If the true mean difference were only 1.234 instead of the model 
estimated 1.54, the power would still exceed 60%. 
Analyses 
The analyses will begin with descriptive statistics. Overall and by group descriptive 
statistics will be calculated and examined graphically. Tests for differences in demographics 
between the randomized group; characteristics of dropouts will be computed using t-tests, chi-
square (or fisher’s exact tests) to understand if potential differences exist, although such 
differences are not expected.   
Primary Analysis 
To test the hypothesis that CTD will improve the 24-hour SBP assessed by change from 
baseline to 12 weeks. A mixed model will be used to analyze the results. The outcome variable 
will be the 24h ambulatory systolic BP. The predictors will be indicator variables for group 
(placebo or CTD), time (baseline and 12 weeks), stratum (loop diuretics use or not) and all their 
interactions. The random component of the mixed model will include subject and time. 
Unstructured covariance will be used with estimation of marginal means by maximum likelihood. 
We expect the interaction between group x time to be significant. If the 3-way interaction term is 
significant, then results will be reported by each stratum. Confirmatory analyses will utilize the 
home systolic BP change from baseline. The random coefficient analysis does not require 
baseline systolic BP as a covariate.   

24 | F i n a l  P r o t o c o l  
 
Ambulatory BP recording, the gold-standard to assess BP, is carried out only twice 
during the trial, but home BP measurements occur every 4 weeks. Patients who drop out but 
have some post baseline measures of home BP (which will occur every 4 weeks) will be used in 
the analyses, thus minimizing the losses to follow up. We will impute ambulatory BP as follows: 
we will use the complete data to build a model that relates the follow up mean 24hour 
ambulatory systolic BP from the baseline 24-hour ambulatory systolic BP and the home 
measures using repeated measures Mixed Model regression - then use the expected value from 
the model for the missing value - and use PROC MI (which generates maybe 5 replicate values 
to insert variability into the imputation so that there is a price to pay for imputing. 
Comparison of the cohort with these measurements will also be done to understand if 
the inferences based on the ambulatory BPs accurately reflect the differences between the 
treatment groups using the home BPs. Repeated measures mixed models (PROC MIXED in 
SAS) will be utilized to assess the overall differences between the treatment group using the 
home blood pressures. Additional analyses will explore the nocturnal patterns between the 
groups in the ambulatory blood pressures as well as the pattern over time given the once a day 
dosing proposed in this study using circadian models of blood pressure in each group 
The null hypothesis we intend to reject is that there is no between group change from 
baseline in albumin excretion rate. Measurements of these markers will occur at weeks 0, 4, 8, 
and 12. The outcome variable will be the log transformed urine albumin/urine creatinine ratio 
(UACR). The predictors will be an indicator variable for group (placebo or CTD), a continuous 
variable of time (baseline, 4, 8 and 12 weeks), stratum and all interaction terms. The random 
component of the mixed model will include subject and time. Unstructured covariance will be 
used with estimation of marginal means by maximum likelihood.   
The null hypothesis we intend to reject is that there is no between group change from 
baseline in markers of extracellular fluid volume as measured by (i) N-terminal pro B-type 
natriuretic peptide (NT-proBNP), (ii) plasma aldosterone to renin ratio (ARR) and (iii) body 
volume. Measurements of these markers will occur at weeks 0, 4, 8, and 12. Thus, three 
different models will be fitted.  In the first model, the outcome variable will be the log 
transformed NT-proBNP. The predictors, fixed variables, and random variables will be as noted 
above.  Similar analyses will be performed for ARR and body volume. To test the hypothesis 
that CTD is causal in this improvement in BP via a reduction in extracellular fluid volume, we will 
evaluate changes from baseline in the following extracellular fluid volume markers: NT-proBNP, 
seated plasma renin, and plasma aldosterone. That is, we will test if the improvement is a 
mediation effect using the technique described by Judd and Kenny55 and elaborated by 
MacKinnon56. The technique, expanded here for more than one potential mediator 
(simultaneously NT-proBNP, seated plasma renin, and plasma aldosterone = mediators), 
employs three regression equations: 
 
Y = β0 + τXp +  ε 
Xi =  β0 + αiXp + ε 
Y = β0 + τ'Xp + β1X1 + … + βiXi + …+ βkXk + ε  for all mediators together 
or  Y = β0 + τ'Xp + βiXi  ε for each mediator separately 
 

