Conditions: Chronic Kidney Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 194
Healthy volunteers: no

Brief summary:
The two doses of sodium bicarbonate being tested are 0.5 and 0.8 mEq/kg-lean body weight (LBW) per day. Sodium bicarbonate, also known as baking soda, may help prevent kidney failure in people with chronic kidney disease. However, the dose to prescribe in order to test this possibility in a clinical trial is uncertain. The BASE pilot clinical trial will help determine the best dose of sodium bicarbonate to prescribe in a future study that will test the long-term safety and efficacy of sodium bicarbonate as a treatment to preserve kidney function in individuals with chronic kidney disease.

Detailed description:

Arms:
arm 1: Participants will receive oral 0.5 milliequivalents (mEq)/kg-lean body weight (LBW)/day of sodium bicarbonate. Half of the total daily dose is taken in the morning and the other half is taken in the evening. (If the number of capsules is an odd number, the greater number of capsules will be taken in the morning.) arm 2: Participants will receive 0.8 mEq/kg-LBW/day of sodium bicarbonate. Half the total daily dose is taken in the morning and the other half is taken in the evening. (If the number of capsules is an odd number, the greater number of capsules will be taken in the morning.) arm 3: Participants will take the same number of placebo capsules as if they were assigned to receive either 0.5 mEq/kg-LBW/day or 0.8 mEq/kg-LBW/day of sodium bicarbonate. Half the total daily dose is taken in the morning and the other half is taken in the evening. (If the number of capsules is an odd number, the greater number of capsules will be taken in the morning.)

Interventions: intervention 1: Lower Dose Sodium Bicarbonate intervention 2: Higher Dose Sodium Bicarbonate intervention 3: Placebo
Intervention descriptions: intervention 1: Lower dose oral Sodium Bicarbonate (0.5 milliequivalents (mEq)/kg-LBW/day) intervention 2: Higher dose oral Sodium Bicarbonate (0.8 mEq/kg-LBW/day) intervention 3: Oral placebo equivalent to either 0.5 mEq/kg-LBW/day or 0.8 mEq/kg-LBW/day of Sodium Bicarbonate

Protocol document:
Prot_SAP_000.pdf: 
Draft BASE Protocol of August 11, 2014 
  
Page i 
 
 
Bicarbonate Administration 
to Stabilize eGFR 
 
(BASE Study) 
 
Pilot Clinical Trials in CKD Protocol 
 
BASE Protocol Version 1.2 
December 12, 2016 
 


 
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  Page ii 
 
BASE Study 
Pilot Clinical Trials in CKD 
 
1  INTRODUCTION ................................................................................................................... 1 
1.1  Executive Summary ............................................................................................................. 1 
1.2  Background .......................................................................................................................... 1 
1.2.2  What is the optimum dose of sodium bicarbonate in the target population? ................. 3 
1.3  Goals .................................................................................................................................... 4 
1.3.1  Specific Aims ............................................................................................................... 4 
1.3.2  Co-Primary Endpoints for Specific Aim 1 ..................................................................... 4 
1.3.3  Benchmarks for co-primary endpoints .......................................................................... 5 
1.3.4  Overall assessment of feasibility .................................................................................. 5 
1.4  Interventions ........................................................................................................................ 6 
1.5  Study Design ........................................................................................................................ 6 
1.5.1  Rationale to include more participants in the higher-dose sodium bicarbonate arm ..... 6 
1.5.2  Rationale for the placebo arm ...................................................................................... 6 
1.5.3  Description of the study phases ................................................................................... 7 
1.6  Sample size ......................................................................................................................... 9 
1.7  Study Timeline ..................................................................................................................... 9 
1.8  Study Visits ........................................................................................................................ 10 
2  PATIENT SELECTION ..........................................................................................................11 
2.1  Introduction ........................................................................................................................ 11 
2.2  Inclusion and Exclusion Criteria ........................................................................................ 11 
2.3  Identification of participants for screening ......................................................................... 12 
2.4  Informed Consent procedures ........................................................................................... 12 
2.4.1  Consent and Withdrawal of Consent for the NIDDK Biosample Repository .................12 
2.5  Privacy and security ........................................................................................................... 13 
3  SCREENING & BASELINE PHASES ....................................................................................13 
3.1  Screening ........................................................................................................................... 13 
3.2  Description of Baseline Phase .......................................................................................... 13 
3.3  Baseline collection of concurrent medications at study entry ........................................... 15 
3.4  Comorbidities assessment ................................................................................................ 15 
3.5  Maximum time allowed in Baseline ................................................................................... 15 
3.6  Reasons for Baseline Phase drop-out .............................................................................. 15 
3.7  Assessment of readiness for randomization ..................................................................... 15 
4  RANDOMIZATION AND RECRUITMENT MONITORING .....................................................16 
4.1  Randomization in an intent-to-treat clinical trial ................................................................ 16 
4.2  Logistics of randomization ................................................................................................. 16 


 
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4.3  How recruitment will be monitored .................................................................................... 16 
5.  TREATMENT ARMS ............................................................................................................17 
5.1  Initiation of intervention ...................................................................................................... 17 
5.1.1  Lower-dose sodium bicarbonate .................................................................................17 
5.1.2  Higher-dose sodium bicarbonate ................................................................................17 
5.1.3  Lower-dose placebo ....................................................................................................17 
5.1.4  Higher-dose placebo ...................................................................................................18 
5.1.5  Dosing schedule .........................................................................................................18 
5.1.6  Calculation of lean body weight ..................................................................................18 
5.1.7  Rationale for LBW entry criteria ..................................................................................18 
5.1.8  Rationale for the selected doses of sodium bicarbonate tested in this Pilot Clinical Trial
 ......................................................................................................................................18 
5.2  Source of sodium bicarbonate and placebo ...................................................................... 20 
5.3  Initial distribution and resupply to participants .................................................................. 20 
5.4  Maintaining blinding ........................................................................................................... 20 
5.5  Unblinding .......................................................................................................................... 20 
6.  FOLLOW-UP ........................................................................................................................21 
6.1  Follow-up visit schedule .................................................................................................... 21 
6.2  Data elements collected during in-person visits ................................................................ 21 
6.3  Monitoring compliance with treatment ............................................................................... 21 
6.4  Participants who start dialysis, undergo kidney transplantation, or become pregnant .... 22 
7  MEASUREMENT TECHNIQUES ..........................................................................................22 
7.1  Serum chemistry panel ...................................................................................................... 22 
7.2  24-hour urine collection & measurements......................................................................... 22 
7.3  Local laboratory tests using random urine samples ......................................................... 22 
7.4  Physical examination measurements ................................................................................ 23 
7.5  Pill Counts .......................................................................................................................... 23 
7.6  Gastrointestinal symptoms questionnaire ......................................................................... 23 
7.7  Collection of biological samples (serum, plasma, urine) for the NIDDK biosample 
repository ......................................................................................................................23 
7.8  Pregnancy test ................................................................................................................... 23 
7.9  Venous blood gas substudy .............................................................................................. 23 
8  ADVERSE EVENTS (AEs) ....................................................................................................23 
8.1  Expected study-related AEs .............................................................................................. 23 
8.2  How AEs will be reported .................................................................................................. 24 
8.3  Serious Adverse Event (SAEs), hospitalization, and death reporting .............................. 24 
8.4  Strategy for the management of adverse events, including reducing or terminating the 
assigned intervention ........................................................................................................ 24 


 
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8.4.1  Reducing and/or stopping the randomized intervention for safety reasons ..................24 
8.4.2  Reducing and/or stopping the randomized intervention for other reasons ...................26 
8.5  Restarting the intervention and/or increasing reduced doses back to the full randomized 
dose ................................................................................................................................... 26 
8.6  Rescue therapy with oral sodium bicarbonate .................................................................. 26 
8.7  DSMB ................................................................................................................................. 27 
9  ANALYSIS PLAN and POWER CALCULATIONS .................................................................27 
9.1 Baseline characteristics ...................................................................................................... 27 
9.2  Analysis plan for Specific Aim 1 ........................................................................................ 27 
9.2.1  Analysis of Co-Primary Endpoints ...............................................................................27 
9.2.2  Secondary Analyses of Feasibility of the Dose Interventions ......................................28 
9.2.3  Statistical Power for Aim 1 Analyses ...........................................................................29 
9.3  Analysis plan for Specific Aim 2 ........................................................................................ 29 
9.3.1  Distributions of weight-standardized urinary NH4+ excretion ........................................30 
9.3.2  Pharmacodynamics analyses of NH4+ excretion ..........................................................30 
9.3.3  Power calculations for comparisons of change in NH4+ between dose groups ............31 
9.4  Analysis of the relationship between bicarbonate dose and serum bicarbonate level ..... 31 
9.5  Exploratory Analyses of Treatment Effects on albuminuria and eGFR ............................ 32 
9.6  Other exploratory pharmacodynamics analyses ............................................................... 32 
9.7  Comparisons of the response of blood pressure, serum bicarbonate, serum potassium, 
and weight after discontinuing treatment ......................................................................... 33 
9.8  How will this study be considered successful? ................................................................. 33 
10  PLANS FOR THE STUDY DESIGN OF THE PHASE 3 TRIAL ...........................................33 
11  REFERENCES ...................................................................................................................33 
12  Table of Abbreviations ........................................................................................................35 
 
 


 
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1  INTRODUCTION 
 
1.1  Executive Summary  
 
Metabolic acidosis is a recognized complication of chronic kidney disease (CKD) that is usually 
treated with oral alkali to mitigate the effects of acidosis on bone and protein [1].  Limited data 
suggest that treatment of acidosis with alkali also slows CKD progression [2, 3]. However, most 
CKD patients have normal serum bicarbonate levels and do not receive alkali because it is not 
recommended by current practice guidelines under these circumstances [4, 5].  Whether alkali 
slows CKD progression in people with normal serum bicarbonate is uncertain, although results 
from several observational studies and one small interventional study support this possibility.  
These data provide a strong rationale to determine whether sodium bicarbonate preserves renal 
function in CKD patients with normal serum bicarbonate in a full-scale trial.  Before proceeding 
with a Phase 3 trial, however, the optimum dose of sodium bicarbonate that would be 
acceptable in terms of safety and compliance needs to be determined, as was discussed at a 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Conference 
“Reducing the Impact of Chronic Kidney Disease: Opportunities for Randomized Clinical Trials” 
in July 2011 [6].  The purpose of the BASE (Bicarbonate Administration to Stabilize EGFR) Pilot 
Clinical Trial is to help inform the decision regarding sodium bicarbonate dose for a Phase 3 trial 
by examining the safety, compliance, and pharmacodynamics of two rational doses of sodium 
bicarbonate in the CKD population that will be enrolled in that trial.  
 
1.2  Background  
 
CKD is a major global health problem, leads to end-stage renal disease (ESRD), promotes 
cardiovascular disease, and shortens life expectancy.  Unfortunately there are few established 
therapies that slow CKD progression.  Results from observational and a few small interventional 
trials have renewed interest in alkali as a strategy to slow CKD progression.  Traditionally, the 
role of alkali in non-dialysis requiring CKD has been relegated to correct systemic acidosis and 
prevent consequent bone demineralization and protein catabolism [1].  However, results from 
two small interventional trials suggest that correcting systemic acidosis also slows CKD 
progression [2, 3].   
 
a. In a non-randomized study, individuals with hypertensive kidney disease, estimated 
glomerular filtration rate (eGFR) 20–59 ml/min/1.73m2, and low serum bicarbonate (<22 
mEq/L) who received chronic sodium citrate 1 mEq/kg-LBW (lean body weight) daily (n=30) 
had higher eGFR after 24 months of treatment compared to the control group (n=29) not 
receiving alkali supplementation [3]. 
 
b. In a randomized study, de Brito-Ashurst et al. assigned 134 CKD patients with low serum 
bicarbonate levels (16–20 mEq/L) to receive either open-label chronic oral sodium 
bicarbonate or no sodium bicarbonate.  In the intervention group, the bicarbonate dose was 
titrated to achieve serum bicarbonate ≥23 mEq/L. The mean dose of sodium bicarbonate 
required to achieve this target was 0.3 mEq/kg/day.  Fewer participants treated with 
bicarbonate had decline in creatinine clearance by >3 ml/min/1.73m2/yr (relative risk [RR] 
0.15; p<0.0001) and fewer required dialysis (RR 0.13; p<0.001) over two years [2].    
 
Although there are no large definitive trials on the effect of bicarbonate supplementation on CKD 
progression in patients with low serum bicarbonate, these results have led to significant interest 
in this area.  Two other ongoing randomized trials, one from the United Kingdom (BiCARB 
Study) and one from Austria (SoBic-Study) are also examining the renal and non-renal benefits 
of correcting systemic acidosis in CKD patients [7, 8].   


 
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The BiCARB Trial is a multicenter, randomized, double-blinded, placebo-controlled trial.  Three 
hundred eighty patients with stage 4 or 5 CKD, serum bicarbonate <22 mEq/L, and age >65 
years will be enrolled.  Participants will receive up to 3000mg per day of sodium bicarbonate to 
achieve serum bicarbonate ≥22 mEq/L.  The primary outcome will be physical function 
measures.  A secondary objective of the BiCARB Trial is to explore the effect of sodium 
bicarbonate on eGFR during the two-year follow-up period [8].   
 
The SoBic-Study is a single-center, randomized, controlled, open-label study of 200 patients 
with stage 3 or 4 CKD with serum bicarbonate <21 mEq/L.  The intervention arm will receive 
oral sodium bicarbonate titrated to target serum bicarbonate level of 24±1 mEq/L.  The expected 
maximum dose in this arm is 5040 mg of sodium bicarbonate daily, although higher doses may 
be required to reach target levels.  The control group will receive a rescue therapy of sodium 
bicarbonate to target serum bicarbonate level of 20±1 mEq/L. The primary objective in this study 
is to compare the change in eGFR between the two arms over a two-year follow-up [7], although 
the study is likely underpowered for this outcome.   
 
1.2.1  Shifting the paradigm of acid-base management in CKD: Focusing on those with 
normal serum bicarbonate 
 
Both BiCARB and SoBic are specifically targeting patients with low serum bicarbonate, probably 
motivated by the common belief that correcting acidosis has a number of pleiotropic benefits.  In 
fact, correcting acidosis is recommended for CKD patients [1].  However, 85% of CKD patients 
have normal serum bicarbonate [5] and are not treated with alkali.  Thus, a major paradigm shift 
in CKD treatment would occur if alkali were indeed shown to preserve renal function in people 
with normal serum bicarbonate concentration. Several lines of evidence support this possibility: 
 
a. Multiple observational studies have shown that higher serum bicarbonate concentrations, 
even within the normal range, are associated with a lower risk of CKD progression, with the 
lowest risk observed near 28 mEq/L [9-12].   
 
b. Mahajan et al. performed a blinded, randomized controlled trial in patients with hypertensive 
nephropathy, stage 2 CKD, and macroalbuminuria, comparing (i) 0.5 mEq/kg-LBW/day 
sodium bicarbonate (n=40), (ii) equimolar sodium chloride (n=40) and (iii) placebo (n=40). 
The groups had similar eGFR by cystatin C (~73 ml/min) and serum bicarbonate (~24 
mEq/L) at baseline.  At the end of the 5-yr study, eGFR decline was significantly less in 
participants treated with sodium bicarbonate (eGFR 66.4 ml/min), compared to those who 
received sodium chloride (eGFR 62.7 ml/min) or placebo (60.8 ml/min) [13].   
 
These data support the promise of alkali as a reno-protective therapy among CKD patients with 
normal serum bicarbonate levels.  Two other ongoing studies are exploring this possibility 
[14,15].  One is testing pleiotropic effects of sodium bicarbonate on muscle, bone, insulin 
sensitivity, and reno-protection in the setting of normal serum bicarbonate.  In this trial, 150 CKD 
patients with eGFR of 15-45 ml/min/1.73m2 and serum bicarbonate 20-27 mEq/L will receive 
either 0.4 mEq/kg-LBW/day of sodium bicarbonate or placebo for two years.  Because the trial 
is not powered to examine the effect on hard renal outcomes (i.e. eGFR), two intermediate 
injury markers, KIM-1 (kidney injury marker-1) and NGAL (neutrophil gelatinase-associated 
lipocalin), are used as surrogate measures [14].  The second study is investigating the effect of 
sodium bicarbonate (0.5 mEq/kg-LBW/day), compared to placebo, on urinary markers of renal 
fibrosis and complement activation in 74 diabetic veterans with stage 2-4 CKD and serum 
bicarbonate 20-28 mEq/L [15]. 
 


 
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1.2.2  What is the optimum dose of sodium bicarbonate in the target population? 
 
Although the studies in CKD patients with normal serum bicarbonate administer a dose of 0.4-
0.5 mEq/kg-LBW/day, the optimum dose, with regard to reno-protective efficacy, safety, and 
compliance, is unknown.  Based on the pathophysiological mechanisms by which alkali may 
reduce kidney injury, doses higher than 0.4-0.5 mEq/kg-LBW/day may increase the chances of 
achieving a positive efficacy result in a Phase 3 trial, so long as higher doses are safe and do 
not diminish compliance.   
 
The proposed mechanism of action of the 
reno-protective effects of alkali is presented 
in Figure 1.  The daily fixed acid load must 
be excreted in order to maintain normal 
systemic pH.  The kidneys accomplish this 
by excreting H+ in the form of ammonium 
(NH4+) and titratable acids (i.e., H2PO4-) 
and reabsorbing filtered bicarbonate.  Of 
these mechanisms, the most adaptable is 
the up-regulation of renal ammonia (NH3) 
production and NH4+ excretion.  In CKD, 
residual nephrons must compensate for the 
loss of functioning nephrons to excrete the 
fixed acid load.  By necessity, NH3 
generation per functioning nephron 
increases [16], leading to high local tissue NH3 concentration.  The generated NH3 leads to 
intrarenal activation of the alternative pathway of complement, further tubulointerstitial injury, 
and CKD progression [17].  In addition, endothelin-1 (ET-1)-mediated H+ secretion in response 
to reduced cellular pH also leads to tubulointerstitial injury [18, 19].  Hence, alkali is expected to 
neutralize the daily acid load, thereby reducing renal NH3 production and ET-1 activity and renal 
fibrosis.  We hypothesize that these compensatory responses and consequent fibrosis could be 
furthered suppressed with doses of sodium bicarbonate greater than 0.4-0.5 mEq/kg-LBW/day.  
 
Whether higher doses are safe in CKD patients with normal serum bicarbonate levels over an 
extended duration is unknown.  There is limited evidence that sodium bicarbonate doses >0.5 
mEq/kg-LBW/day are safe, at least in the short-term.  In a study by Abramowitz et al., 20 CKD 
patients with serum bicarbonate levels of 20-24 mEq/L received escalating doses of oral sodium 
bicarbonate (0.3, 0.6, and 1.0 mEq/kg-LBW/day) over 2-week intervals on each dose [20].  No 
significant adverse effects (including weight gain, blood pressure increase, or hypokalemia) 
were observed with the highest dose.  It should be noted that the duration of exposure was 
short (2 weeks) and the sample size was small. 
 
While a sodium bicarbonate dose of 0.5 mEq/kg-LBW/day administered over 5 years appeared 
to be safe in CKD patients in the Mahajan et al. study [13], the participants in that study had 
early (stage 2) CKD and the sample size was small (n=40).  In contrast, it is likely that our 
potential Phase 3 trial will enroll participants with more advanced CKD (i.e., stages 3 and 4) in 
order to accumulate sufficient renal event rates during follow-up.  Whether more advanced CKD 
patients can tolerate bicarbonate doses of 0.5 mEq/kg-LBW/day or higher is uncertain and will 
be examined as the main goal in this Pilot Clinical Trial in preparation for a Phase 3 Trial.  A 
secondary objective is to assess the pharmacodynamics of two different doses of oral sodium 
bicarbonate, by measuring change in urinary NH4+ excretion, which will also facilitate dose 
selection for the Phase 3 trial 
. 
 
Figure 1.  Proposed mechanisms of renal injury induced by 
the daily acid load in CKD and how alkali treatment attenuates 
this injury.  (ET-1 = endothelin-1) 


 
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1.3  Goals 
 
The long-term goal is to conduct a randomized, double-blinded, placebo-controlled Phase 3 trial 
that will determine if chronic oral sodium bicarbonate therapy slows CKD progression in patients 
with normal serum bicarbonate levels.   
 