25 | F i n a l  P r o t o c o l  
 
Y is the outcome result (e.g., change in 24-hour ambulatory systolic BP), Xp is the 
treatment and Xi represent the k purported mediators. the total effect of the treatment on the 
outcome (measured by the coefficient, τ ) is the sum of direct effect (τ′) of the treatment and the 
mediated, or indirect, effects (αiβi). Mediation is established when four conclusions are met:  (1) 
the treatment predicts the outcome variable (supported by a test of statistical significance of τ in 
equation [A]); (2) the treatment causes the potential mediator (αi is significant in [B]); (3) the 
mediator causes the outcome variable controlling for the treatment (βi is significant in [C] and τ' 
< τ which provides evidence for mediation rather than suppression); and (4) the mediated effect 
is statistically significant. For mediators that satisfy conclusions 1 through 3, the significance of 
the mediation (conclusion 4) will be determined via interval estimation of the mediated effect 
using the asymptotic variance derivation of Sobel57, since the outcomes are the continuous 
measures. Additional analyses that look at thresholds of change (binary, successful reduction in 
SBP or not) wilI utilize the bootstrap methods4 for binary outcomes successful reduction in SBP 
or not when logistic regression is utilized. The proportion of the effect mediated is calculated as 
the ratio of the indirect effect to the total effect, or αβ/τ.  
Pre-specified sub-group analysis for BP response 
• 
Effect of age: The effect of age 65 or more and <65 will be tested using 
interaction effects. 
• 
Effect of sex, presence/absence of albuminuria (>300 mg/g cr at baseline) will be 
assessed as above. 
• 
Effect of volume overload: Volume overloaded subjects are more likely to show 
improvement with CTD therapy. In people with volume overload, renin and 
aldosterone levels are expected to be low, N-terminal pro B-type natriuretic 
peptide levels elevated and 24-hour urine Na high. We will dichotomize the 
baseline levels of these markers and examine the outcome on ambulatory BP 
using interaction effects. 
Safety analysis 
The number of subjects who experience hypokalemia, hypercalcemia, gout, 
hospitalization for diabetes mellitus, transient elevations in serum creatinine concentration, and 
symptomatic orthostatic hypotension will be counted for each group and compared using a 
Poisson regression model using terms for treatment and treatment x stratum. The statistical 
significance of the treatment term will be used to indicate differences between CTD and 
placebo. If the interaction term is significant then the event rates will be reported for each 
stratum. The mean change from baseline in serum potassium, calcium, estimated GFR, uric 
acid, HgbA1C, PTH intact, and orthostatic BP will be calculated using mixed models as noted 
above. 
Secondary analysis 
1. The mean change from baseline in 24-hour diastolic BP. 

26 | F i n a l  P r o t o c o l  
 
2. The proportion of subjects who achieve at least a 10-mmHg reduction in ambulatory 
systolic BP or a 5-mmHg reduction in diastolic BP will be called responders. 
Responders will be compared by group.   
3. The proportions of responder subjects who achieve final ambulatory BP of 
<130/80mmHg by group. 
4. Some data support lowering of nocturnal BP with the use of diuretics. We will 
analyze the dipping state by treatment. Dipping will be defined as at least 10% drop 
in systolic BP with sleep. Between group differences in the above analyses will be 
compared using interaction tests in a logistic regression model. 
5. The time-course of systolic home BP will be analyzed using week as a continuous 
variable. It is expected that the drop in BP in the initial 4 weeks will be steep in the 
CTD group and then will taper off. In contrast, the placebo group is expected to have 
a flat response or a linear decline. Accordingly, we will use a term for week and 
square of the week in the CTD group only. Between group differences will be tested 
using marginal means. 
 