The goal of this Pilot Clinical Trial is to determine the dose of sodium bicarbonate to be 
employed in the Phase 3 trial.  To achieve this goal, we will conduct a 28-week three-arm, 
parallel, randomized, double-blinded, placebo-controlled trial in 192 patients with moderate-to-
severe CKD and normal serum bicarbonate levels.  In addition to placebo, there will be two 
active treatment groups, a lower-dose sodium bicarbonate group and a higher-dose sodium 
bicarbonate group.  The dose of sodium bicarbonate that will be tested in the lower-dose group 
is 0.5 mEq/kg-LBW/day.  The dose of sodium bicarbonate that will be tested in the higher-dose 
group is 0.8 mEq/kg-LBW/day. 
 
1.3.1  Specific Aims 
 
Specific Aim 1.  The primary aim of this Pilot Clinical Trial is to determine the feasibility, in 
terms of safety and tolerability, of prescribing one of two doses of oral sodium bicarbonate (0.5 
or 0.8 mEq/kg-LBW/day) in a Phase 3 trial that will test whether this intervention slows CKD 
progression in patients with moderate-to-severe CKD and normal serum bicarbonate 
concentration.  The primary analysis will examine, as co-primary endpoints, the percentage of 
participants in each dose group that are prescribed at the end of the 28-week intervention 
period: 
a. the full randomized dose of sodium bicarbonate according to the protocol, and 
b. at least 25% of the randomized sodium bicarbonate dose according to the protocol. 
 
 
Specific Aim 2.  A secondary objective of the Pilot Clinical Trial is to determine the effect of the 
0.5 and 0.8 mEq/kg-LBW/day sodium bicarbonate doses on urinary NH4+ excretion, compared 
to placebo, as a pharmacodynamic assessment.   
 
 
Hypothesis: Urinary NH4+ excretion will decrease with both sodium bicarbonate doses, 
however, the magnitude of the reduction will be greater with the higher dose. 
 
1.3.2  Co-Primary Endpoints for Specific Aim 1 
 
The two co-primary endpoints provide an assessment of the feasibility, in terms of safety and 
tolerability, to implement either dose in a Phase 3 trial.  These endpoints are influenced by a 
number of factors, including medication intolerance (e.g., due to gastrointestinal symptoms or 
fluid retention), side effects (e.g., difficult-to-manage hypertension, hypokalemia, or metabolic 
alkalosis), and participant drop-out or loss to follow-up.  Although compliance will be evaluated 
by pill counts, compliance will not be considered in the co-primary endpoints assessments 
because (i) poor compliance will not trigger a reduction in the prescribed dose unless there is 
intolerability or an adverse safety event, and (ii) obtaining pill counts from participants has many 
limitations.  Nonetheless, the compliance data will be analyzed secondarily. 
We anticipate that most participants in each active treatment arm will complete the study 
prescribed the full dose as randomized according to the protocol because they did not have a 
protocol mandated dose reduction due to side effects or intolerance.  On the other hand, some 
participants may require a reduction in the prescribed dose due to side effects or intolerance (as 
discussed in Section 8).  Participants who do not complete the study will be considered 
treatment failures.   


 
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Therefore, the appropriateness of employing one of these sodium bicarbonate doses in a Phase 
3 trial will be evaluated by two co-primary safety and tolerability endpoints in this Pilot Study: 
1. The percent of participants within each active treatment arm who are prescribed the full 
randomized sodium bicarbonate dose according to the protocol at the end of the 28-week 
intervention period, and 
2. The percent of participants within each active treatment arm who are prescribed at least 
25% of the randomized sodium bicarbonate dose according to the protocol at the end of the 
28-week intervention period. 
 
The  participant's prescribed dose at the end of the intervention period will be compared to the 
participant's randomized dose to determine if an intended dose reduction occured as described 
in Section 8.  
 
1.3.3  Benchmarks for co-primary endpoints  
 
We would consider that the benchmark is achieved if:  
1. at least 67% of participants in each active treatment arm are prescribed the full randomized 
sodium bicarbonate dose according to the protocol at the end of the 28-week intervention 
period, and 
2. at least 80% of participants in each active treatment arm are prescribed at least 25% of the 
randomized sodium bicarbonate dose according to the protocol at the end of the 28-week 
intervention period. 
 
For example, if 70% of participants in an active treatment arm are prescribed the full 
randomized dose at the end of the 28-week intervention period, an additional 10% in that arm 
would need to complete the intervention period on at least 25% of the randomized dose to 
achieve 80% and satisfy the second criterion. 
 
Our rationales for these benchmark cutoffs consider: (i) a potential loss to follow-up and drop-
out rate of 5-15% in the active treatment arm, (ii) that, in order for a dose to be prescribed in a 
longer-duration Phase 3 trial, the vast majority of participants who are not lost to follow-up or do 
not drop-out should not require a dose reduction for safety or intolerance during this shorter 28-
week Pilot Study, and (iii) participants who take lower than the randomized doses may still 
benefit from the therapy, so long as the percentage of such participants is low in this 28-week 
Pilot Study. 
 
Therefore, if the total percent of (i) participants taking <25% of the randomized dose at the end 
of the intervention period, (ii) loss to follow-up, and (iii) drop-out is >20% in an active treatment 
arm, the feasibility of employing that dose in a longer-duration Phase 3 trial would be 
questionable.  Also, if <67% of participants are prescribed the full randomized dose for that 
treatment arm at the end of the intervention period, this would also suggest that such a dose 
would not be feasible in a long-term Phase 3 clinical trial.     
 
1.3.4  Overall assessment of feasibility 
 
In addition to the co-primary safety and tolerability endpoints in Specific Aim 1, the 
appropriateness of the dose interventions for a Phase 3 trial will also consider the response of 
urinary NH4+ excretion to the two dose levels of sodium bicarbonate in Specific Aim 2 and 
participant compliance as assessed by pill counts. As mentioned, compliance will not be 
considered in the co-primary endpoints analyses.  Hence, the determination of whether one of 
these doses is suitable for evaluation in a Phase 3 trial will be based first on whether pre-


 
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specified benchmarks for the co-primary safety and tolerability endpoints are achieved, but will 
also consider the full spectrum of results of the Pilot Clinical Trial as well as the results of other 
sodium bicarbonate interventional trials.  
1.4  Interventions 
 
Capsules containing one gram of sodium bicarbonate powder will be prepared for this Pilot 
Clinical Trial.  One gram of sodium bicarbonate delivers 12 mEq of bicarbonate and 275 mg of 
elemental sodium.  The number of pills prescribed will be determined by the participant's LBW 
and treatment assignment (see Table 2 below).  Matching placebo capsules will contain 
cornstarch. 
1.5  Study Design 
 
The study is a three-arm, parallel, randomized, double-blinded, placebo-controlled trial.  
Although this is a three-parallel-arm study, the placebo group will be divided into lower-dose and 
higher-dose placebo groups to maintain the blind.  Except for pill count summaries, analyses 
that include comparisons with placebo will consider the two placebo groups jointly.  The three 
study arms are:   
 
1. Higher-dose (0.8 mEq/kg-LBW/day) oral sodium bicarbonate (n=88) 
2. Lower-dose (0.5 mEq/kg-LBW/day) oral sodium bicarbonate (n=52) 
3. Placebo (n=52). 
 
1.5.1  Rationale to include more participants in the higher-dose sodium bicarbonate arm 
 
The rationale to include more participants in the higher-dose arm is the following.  There are two 
other ongoing studies comparing 0.4-0.5 mEq/kg-LBW/day sodium bicarbonate with placebo in 
similar, albeit somewhat different patient populations.  These other trials will also contribute 
substantial amounts of data on safety and tolerability of the 0.5 mEq/kg-LBW/day dose, 
although they will not provide direct comparisons with a higher dose.   Assigning more 
participants to the 0.8 mEq/kg-LBW/day dose in this Pilot Clinical Trial will provide more 
experience with this dose, which is essential for selecting the dose for the Phase 3 trial. 
 
1.5.2  Rationale for the placebo arm 
 
Although direct comparisons of the active treatment groups with the placebo group will not be 
required to determine if the pre-specified benchmarks for the co-primary safety and tolerability 
endpoints are met, there are several reasons to include a placebo group in this Pilot Clinical 
Trial.  First, a placebo group is required for Specific Aim 2, which will evaluate the reduction in 
urinary NH4+ excretion by sodium bicarbonate compared to placebo.  Second, if a placebo group 
were not included the investigators and participants would know that they are receiving sodium 
bicarbonate, which could influence medical management during the Pilot Clinical Trial as well as 
participant's perception of side effects.  Third, the inclusion of a placebo group will provide 
estimates of the proportions of participants who are classified as failures by the co-primary 
endpoints due to factors unrelated to the actual exposure of the participant to sodium 
bicarbonate; these estimates will clarify the interpretation of the failure rates observed for the 
co-primary endpoints in the two active treatment groups.  Fourth, evaluation of pill counts in the 
placebo group will address the extent to which pill burden contributes to limitations in 
compliance, independent of side effects.  Finally, several potential side effects of sodium 
bicarbonate, such as increase in blood pressure and fluid retention, commonly occur in CKD 
patients.  Inclusion of a placebo group will better allow us to assess the safety of sodium 


 
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bicarbonate in this population.   
 
1.5.3  Description of the study phases 
 
The study consists of three consecutive phases after enrollment (Figure 2): 
 
1. Baseline Phase.  During baseline, participants will take 2 placebo capsules twice daily for 
two weeks.  In addition, blood pressure (BP) will be reduced to <150/100 mm Hg, locally 
measured serum potassium targeted to 3.5-5.5 mEq/L, and angiotensin converting enzyme-
inhibitor (ACE-I) or angiotensin receptor blocker (ARB) dose will be optimized (i.e., tolerable 
dose up to the maximum recommended dose).  Participants will be randomized if 
compliance with the placebo is at least 80%, BP is <150/100 mm Hg, serum potassium is 
3.5-5.5 mEq/L, the average of the two most recent serum bicarbonate concentrations 
measured during baseline is 20-28 mEq/L, and the ACE-I or ARB is optimized in the opinion 
of the site investigator. 
2. On-Treatment Phase.  Participants take the assigned intervention for 28 weeks. 
3. Off-Treatment Phase.  Participants take no research pills for 4 weeks and then return for a 
close-out visit. 
 
Figure 2.  Design of the BASE Pilot Clinical Trial 
 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 8 
 
 
Lower-dose 
NaHCO3 
N=52 
Higher-dose 
NaHCO3 
N=88 
Placebo 
 
N=52 
Randomize 
N=192 
Screening 
Baseline Phase 
• Participants take 2 placebo capsules twice daily 
• BP reduced to <150/100 
• Optimize ACE-I/ARB dose 
• Target K+ to 3.5-5.5 mEq/L 
Exclude	
Placebo compliance ≥ 80% 
BP < 150/100 
ACE-I/ARB dose optimized 
K+ 3.5-5.5 mEq/L 
Serum HCO3
- 20-28 mEq/L 
yes	
0.5 mEq/kg/d 
Week 0-4 
Week 4-28 
0.5 mEq/kg/d 
0.5 mEq/kg/d 
0.8 mEq/kg/d 
Placebo 
Placebo 
Off-Treatment 
Off-Treatment 
Off-Treatment 
Week 28-32 
no	
 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 9 
 
1.6  Sample size  
 
One hundred ninety-two (192) participants will be randomized.  Fifty-two (52) will be assigned to 
the placebo group (26 each to the lower-dose and higher-dose placebo groups), eighty-eight 
(88) to the higher-dose sodium bicarbonate group, and fifty-two (52) to the lower-dose sodium 
bicarbonate group.  It is recognized that some participants will be excluded prior to 
randomization, so a higher number of participants will be enrolled in baseline as needed based 
on the observed exclusion rate as the trial unfolds. 
 
1.7  Study Timeline  
 
Participants will be enrolled over an 18-month period.  We anticipate the last participant will be 
randomized before the end of the 21st month and the last visit will occur before the end of the 
29th month. 
 
 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 10 
 
1.8  Study Visits  
 
Table 1. Summary of visit schedule 
 
PERIOD 
Screening 
Baseline 
Random-
ization† 
On Treatment 
Off 
Treatment 
VISIT NAME 
S0 
B0 
B1 
B2,3,etc‡ 
 
W0† 
W4 
W8 
W12 
W16¶ 
W20 
W24¶ 
W28 
W32 
TIME (approximate number of 
weeks from randomization) 
-12 
-8 to -2 
 
0 
4 
8 
12 
16 
20 
24 
28 
32 
Medical history review 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication review 
x 
x 
x 
x 
 
 
x 
x 
x 
 
x 
 
x 
x 
Height^, Weight, Blood pressure, 
Pulse, Edema 
x 
x 
x 
x 
 
 
x 
x 
x 
 
x 
 
x 
x 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (local) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum (local): Chemistry panel 
(Bicarbonate, Potassium,  
Creatinine, Sodium, Chloride, 
Urea Nitrogen, Glucose, Calcium) 
x 
x 
x 
x* 
 
 
x 
x 
x 
 
x 
 
x 
x 
Serum (local): Phosphorus and 
Albumin 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
Spot Urine (local): Albumin 
/Creatinine  
x 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
Dispense study medication 
 
x 
 
 
 
x 
x 
x 
x 
 
x 
 
 
 
Venous blood gas+ 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
Randomization 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
24-hour urine (central) 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
 
Gastrointestinal symptoms 
questionnaire  
 
x 
x 
 
 
 
x 
x 
x 
 
x 
 
x 
x 
Pill counts 
 
 
x 
 
 
 
x 
x 
x 
 
x 
 
x 
 
Adverse events assessment 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Collection of blood/urine for 
biorepository 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
 
^ measured only at screening visit 
* if required to assess serum K+ and HCO3- prior to randomization 
‡ additional baseline visits may be held to achieve target blood pressure, potassium, and optimize ACE-I/ARB dose 
†The purpose of W0 is to dispense randomized drug. Randomization will sometimes be done at a baseline visit.  If this occurs,  a separate W0 visit is not required. 
¶ conducted by telephone 
+ venous blood gas substudy participants


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 11 
 
2  PATIENT SELECTION  
 
2.1  Introduction 
 
The participant characteristics in the Pilot Clinical Trial are selected to match the entry criteria 
that we anticipate will be used in the Phase 3 trial, with a few exceptions. Participants will have 
normal to slightly low serum bicarbonate (20-28 mEq/L) and moderate to severe CKD.  
 
2.2  Inclusion and Exclusion Criteria 
 
A. Inclusion 
1. Serum bicarbonate 20–28 mEq/L at screening (the average of the two most recent values in 
Baseline must be 20-28 mEq/L prior to randomization)   
2. Moderate to severe CKD at the time of screening, defined as one of the following: 
a. eGFR 20.0–44.9 ml/min/1.73m2 or 
b. eGFR 45.0–59.9 ml/min/1.73m2 plus random urinary albumin:creatinine (ACR) ≥50 
mg/gm  
3. Blood pressure <160/100 mm Hg at screening (must be <150/100 mm Hg prior to 
randomization) 
4. Lean body weight 37.5–96.0 kg  
5. Age allowing legal consent without parental involvement (18-21 years, depending on 
individual state regulations) 
6. Able to provide consent 
7. Able to travel to study visits 
8. Able to read English 
9. In the opinion of the site investigator, willing and able to follow the study treatment regimen 
and comply with the site investigator's recommendations 
10. In the opinion of the site investigator, medically stable 
11. Have at least one ankle available to measure for edema 
 
B. Exclusion 
1. Use of chronic daily oral alkali (such as sodium bicarbonate, sodium citrate, potassium 
citrate, etc) with one exception: calcium carbonate ≤1500 mg/day is allowed, as some will 
take this for the indication of bone health 
2. In the judgment of the PI, the participant’s blood pressure medication regimen cannot be 
escalated (by adding a drug or increasing a dose) if the participant’s blood pressure were 
uncontrolled 
3. Serum potassium <3.3 or ≥5.5 mEq/L at screening (must be 3.5-5.5 mEq/L prior to 
randomization) 
4. Self-reported vegetarian 
5. New York Heart Association Class 3 or 4 heart failure symptoms, known left ventricular 
ejection fraction ≤30%, or hospital admission for heart failure within the past 3 months 
6. Frequent urinary tract infections (≥2 in the past year) 
7. Presence of indwelling urinary catheter or urinary conduit (such as neobladder or urostomy) 
8. Factors judged to limit adherence to interventions (e.g., alcoholism, history of missing clinic 
visits, chronic gastrointestinal disorder that makes compliance with the intervention 
unreliable) 
9. Organ transplant recipients (excluding cornea) 
10. Active glomerular disease requiring or potentially requiring immunosuppressive treatment 
11. Chronic immunosuppressive therapy for any indication.  This does not include oral steroids 
<10 mg per day, inhaled steroids, or topical steroids 
12. Anticipated initiation of dialysis or kidney transplantation within 12 months as assessed by 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 12 
 
the site investigator 
13. Current participation in another interventional research study 
14. Malignancy requiring therapy within 2 years (skin cancer other than melanoma and localized 
prostate cancer are exempted) 
15. Pregnancy or planning to become pregnant or currently breast-feeding.  Women of 
childbearing potential (pre-menopausal and not surgically sterilized) will have urine 
pregnancy test before enrollment. 
16. Life expectancy <12 months as determined by the site investigator 
17. Institutionalized individuals, including prisoners and nursing home residents 
18. Plans to leave the immediate area within the next 12 months 
19. Routinely leaves town for multiple weeks each year such that protocol visits would be 
missed 
20. Chronic use of supplemental oxygen 
21. Use of both ACEI and ARB 
 
For laboratory criteria, local results will be used.  These lab tests can be performed at the time 
of screening, or results measured within 2 calendar months of the screening visit can be used to 
determine eligibility.  When multiple measures are available, the most recent results will be used 
to determine eligiblity. 
 
Exclusion criteria 6 (frequent urinary tract infections ≥2 in the past year) and 7 (presence of 
indwelling urinary catheter or urinary conduit, such as neobladder or urostomy) are included 
because these may affect urinary NH4+ concentration.  These urinary exclusion criteria are not 
expected to be included in the Phase 3 trial because urinary NH4+ is not expected to be 
measured in that trial. 
 
2.3  Identification of participants for screening 
 
Patients will be screened from clinics at recruiting institutions.  It is expected that at most 
institutions, BASE Trial personnel will review the local medical record to identify patients who 
meet key entry criteria such age, eGFR, and other laboratory criteria. A waiver of Health 
Insurance Portability and Accountability Act (HIPAA) authorization and waiver of informed 
consent will be obtained from local Institutional Review Boards (IRBs) for any pre-reviews of  
medical records.   
 
2.4  Informed Consent procedures 
 
It is expected that most patients will be approached at the time of their routine clinic visits.  This 
will occur as follows.  After obtaining verbal permission from the clinical provider, study 
coordinators will approach potential participants at the time of the routine clinic visit and inform 
them of the nature and purpose of the trial in a private room.  Patients expressing interest in 
participation will be told about the entry criteria and given ample time to ask questions about the 
study, risks, benefits, and study-related procedures.  Patients will be informed that research 
participation is voluntary and the refusal to participate will in no way affect their medical care.  
Those who meet the entry criteria and are interested in participating will sign the informed 
consent document and will be provided with a copy of the signed informed consent document.   
 
2.4.1  Consent and Withdrawal of Consent for the NIDDK Biosample Repository  
 
Participants may consent or withdraw consent for the Repository at any time during the BASE 
Pilot Study.  If a participant consents to the NIDDK Biosample Repository, his or her samples 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 13 
 
will be stored at the NIDDK Biosample Repository indefinitely.  A participant may withdraw 
consent for the Repository during the study by notifying the principal investigator at the site.  
This physician will notify the DCC staff of this request in writing.  The DCC will then notify the 
NIDDK repository.  After obtaining approval from NIDDK, the Repository will destroy and discard 
the samples with its biological and laboratory waste.  The DCC will follow through to make sure 
the samples have been destroyed.  After the BASE Pilot Study ends, the BASE study IDs will be 
removed and participants may no longer withdraw consent for the Biosample Repository, as 
there will no longer be a way to link any individual with any stored specimen. 
2.5  Privacy and security 
 
Local clinical sites will store participant information in a secure manner, and HIPAA privacy rules 
will be followed.  For purposes of this study, participants will be identified only by an assigned 
identification number and a randomly generated alphanumeric code.  The study database will 
be password protected, and clinical site personnel will be restricted from seeing data for 
participants from centers other than their own.  The study database will reside on a password-
protected computer at the Data Coordinating Center (DCC).  No individual identifiers (participant 
name, social security number, or device serial number) will be stored.  Data will be entered with 
strong encryption and a Thawte, Inc., system will be used for secure transmission of data from 
clinical sites to the DCC.  The DCC ensures accuracy and reliability of computer systems used 
for this study with detailed edit checks and tests of data interface screens, reports, and 
procedures before implementation.  Computer-generated, time-stamped audit trails are kept.  
The database is incrementally backed up daily, with full back ups performed weekly.  Backups 
are stored at a secure location separate from the site of the database server.   
 