Alternative study design considerations and clarifications 
Choice of CTD:  CTD was selected over HCTZ since it has a longer half-life (40-60 hrs 
versus 2.5 hrs in those with normal renal function) and potentially greater BP lowering effects.  
According to KDOQI, compared to hydrochlorothiazide, CTD may be effective at a lower GFR 
(KDOQI provides no reference). Although metolazone has been used in high doses in people 
with CKD, but it is nearly 10 times as expensive as CTD. CTD is generic and inexpensive and 
therefore we have selected it over others 
Choice of torsemide as loop diuretic: Compared to furosemide, torsemide has more 
predictable bioavailability. Whereas the bioavailability of furosemide can vary from 10-100% 58, 
the bioavailability of torsemide is between 78-92% 59. Among those with renal failure, the 
bioavailability of torsemide is 100% 60. Thus, with torsemide use, more predictable absorption 
and less inter-individual variation in diuretic responses are expected 61. Although bumetanide 
has more predictable bioavailability than furosemide, it is less natriuretic than furosemide 62.  
Furthermore, torsemide has a longer half-life and its use as once daily diuretic is likely to 
enhance adherence. In a RCT that we performed among participants with CKD, the anti-
hypertensive effect of torsemide given once a day was similar to furosemide given twice daily 63.  
Accordingly, we have chosen torsemide as the agent of choice for a loop diuretic.  
Choice of fixed-dose versus forced-titration study: Since we do not know the dose at 
which chlorthalidone will produce a decline in BP, we have designed this as a forced-titration 
study.  It is quite likely, that the BP lowering effects will vary according to the GFR. Therefore, 
titration of dose may be required. Thus, the dose at which CTD improves BP will be 
individualized in this protocol. 
 

27 | F i n a l  P r o t o c o l  
 
TIMETABLE/MILESTONES 
 We expect to recruit and randomize a total of 160 participants in the first 4.5 years and 
complete the study in 5 years. 
DATA SAFETY MONITORING BOARD (DSMB) 
A DSMB will meet periodically to review the progress of the trial. Should signal of harms 
emerge, the trial can be terminated early. This will be in addition to periodic and mandatory 
reporting requirement to the IRB. No interim efficacy analysis is planned. 
 
HUMAN SUBJECTS 
Protection of Human Subjects 
The trial has been designed to reflect current clinical practices. The titration scheme of 
the drugs reflects current clinical practice. After completion of the 12 weeks of active drug or 
placebo, the medication will be stopped. To protect against excessive rise in blood pressure, 
subjects will be called 2 weeks after stopping medication such that open label chlorthalidone 
can be prescribed should the home BP rise 7/4 mmHg or more.  
Risks 
1. Risks associated with taking chlorthalidone include drop in blood concentrations of 
various electrolytes such as potassium, sodium, and chloride. This drug can 
aggravate diabetes, gout, and increase blood calcium. Other side effects include 
excessive drop in blood pressure especially when standing and impotence. 
2. Risks related to blood pressure changes and blood pressure medication changes. 
Risks of blood pressure drop include: light headedness, dizziness, kidney injury, or 
rarely stroke or myocardial ischemia or infarction. The risks of blood pressure rising 
excessively include stroke, heart failure, myocardial ischemia or infarction, or 
epistaxis.  
3. Pain, bruising, and rarely infection from drawing blood from a vein in the arm 
4. Lower quality of sleep and discomfort while sleeping while wearing the 24-hour blood 
pressure monitor. 
5. Discomfort from the blood pressure machine cuff. 
6. Discomfort from being enclosed within the BODPOD for body composition 
measurement. Patients will be asked if they have a fear of closed spaces before 
starting the measurement. 
7. Risks related to possible loss of confidentiality.  
Protection against risks and reporting of adverse events 
To protect against risks, we are only recruiting subjects, who have poorly controlled 
hypertension by ambulatory BP monitoring.  
1. Subjects will be closely monitored while receiving chlorthalidone and they will be 
questioned about possible side effects. 

28 | F i n a l  P r o t o c o l  
 
2. Blood pressure will be monitored continuously, and other possible side effects will be 
monitored through blood tests we are obtaining. 
3. Blood will be drawn by a trained phlebotomist and whenever possible it will be 
obtained at a time when blood is being obtained for other tests the subject’s doctor 
has ordered. 
4. All patient charts are kept in an office locked after normal working hours and when 
no one is in the office. All electronic databases are password protected. 
5. We will make sure all subjects are wearing the correct cuff size.  
6. The automatic blood pressure monitor will be set for the sound to be turned off at 
night to minimize the disruption of sleep. 
Adverse experience will be recorded to include the date and time of onset, description, 
severity, duration and outcome, etiology, relationship to study drug, and action taken.  
 