In those instances where a participant document (such as a hospital discharge summary or 
death certificate) is sent to the DCC, the site study coordinator will de-identify this prior to 
electronically transmitting it to the DCC.   
 
Clinical site and DCC staff members will be required to change their passwords every 75 days, 
and staff who are no longer active in the study will be blocked from database access. 
 
3  SCREENING & BASELINE PHASES 
 
3.1  Screening 
 
Screening will consist of completion of the screening form and collection and documentation of 
laboratory data.  Participants who have signed the consent document, but do not have the 
necessary laboratory data specified in the entry criteria within two calendar months will have the 
missing screening tests performed as part of the study protocol.  If laboratory entry criteria are 
not met, participants can be considered for rescreening later at the discretion of the investigator. 
3.2  Description of Baseline Phase 
 
The purpose of the Baseline Phase is to assess the participant for potential non-compliance, 
titrate antihypertensive medications to achieve goal blood pressure (<150/100 mm Hg), adjust 
serum potassium to the target range (3.5-5.5 mEq/L), and adjust ACE-I/ARB to the maximum 
tolerable dose prior to randomization.  Although participants can be randomized if blood 
pressure is <150/100 mm Hg, blood pressure will be treated to target <140/90 mm Hg during 
the study.   
 
It is anticipated that the Baseline Phase will consist of 2 to 4 visits, but more visits may be held if 
necessary.  The visits during Baseline will be approximately two weeks apart.  


 
BASE Protocol Version 1.2–December 12, 2016 
 
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Patients who agree to participate in the study and meet all entry criteria will be scheduled for the 
first baseline visit (B0).  B0 will occur within 4 weeks of the screening visit.  Participants who do 
not attend B0 within four weeks of screening  may be rescreened after one week has passed.  
 
Goals of Baseline Phase: 
 
1. Assess for potential non-compliance.  At B0, participants will be given 100 placebo capsules 
and asked to take two pills twice daily until the next visit (B1).  The B1 visit will be scheduled 
to occur in two weeks (range of 7-25 days to better accomodate the participant's schedule).  
Participants will bring back the pill bottle and pill counts will be performed.  If compliance as 
assessed by the pill count is <80%, the participant will be removed from the study.  
Participants with ≥80% pill count compliance can proceed to randomization provided other 
Baseline targets are achieved.  
 
2. Obtain 24 hour urine collection.  Participants will be provided with urine collection supplies 
and instructions on how to collect the first 24-hour sample at B0.  Participants will bring in 
the 24-hour urine collection to the B1 visit.  If the 24-hour urine collection is deemed 
inadequate, it will be repeated prior to randomization provided other Baseline targets are 
achieved.  Adequacy will be determined by asking the participant if they emptied their 
bladder prior to beginning the collection, did not miss collecting any urine, and if the time of 
the urine collection was close to 24 hours, as defined in the Manual of Operations. 
 
3. Reduce blood pressure to <150/100 mm Hg.  Blood pressure will be measured three times, 
one minute apart, and the mean of the second and third measure will be considered the 
BASE protocol visit blood pressure.  The target BP during BASE is <140/90 mm Hg; 
however, participants can be randomized if blood pressure is <150/100 mm Hg.  If blood 
pressure is above target, life-style changes (i.e., dietary salt restriction) and/or 
antihypertensive therapy will be initiated or escalated at the discretion of the site 
investigator.  Maximizing ACE-I/ARB dose will be given priority.  
 
4. Target serum potassium 3.5-5.5 mEq/L.  If serum potassium is below goal, dietary 
recommendations and/or potassium supplements will be given at the discretion of the 
investigator.  If serum potassium is above target and the sample is not hemolyzed, then 
potassium will be lowered at the discretion of the investigator.  (If serum potassium is above 
target and the sample is hemolyzed, it will be repeated.) The strategy may include dietary 
potassium restriction, diuretics, reducing ACE-I/ARB dose, and blood glucose control.  If 
diuretics or ACE-I/ARB doses change during baseline, the serum potassium will be repeated 
so it reflects serum potassium on the most recent diuretic and ACE-I/ARB dose. 
 
5. Initiate, titrate ACE-I/ARB.   If a participant is not on ACE-I/ARB, she/he will be questioned 
about prior use and side effects.  If there is a history of allergic reactions or documented 
intolerance, ACE-I/ARB will not be started.  If there has been no prior exposure, an ACE-
I/ARB will be started at the discretion of the investigator, taking into consideration blood 
pressure and potassium concentration. ACE-I/ARB dose will be increased to the maximum 
dose for proteinuric participants (i.e., the equivalent of 40 mg/d of lisinopril) provided that 
blood pressure and serum potassium are acceptable. If a participant is not uptitrated to the 
equivalent of 40 mg/day of lisinopril, the reason will be documented.  The rationales of 
maximizing the ACE-I/ARB dose in the Baseline Phase are two-fold: (i) the reno-protective 
effects of bicarbonate in the Phase 3 trial should be examined on the background of 
currently acceptable therapy; and (ii) avoidance of ACE-I/ARB dosage manipulation after 
randomization in the trial, which may affect serum potassium and bicarbonate 
concentrations and eGFR.  


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 15 
 
 
Achievement of the compliance goal is defined as a pill count compliance ≥80%.  Achievement 
of the blood pressure requirement is defined as the last protocol measured blood pressure 
<150/100 mm Hg.  Achievement of the serum potassium goal is defined as the last protocol 
measured serum potassium with the range of 3.5-5.5 mEq/L.  Achievement of the serum 
bicarbonate goal (20-28 mEq/L) is defined as the average of the two most recent serum 
bicarbonate measures obtained during baseline.  Achievement of appropriate ACE-I/ARB dose 
will be determined by the site investigator and will take into account the participant's blood 
pressure, serum potassium, and proteinuria status. 
 
Participants can spend a maximum of 12 weeks in the Baseline Phase.  The minimum number 
of Baseline visits will be two, which allows us to identify potential non-compliers using the 
placebo capsules.  More visits can be held if necessary to achieve target BP and potassium, 
and to titrate the ACE-I/ARB dose so long as the time spent in Baseline is not > 12 weeks.  
Those who do not achieve all goals by the end of the Baseline Phase will be removed from the 
trial but can be rescreened after one week has passed from the date of baseline drop-out, at the 
discretion of the investigator. Participants who satisfy all Baseline Phase criteria and are still 
willing will proceed to randomization.   
 
3.3  Baseline collection of concurrent medications at study entry 
 
Participants will be asked to bring in their medications including over-the-counter preparations to 
the first baseline (B0) visit.  Study staff will record these. 
 
3.4  Comorbidities assessment 
 
Study staff will record medical history, including history of tobacco and alcohol use. 
 
3.5  Maximum time allowed in Baseline 
 
The maximum time allowed between screening and B0 is 4 weeks.  The maximum time from B0 
to randomization is 12 weeks. 
 
Since consented participants will have blood pressure and potassium concentrations near the 
level required to proceed beyond Baseline, we anticipate that most will be randomized within 8 
weeks of screening.  Hence, the target time from screening to randomization is 8 weeks. 
 
3.6  Reasons for Baseline Phase drop-out 
 
Study staff will document reasons for pre-randomization drop-out during Baseline. 
 
3.7  Assessment of readiness for randomization 
 
Study staff will run the "Ready-to-Randomize Report" checklist for each participant to check that 
the participant meets all criteria. 


 
BASE Protocol Version 1.2–December 12, 2016 
 
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4  RANDOMIZATION AND RECRUITMENT MONITORING  
 
4.1  Randomization in an intent-to-treat clinical trial 
 
The study site investigator or a designated site investigator will review the screening and 
Baseline data and the Ready to Randomize report and confirm that the participant is eligible and 
should be randomized.   Randomization marks the participant's official and irrevocable entry into 
the Follow-up period. Once a participant has been randomized, efforts will be made to conduct 
all evaluation and data collection irrespective of whether the participant starts the study 
treatment regimen, how long the participant continues on the study treatment regimen, and how 
well the participant complies with the study treatment regimen.  
Routine data collection will end when a participant begins dialysis, receives a pre-emptive 
kidney transplant, dies, or is deemed completely lost to follow-up.   
If a participant withdraws consent for some types of data collection, other data will continue to 
be collected. All efforts will be made to continue data collection through the end of study follow-
up even if a participant’s medication never begins, the participant is not compliant, or the 
participant must stop randomized medications for a safety-related reason or any other reason.  
The primary analysis will be performed as intent-to-treat, that is, by randomized treatment 
group. 
4.2  Logistics of randomization 
 
The DCC will prepare randomization schedules prior to the start of recruitment. Randomization 
will be stratified by participating site. Randomly permuted blocks of different sizes, ordered in a 
random sequence, will be used to help meet the protocol-defined ratios of numbers of 
participants assigned to each treatment regimen.  This method guarantees that at no time 
during randomization will the number of participants in any arm be grossly off target and 
ensures that the sites will be unable to predict assignments of future participants based on 
knowledge of assignments of past participants. All randomization schedules will remain 
confidential and known only by select members of the DCC staff. 
Baseline data that have been categorized as essential must be in the database and support 
eligibility in order for a subject to be randomized. The study coordinator can run the Ready to 
Randomize Report at any time during baseline to check the participant's status with respect to 
meeting eligibility requirements. 
When the site investigator signs off that a participant should be randomized and the participant’s 
Ready to Randomize Report shows eligibility criteria have been met, the Study Coordinator will 
use his or her current database password to access an on-line interactive randomization 
program. The program will verify eligibility and Baseline criteria to confirm that the participant is 
eligible and ready to be randomized and a randomized treatment assignment will be recorded 
for that participant, based upon his or her stratum. The study is blinded, so treatment 
assignment will not be displayed. The computer will display the participant’s initial bottle 
numbers for the appropriate number of bottles given his or her LBW and treatment assignment.  
Confirmation of randomization will be displayed on the screen and emailed to the participating 
Clinical Center.  The treatment assignment will be used to assign the participant with his or her 
first four weeks coded packages of study drug.  
4.3  How recruitment will be monitored 
 
The DCC will email study-wide weekly recruitment reports showing study-wide weekly and 
cumulative enrollment in baseline and randomization. The reports will include each site’s current 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 17 
 
baseline goal, achievement of baseline goal, randomization goal, and achievement of 
randomization goal.  Clinical site investigators will meet regularly with their study teams to 
discuss progress on weekly goals, identify barriers and problems, and revise recruitment plans 
as necessary. The investigators from multiple sites will meet by conference call at regular 
scheduled intervals to review each site’s recruitment progress, share problems and successes, 
and revise recruitment plans as necessary. 
 
5.  TREATMENT ARMS 
 
5.1  Initiation of intervention 
 
Participants who have met eligibility criteria, provided informed consent, and successfully 
completed the Baseline Phase will be randomized.   
 
Participants will be randomized to one of four groups: 
1. Lower-dose (0.5 mEq/kg-LBW/day) oral sodium bicarbonate 
2. Higher-dose (0.8 mEq/kg-LBW/day) oral sodium bicarbonate 
3. Lower-dose oral placebo 
4. Higher-dose oral placebo 
 
5.1.1  Lower-dose sodium bicarbonate 
 
52 participants will be randomized to the lower-dose sodium bicarbonate group.  They will take 
0.5 mEq/kg-LBW daily during the On-Treatment Phase of the Pilot Clinical Trial.  The number of 
capsules will be rounded to the nearest whole capsule.   
 
5.1.2  Higher-dose sodium bicarbonate 
 
88 participants will be randomized to the higher-dose sodium bicarbonate group.  They will take 
0.5 mEq/kg-LBW daily for the first four weeks post randomization, W0 to W4. The clinical center 
will evaluate the following at W4: 
 
 
Systolic blood pressure ≥170 mm Hg 
 
Diastolic blood pressure ≥110 mm Hg 
 
Increase in weight by ≥5 kg from baseline 
 
Severe edema defined as >10% increase in total ankle circumference from baseline 
 
Severe  GI symptoms  as reported on the GI symptoms questionnaire 
 
If none of these has occured, the clinical center team will increase the dose to 0.8 mEq/kg-LBW 
daily at W4.  The number of capsules will be rounded to the nearest whole capsule. 
This dose will be continued for the remainder of the On-Treatment Phase.  If adverse events are 
observed at the W4 visit, including results from lab work measured at the W4 visit, this adverse 
event will be managed as described in section 8 below.   
5.1.3  Lower-dose placebo 
 
26 participants will be randomized to the lower-dose placebo group.  They will take the same 
number of capsules as if they were assigned to receive 0.5 mEq/kg-LBW/day of sodium 
bicarbonate during the On-Treatment Phase.  The number of capsules will be rounded to the 
nearest whole capsule. 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 18 
 
5.1.4  Higher-dose placebo 
 
26 participants will be randomized to the higher-dose placebo group. During the first four weeks, 
these participants will take the same number of capsules as if they were to take 0.5mEq/kg-
LBW/day of sodium bicarbonate.  If there are no significant side effects, as discussed in Section 
5.1.2, they will increase the number of capsules to the amount that they would have taken had 
they been assigned to receive 0.8 mEq/kg-LBW/day of sodium bicarbonate.  The number of 
capsules will be rounded to the nearest whole capsule. 
 
5.1.5  Dosing schedule 
 
Participants will take half the total daily dose in the morning and the other half in the evening.  If 
the number of capsules is an odd number, the greater number of capsules will be taken in the 
morning. 
 
5.1.6  Calculation of lean body weight 
 
Gender-specific formulas to calculate LBW are presented below [21, 22].  Body mass index 
(BMI) is calculated as the weight (in kg) divided by the height (in meters2). 
 
 
5.1.7  Rationale for LBW entry criteria 
 
Only participants with LBW 37.5-96 kg will be enrolled in the Pilot Clinical Trial.  The rationale to 
exclude people with LBW >96 kg is to limit the maximum number of pills to 6 per day for those 
in higher-dose assignments.  The reason to exclude people with LBW <37.5 kg is because there 
will be no separation in the number of pills between the higher-dose and the lower-dose groups 
for some weights <37.5 kg.  For example, a participant with LBW of 36 kg would take 2 pills per 
day (after rounding) whether assigned to the 0.5 or 0.8 mEq/kg-LBW/day dose levels.  It is 
unlikely that these LBW restrictions will limit recruitment appreciably, as 94% of participants in 
the Chronic Renal Insufficiency Cohort (CRIC) Study have LBW within these ranges.     
 
5.1.8  Rationale for the selected doses of sodium bicarbonate tested in this  
 
Pilot Clinical Trial 
 
The rationale to use the 0.5 mEq/kg-LBW/day dose of sodium bicarbonate is because of a 
previous positive experience in terms of efficacy and safety with this dose [13].  The rationale to 
use 0.8 mEq/kg-LBW/day as the higher dose of sodium bicarbonate is two-fold.  First is for 
safety, as this limits the extra sodium load to ≤1.65 grams.  Second, is to reduce pill burden, as 
this dose in this formulation limits the number of pills to six per day.  We are concerned that 
compliance will be poor if participants are required to take ≥7 pills per day.   
 
Table 2 presents the number of pills per day, daily bicarbonate dose delivered (mEq), actual 
dose received for the level of LBW (mEq/kg-LBW) per day, and the additional daily sodium load 
according to LBW. 
 
 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 19 
 
 
Table 2.  Number of pills, daily dose of bicarbonate, actual dose delivered per kg-LBW per day, 
and milligrams of sodium for representative LBW.  Shaded region shows the LBW ranges 
expected to be most frequently encountered in the Pilot Clinical Trial. 
 
  
# capsules/day 
HCO3- delivered  
(mEq/day) 
Actual Dose 
(mEq/kg-LBW/day) 
Na+ delivered 
(mg/day) 
DOSE 
0.5 
0.8 
0.5 
0.8 
0.5 
0.8 
0.5 
0.8 
LBW (kg) 
  
  
  
  
  
  
 
 
37.5 
2 
3 
24 
36 
0.64 
0.96 
550 
825 
38 
2 
3 
24 
36 
0.63 
0.95 
550 
825 
40 
2 
3 
24 
36 
0.60 
0.90 
550 
825 
42 
2 
3 
24 
36 
0.57 
0.86 
550 
825 
44 
2 
3 
24 
36 
0.55 
0.82 
550 
825 
46 
2 
3 
24 
36 
0.52 
0.78 
550 
825 
48 
2 
3 
24 
36 
0.50 
0.75 
550 
825 
50 
2 
3 
24 
36 
0.48 
0.72 
550 
825 
52 
2 
4 
24 
48 
0.46 
0.92 
550 
1100 
54 
2 
4 
24 
48 
0.44 
0.89 
550 
1100 
56 
2 
4 
24 
48 
0.43 
0.86 
550 
1100 
58 
2 
4 
24 
48 
0.41 
0.83 
550 
1100 
60 
3 
4 
36 
48 
0.60 
0.80 
825 
1100 
62 
3 
4 
36 
48 
0.58 
0.77 
825 
1100 
64 
3 
4 
36 
48 
0.56 
0.75 
825 
1100 
66 
3 
4 
36 
48 
0.55 
0.73 
825 
1100 
68 
3 
5 
36 
60 
0.53 
0.88 
825 
1375 
70 
3 
5 
36 
60 
0.51 
0.86 
825 
1375 
72 
3 
5 
36 
60 
0.50 
0.83 
825 
1375 
74 
3 
5 
36 
60 
0.49 
0.81 
825 
1375 
76 
3 
5 
36 
60 
0.47 
0.79 
825 
1375 
78 
3 
5 
36 
60 
0.46 
0.77 
825 
1375 
80 
3 
5 
36 
60 
0.45 
0.75 
825 
1375 
82 
3 
6 
36 
72 
0.44 
0.88 
825 
1650 
84 
4 
6 
48 
72 
0.57 
0.86 
1100 
1650 
86 
4 
6 
48 
72 
0.56 
0.84 
1100 
1650 
88 
4 
6 
48 
72 
0.55 
0.82 
1100 
1650 
90 
4 
6 
48 
72 
0.53 
0.80 
1100 
1650 
92 
4 
6 
48 
72 
0.52 
0.78 
1100 
1650 
94 
4 
6 
48 
72 
0.51 
0.77 
1100 
1650 
96 
4 
6 
48 
72 
0.50 
0.75 
1100 
1650 
 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 20 
 
5.2  Source of sodium bicarbonate and placebo 
 
Eminent Services Corporation will prepare the sodium bicarbonate and placebo capsules 
according to good manufacturing practice (GMP) standards. Each capsule of active treatment 
will contain one gram of sodium bicarbonate.  Matching placebo capsule will contain cornstarch.  
Fisher Clinical Services  will bottle the capsules, label the bottles with code numbers to maintain 
the study’s double blind, and ship the bottles to the participating clinical centers approximately 
quarterly. 
5.3  Initial distribution and resupply to participants 
 
Each participant's initial supply (provided just after randomization) and subsequent resupplies 
will be initiated by the site study coordinator.  The study coordinator will determine which bottles 
to give to a participant by running the online Bottle Number Assignment report.  It is anticipated 
that the coordinator will hand the appropriate bottles directly to the participant or accompany the 
participant to the local clinical center pharmacy, where the local pharmacist will hand the bottles 
to the participant. 
5.4  Maintaining blinding  
 
Clinical Center personnel will know whether a participant has been randomized to the higher or 
lower dose but will be blinded as to whether a participant has been randomized to active sodium 
bicarbonate or placebo.   
 
The encapsulator will prepare the sodium bicarbonate and the cornstarch placebo capsules in 
such a way that the placebo resembles the active drug (sodium bicarbonate) in appearance, 
taste, and smell.  It is recognized that participants receiving active sodium bicarbonate may 
experience bloating because bicarbonate produces carbon dioxide when exposed to 
hydrochloric acid in the stomach.   
 