Should a serious adverse experience (defined as death, hospitalization or prolongation 
of hospitalization, life-threatening or permanently disabling) occur at any time and is deemed 
possibly, probably, or definitely related to the study drug, the Investigator will report the incident 
to the IRB following the locally accepted regulations. 
Adverse events of special interest 
Due to the relatedness of many adverse events with use of thiazide diuretics we will use 
the following list as adverse events of special interest (AEOSI) 
 
Acute gout: clinical diagnosis in the presence of symptoms. 
Acute kidney injury (AKI) 
Mild AKI: an increase in serum creatinine of ≥ 25% but < 50% from baseline value.  
Severe AKI: an increase in serum creatinine of ≥ 50% from baseline value. 
Dizziness: symptoms with observed decrease in blood pressure < 20 mmHg systolic while 
standing. If decrease in blood pressure is > 20 mmHg, see orthostatic hypotension . 
Orthostatic hypotension: greater than 20 mmHg drop in systolic blood pressure within 3 minutes 
of standing when in the presence of symptoms. 
Hypercalcemia: serum calcium concentration > 10.5 mg/dL. 
 
Hyperglycemia: in patients without diabetes when random glucose is > 200 mg/dL or in patients 
with diabetes when random glucose > 300 mg/dL (mild/moderate); severe when random 
glucose is > 400 mg/dL. 
 
Hyperkalemia: serum potassium concentration > 5.5 mmol/L. 
Hyperuricemia: serum uric acid concentration > 12.0 mg/dL in patients with a serum creatinine 
concentration > 2.0 mg/dL. 

29 | F i n a l  P r o t o c o l
Hypokalemia: serum potassium concentration < 3.5 mmol/L but ≥ 3.0 mmol/L (mild); serum 
potassium concentration < 3.0 mmol/L (moderate to severe). 
Hypomagnesemia: serum magnesium concentration < 1.80 mg/dL 
Hyponatremia: serum sodium concentration < 135 mmol/L. 
SIGNIFICANT PROTOCOL AMENDMENTS 
Table 3: Listing of significant protocol amendments and rationale of amendments 
Date amended 
Description of amendment 
Rationale for amendment 
7/28/2016 
Add home BP diary and modify exclusion 
criteria for two weeks run in (formerly home 
BP < 130/80, now clinic BP < 110 systolic). 
Less restrictive exclusion. Only 
those with clinic BP of <110 mmHg 
at visit 2 will be excluded from the 
trial. Prior to this amendment, those 
with home BP <130/80 mmHg were 
excluded. 
10/14/2016 
The threshold for randomization to the 
treatment arm (chlorthalidone vs. placebo) is 
revised from an average 24-hour ambulatory 
blood pressure of ≥135 mmHg systolic or ≥85 
mmHg diastolic to a new threshold of ≥130 
mmHg systolic or ≥80 mmHg diastolic. 
To make 24h ambulatory BP 
thresholds for the diagnosis of 
poorly controlled hypertension 
consistent with prevailing 
guidelines 
1/17/2017 
Updated the definitions of adverse events of 
special interest. 
Definitions were amended to reflect 
the relatedness of adverse events 
to use of thiazide diuretics.  
2/2/2017 
The protocol is amended to include a follow-
up sub-study and informed consent 
documents are added for the sub-study. 
Further, the informed consent statements are 
amended to include fasting for blood draw and 
delayed blood pressure medication 
administration as visit procedure. IU Health is 
added as a recruitment site and the relevant 
Broaden the recruitment site to 
increase trial recruitment. Follow up 
to assess long-term consequences 
of participation in the trial 

30 | F i n a l  P r o t o c o l
sections of the questionnaire are updated to 
include these changes. 
6/7/2017 
This amendment removed an external site for 
the trial.  
The external site was closed due to 
nonperformance, thus the informed 
consent statements will be 
amended to state that 160 subjects 
(e.g., enrollment target for this 
study) will be recruited locally.  
10/5/2017 
Dr. Wanzhu Tu of the IU Department of 
Biostatistics is added as key study personnel 
as he will serve as an unblinded statistician for 
the study and provide interim reports to the 
data and Safety Monitoring Board (DSMB) 
and will assist with results reporting at the 
conclusion of the trial.  
External site was also the data 
coordinating center.  With external 
site closure, data needed to be 
moved to Indiana University. 
12/14/2018 
Questionnaire being used to collect data from 
the subject for the substudy over the phone 
uploaded to the notes and attachment tab.  
We will get verbal consent from the subjects 
that do not want to come into the office. 
Some subjects are unable to come 
in for the sub study due to 
advanced illness or time 
commitment issues but are 
interested in allowing us to ask 
them questions and review their 
medical records.  
12/14/2019 
Instead of BNP, changed volume marker to 
NT-proBNP. 
NT-proBNP is more stable in 
freezer than BNP which is why we 
have changed this biomarker 

31 | F i n a l  P r o t o c o l
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