It is also recognized that knowledge of urinary NH4+ results could unblind clinical center staff 
members, since NH4+ is expected to decrease with sodium bicarbonate and remain unchanged 
with placebo.  Thus, the Central Laboratory at Litholink will measure urinary NH4+ and transmit 
results to the DCC but these results will not be forwarded to the local clinical centers. 
 
While it is possible, we do not expect that serum bicarbonate levels will increase with active 
treatment based on results from previous studies [13, 20]. Serum bicarbonate levels may 
decrease in participants receiving placebo as a result of natural CKD progression.  Since serum 
bicarbonate is measured locally, investigators cannot easily be kept blinded to serum 
bicarbonate results.  Blinding data will be captured on the visit form at the end of treatment 
(Week 28) to allow for evaluation of the double blind. 
5.5  Unblinding 
 
Emergency unblinding is not expected to be necessary as knowledge of the treatment group 
would not affect clinical care.  The potential side effects of sodium bicarbonate, such as edema, 
hypertension, and hypokalemia are common in CKD and those taking diuretics and can be 
managed without unblinding the treatment assignment of the participant.  In the rare 
circumstance that the investigator feels that unblinding would be helpful or influence participant 
management, the investigator will formally request unblinding.  Unblinding will be reviewed and  
confirmed by the Event Review Committee. 
 


 
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6.  FOLLOW-UP  
 
6.1  Follow-up visit schedule 
 
The follow-up visit schedule is presented in Table 1.  In-person follow-up visits will occur at 4 
weeks (W4), 8 weeks (W8), 12 weeks (W12), 20 weeks (W20), 28 weeks (W28) and 32 weeks 
(W32) after randomization (W0).  Additional PRN follow-up visits will be held at the discretion of 
the site investigator.  A W16 and W24 follow-up telephone call (phone visit) will be made 
between the W12 and W20 and the W20 and W28 visits to reinforce compliance and assess for 
potential adverse events, including a review of recent home blood pressure measurements (if 
available), that would require a special follow-up visit.  Additional telephone calls will occur at 
the discretion of the site investigator and/or study personnel. 
 
6.2  Data elements collected during in-person visits 
 
Table 3.  Data collected during follow-up. 
 
Data Elements 
Visits Assessed 
 Review non-study medications 
 Targeted physical exam 
 Serum chemistry panel: Na+, K+, Cl-, HCO3-, 
BUN, Cr, Ca2+ 
 Adverse event assessment 
 Gastrointestinal symptoms questionnaire 
All follow-up visits 
 Pill count 
All visits except W32 
 Serum phosphorus and albumin 
 Random urinary albumin/creatinine 
 Venous blood gas (substudy) 
B0, W12, W28 
 24-hour urine collection 
 Collection of blood for biorepository 
B1, W12, W28 
 
6.3  Monitoring compliance with treatment 
 
Compliance will be reinforced monthly, either at the face-to-face visit or via telephone in 
between study visits.  Compliance at visits will be determined using pill counts.  We are aware 
of other methods of assessing pharmacoadherence and recognize the potential shortcoming of 
the pill-count technique, but decided that this is an optimal approach, taking into account several 
factors including costs.  The pharmacodynamics that we are proposing to assess in Specific 
Aim 2 reflects pharmacoadherence, but is also affected by other factors, such as 
gastrointestinal absorption of bicarbonate. 
 
Only those who demonstrate appropriate compliance during Baseline will be randomized.  After 
randomization, those who show poor compliance by pill counts (<80%) or by phone discussion 
will be queried about barriers to compliance.  Participants will be counseled about the 
importance of taking the assigned treatment and asked to think of ways they can improve 
compliance.  If the reason for non-compliance is abdominal discomfort, a proton-pump inhibitor 
may be recommended or prescribed to inhibit gastric acid production and consequent carbon 
dioxide gas-forming effects of bicarbonate.  Other strategies to improve compliance, such as 
filling pillboxes, will be discussed with the participant; study coordinators will assist participants 


 
BASE Protocol Version 1.2–December 12, 2016 
 
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in obtaining and filling pillboxes if this seems advisable.  Additional follow-up phone calls will be 
performed as needed to reinforce compliance. 
 
6.4  Participants who start dialysis, undergo kidney transplantation, or become pregnant 
 
Participants who start chronic dialysis during the study will be censored, given the complex 
nature of acid-base physiology in these patients.  Participants who receive a pre-emptive kidney 
transplant during the study will also be censored because many other confounding factors, such 
as transplant rejection, delayed graft function, and calcineurin inhibitor nephrotoxicity, will have 
major impact on kidney function and acid-base status.  Participants who become pregnant will 
also be censored. 
 
7  MEASUREMENT TECHNIQUES  
 
7.1  Serum chemistry panel 
 
Local clinical laboratories at each clinical site will measure serum chemistry panel (Na+, K+, Cl-, 
HCO3-, BUN, creatinine, glucose, Ca2+, albumin, phosphorus).  The local laboratory, instead of 
the Core Laboratory, will perform these measurements primarily because falsely low serum 
bicarbonate results commonly occur when the assay of serum samples is delayed [23].  Also, 
serum bicarbonate and potassium results must readily be available to the local investigators as 
these are important safety measurements.  
 
Serum creatinine will be used to estimate GFR.  eGFR will be calculated using the CKD-
Epidemiology (CKD-EPI) equation [24].   
 
7.2  24-hour urine collection & measurements 
 
Participants will be provided with instructions and supplies to perform the 24-hour urine 
collection (see Manual of Operating Procedures for details).  24-hour urine measurements will 
be performed by a Central Laboratory (Litholink) and include the following: 
 
Measurement 
Rationale 
NH4+  
Pharmacodynamics marker 
Na+, K+, Cl- 
Compare urinary anion gap with NH4+ measurement 
Phosphate 
Used with urine pH to estimate titratable acid excretion 
Creatinine 
To calculate creatinine clearance  
Urea 
Used with urine K+ to calculate net endogenous acid production 
(NEAP), and estimate protein intake [26] 
pH 
Used with urine phosphate to estimate titratable acid excretion.  Also 
to explore effect of the intervention on urine pH. 
 
7.3  Local laboratory tests using random urine samples 
 
Urine albumin and creatinine will be performed locally at each clinical center's laboratory using 
standard assays in that laboratory.  
 


 
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7.4  Physical examination measurements 
 
Height will be measured at baseline.  Weight will be measured at each visit using standard clinic 
equipment.  After 5 minutes of quiet rest, blood pressure will be measured three times, one 
minute apart.  The average of the second and third measurements will be used for data analysis 
and clinical decision-making. Pulse will be recorded from the third blood pressure measurement 
(or measured once after completing the blood pressure measurements).  Edema will be 
assessed by measuring ankle circumference 7 cm proximal to the medial malleolus bilaterally 
[27], and severe edema will be defined as a >10% increase in total ankle circumference from 
baseline. 
 
7.5  Pill Counts 
 
Study personnel or local research pharmacy personnel will perform pill counts.   
 
7.6  Gastrointestinal symptoms questionnaire 
 
Participants will be asked to complete a gastrointestional symptoms questionnaire at each 
follow-up visit to assess the tolerability of the intervention.   Briefly, participants will be asked to 
rate symptoms of nausea, bloating, and diarrhea on a scale of 1-5. 
 
7.7  Collection of biological samples (serum, plasma, urine) for the NIDDK biosample 
repository 
 
Serum, plasma, and random urine samples will be collected at B1, W12, and W28.  These will 
be sent in batches to the NIDDK Repository.  The details of the collection procedure are in the 
Manual of Operations.   
 
7.8  Pregnancy test 
 
Serum or urine pregnancy tests, if required, will be perform at the local clinical site using the 
laboratory's standard technique. 
 
7.9  Venous blood gas substudy 
 
Venous blood gas measurements will be obtained in a subset of study participants at B0, W12, 
and W28 to evaluate the effect of the two dose levels on acid-base status indicators.  The 
details of the collection and measurement processes are in the MOP.  Briefly, venous blood will 
be collected 2 minutes after release of the tourniquet.  Blood gas measurements will be 
obtained using the Abbott iSTAT handheld device with CG8+ cartridge, which measures pH, 
pO2, pCO2, total CO2, HCO3- (calculated), base excess, oxygen saturation, ionized calcium, 
sodium, potassium, glucose, hematocrit, and hemoglobin.  
 
8  ADVERSE EVENTS (AEs) 
 
8.1  Expected study-related AEs 
 
Sodium bicarbonate may cause bloating, belching and abdominal discomfort when it neutralizes 
gastric acid, resulting in the formation of carbon dioxide.  Sodium bicarbonate may also cause 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 24 
 
edema to develop or worsen, increase fluid weight, and increase blood pressure, although 
previous studies using sodium bicarbonate have not reported significant changes in edema, 
weight, or blood pressure (as discussed in Section 1.2.2 above).  Other studies suggest that the 
fluid retention that occurs with excess sodium is greater when it is accompanied by the chloride 
anion (i.e., table salt) rather than the bicarbonate anion [28-30].  If retained rather than excreted 
in the urine, sodium bicarbonate may cause metabolic alkalosis and hypokalemia.  These are 
anticipated AE that participants will be informed about and will be monitored during the course 
of this Pilot Clinical Trial. 
 
The following are considered "expected AE," although they may not occur. 
 
Serum bicarbonate >32 mEq/L 
 
Systolic blood pressure ≥170 mm Hg 
 
Diastolic blood pressure ≥110 mm Hg 
 
Serum potassium <3.0 mEq/L 
 
Increase in weight by ≥5 kg from baseline 
 
Severe edema 
 
Severe GI symptoms as documented on the GI symptoms questionnaire 
 
Serum bicarbonate ≤16 mEq/L (serum bicarbonate may fall as a result of natural CKD 
progression, particularly in the placebo group) 
8.2  How AEs will be reported 
 
AE that are based on laboratory measurements will be detected when results are sent to the 
DCC.  AE based on physical examination or symptoms will be transmitted to the DCC by filling 
out a web-based study form. 
 
8.3  Serious Adverse Event (SAEs), hospitalization, and death reporting 
 
The following SAEs will be reported in detail to the DCC, Data Safety Monitoring Board (DSMB) 
and the Event Review Committee.   
 
1. Death  
2. Life-threatening event 
3. Hospitalization  
4. Persistent or significant disability/incapacity 
5. Emergency room visit for: 
a) Edema, heart failure, or pulmonary edema 
b) Hypertension 
c) Low serum potassium level 
d) High serum potassium level 
e) High serum bicarbonate level 
f) Low serum bicarbonate level. 
 
8.4  Strategy for the management of adverse events, including reducing or terminating 
the assigned intervention 
8.4.1  Reducing and/or stopping the randomized intervention for safety reasons 
 
In general, the anticipated side effects of sodium bicarbonate can be medically managed by 
adjusting antihypertensive and/or diuretic agents, providing potassium replacement, and by 
dietary changes.  At every visit during the trial, blood pressure will be recorded and reviewed by 
the site investigator and adjustments to the antihypertensive and/or diuretic regimen will be 


 
BASE Protocol Version 1.2–December 12, 2016 
 
  Page 25 
 
made to target blood pressure <140/90 mm Hg, although participants will be randomized if 
blood pressure is < 150/100 mm Hg.  Similarly, serum potassium will be measured and 
reviewed with adjustments to target potassium to 3.5-5.5 mEq/L.   Excess fluid will be treated 
with diuretics at the discretion of the investigator.  These adjustments are designed to keep 
participants on the assigned intervention and randomized dose level, prevent the development 
of serious side effects, and minimize dose reduction and discontinuation of treatment as much 
as possible. 
 
If medical management is ineffective, doses of the assigned intervention will be reduced by 1/2 
followed by discontinuation of therapy if the side effect persists.   The strategy for dose 
reduction and discontinuation of the assigned intervention, if necessary, for anticipated 
problems are: 
 
1. Serum bicarbonate >32 mEq/L  
 
When the first serum bicarbonate >32 mEq/L is measured, the intervention dose will be 
reduced by 50% and diuretics will be adjusted as appropriate.  The participant will return 
for a visit at least one week later (preferably within two weeks).   
 
If serum bicarbonate is >32 mEq/L at the next visit despite these changes, the 
intervention will be stopped.  Participants will continue to have serum bicarbonate 
measured (preferably every week) until it is ≤30 mEq/L. 
 
Plasma ionized calcium will be checked if serum bicarbonate is >32 mEq/L at any visit.  
Management of low ionized calcium will be at the discretion of the site investigator. 
 
2. SBP ≥170 or DBP ≥110 mm Hg  
 
Potential reasons for elevated blood pressure will be explored with the participant, such 
as poor compliance or running out of anti-hypertensive medications.  Recent home blood 
pressure readings, if available, will also be considered in the management plan.  If 
potential explanations are identified, then appropriate action will be taken.  The 
participant will follow-up one week later (preferably within two weeks).   
 
If no identifiable cause of the elevated blood pressure is identified, the anti-hypertensive 
and/or diuretic therapy will be escalated.  The participant will return for a visit at least one 
week later (preferably within two weeks).   
 
If blood pressure at these levels is observed at the second visit, the anti-hypertensive 
and/or diuretic therapy will be escalated and the intervention dose will be reduced by 
50%.  The participant will return for a visit at least one week later (preferably within two 
weeks).   
 
If blood pressure at these levels is observed at the third visit, the intervention will be 
stopped and the anti-hypertensive and/or diuretic therapy will be escalated.  Participants 
will continue to have PRN visits (preferably every week) until blood pressure is <160/90 
mm Hg. 
 
3. Serum potassium <3.0 mEq/L  
 
When the first serum potassium <3.0 mEq/L is observed, the intervention dose will be 
reduced by 50%, diuretics will be adjusted as appropriate, and potassium replacement 
will be prescribed.  The participant will return for a visit at least one week later (preferably 
within two weeks).   
 
If serum potassium <3.0 mEq/L is observed at the next visit, the intervention will be 
discontinued, diuretics adjusted as appropriate, and potassium replacement will be 
prescribed.  Participants will continue to have potassium checked (preferably every week) 
until >3.5 mEq/L. 
 
 
 


 
BASE Protocol Version 1.2–December 12, 2016 
 
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4. Clinically severe fluid retention and weight gain 
 
If in the opinion of the investigator clinically severe fluid retention is observed and another 
cause of excess fluid retention cannot be readily identified, then the dose of the 
intervention will be reduced by 1/2 and diuretics will be adjusted.  If fluid retention 
remains severe, the assigned intervention will be discontinued.   
 
The BASE Trial Event Review Committee (ERC) will review the data for any participant who is 
told to stop blinded medications for safety reasons.  The ERC will confirm whether or not the 
participant met the protocol definition to stop blinded medications for safety reasons. 
 
8.4.2  Reducing and/or stopping the randomized intervention for other reasons 
 
1. Abdominal discomfort 
 
If abdominal upset such as bloating or excess burping is felt to be due to the intervention 
and affecting or potentially affecting compliance, a proton pump inhibitor may be 
prescribed to reduce gastric acid production.  If these symptoms persist, the dose of the 
intervention will be reduced by 1/2, followed by discontinuation of therapy if symptoms 
persist.   
2. The assigned intervention will be discontinued for these reasons as well, however these 
events will be considered censoring events. 
 
Initiation of chronic dialysis 
 
Kidney transplant 
 
Pregnancy 
 
8.5  Restarting the intervention and/or increasing reduced doses back to the full 
randomized dose 
 
The decision to increase the dose back to the randomized dose or to restart therapy will be at 
the discretion of the site investigator and will consider whether the reason(s) for reducing or 
stopping treatment have resolved as well as the participant's willingness to restart or escalate 
the assigned treatment.   
8.6  Rescue therapy with oral sodium bicarbonate 
 
1. Serum bicarbonate ≤ 16 mEq/L 
 
Although unlikely during this short Pilot Clinical Trial, serum bicarbonate may fall due to 
natural progression of CKD, particularly in the placebo group.  Rescue therapy with open-
label sodium bicarbonate will be initiated if serum bicarbonate is ≤16 mEq/L on two 
consecutive measurements at least one week apart.  In this circumstance, open-label 
sodium bicarbonate will be given to target serum bicarbonate of 20-22 meq/L.  
Participants will not discontinue study medications if open-label sodium bicarbonate is 
prescribed. 
 
2. Serum bicarbonate 17-19 mEq/L with refractory hyperkalemia 
 
Rescue therapy will also be instituted if serum bicarbonate is 17-19 mEq/L and serum 
potassium is ≥5.5 mEq/L and the hyperkalemia is unresponsive to other interventions 
(such as reducing ACE-I/ARB dose and dietary potassium restriction) or is present 
because of concomitant hyperglycemia.  In these circumstances, open-label sodium 
bicarbonate will be given to target serum bicarbonate of 20-22 meq/L.  Participants will 
not discontinue study medications if open-label sodium bicarbonate is prescribed. 
 


 
BASE Protocol Version 1.2–December 12, 2016 
 
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8.7  DSMB 
 
NIDDK has established an independent DSMB for this clinical trial.  The DSMB includes 
experienced nephrologists, biostatisticians, and other experts.   The DSMB is advisory to the 
NIDDK.  Initially, the DSMB will serve as a protocol review committee and review the design of 
the trial prior to implementation.   Upon initiation of the clinical trial, the DSMB will meet at least 
once annually, or more often as necessary, to review the progress of the trial including 
recruitment, data quality, participant safety, and final analyses of outcomes. A summary of the 
open discussions of the DSMB is sent to the Principal Investigators by the NIDDK Project 
Scientist.  The recommendation of the DSMB to continue the trial (or not) will be made available 
to each clinical center so this can be submitted to each IRB for annual renewal. 
 
9  ANALYSIS PLAN and POWER CALCULATIONS 
9.1 Baseline characteristics 
 
Participant characteristics will be summarized using standard descriptive statistics for all 
enrolled participants and, separately, by randomized group, for randomized participants. These 
summaries will be provided for the full cohort, and for subgroups defined by age, gender, and 
baseline eGFR. If substantial deviations of the distribution of urinary NH4+ or other continuous 
variables used as outcome variables are identified, consideration will be given to transforming 
these variables to better approximate normality prior to subsequent analyses.  
 
9.2  Analysis plan for Specific Aim 1 
9.2.1  Analysis of Co-Primary Endpoints 
 
The primary analysis of safety and tolerability will tabulate the proportions of the participants 
assigned to each of the three dose interventions (placebo, 0.5 mEq/kg-LBW/day, and 0.8 
mEq/kg-LBW/day) who: 
 
1.  Are prescribed the full randomized sodium bicarbonate dose according to the protocol at the 
end of the On-Treatment Phase of the Pilot Clinical Trial, and  
 
2.  Are prescribed at least 25% of the randomized dose according to the protocol at the end of 
the On-Treatment Phase of the Pilot Clinical Trial.  
 
The dose prescribed for each participant at the last On-Treatment visit (week 28) will be used to 
determine whether the participant completes the study on the full randomized prescription or at 
least 25% of the randomized prescription.  This will take into consideration any protocol 
mandated reductions that should have occurred at the last On-Treatment visit had the Pilot 
Clinical Trial continued.  We will not consider whether the prescription could have been 
restarted or if the dose could have been increased at the last On-Treatment visit, because it 
would be uncertain whether restarting or increasing the dose would have been safe or tolerated.  
 
Because participants who fail to complete the intervention period will be designated as failures 
for both of the co-primary endpoints, these endpoints will be defined for all randomized 
participants. The primary analysis (safety and tolerability) will be regarded as supporting a dose 
intervention for evaluation in a Phase 3 trial if: 
 
1.  At least 66.7% of participants in each intervention arm are prescribed the full randomized 
sodium bicarbonate dose according to the protocol at the last On-Treatment visit (W28), and 
 


 
BASE Protocol Version 1.2–December 12, 2016 
 
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2.  At least 80% of participants in each intervention arm are prescribed at least 25% of the 
randomized dose according to the protocol at the last On-Treatment visit (W28) 
 
In further analyses, exact 90% binomial confidence intervals will be constructed for the 
proportions of subjects reaching each of the co-primary endpoints in each of the three dose 
groups, and for differences between the proportions reaching each of the co-primary endpoints 
in the active dose groups vs. the placebo group. 
 
9.2.2  Secondary Analyses of Feasibility of the Dose Interventions 
 
Main Secondary Analyses. Exact 90% binomial confidence intervals will also be constructed for 
the proportions of individuals in each treatment group who: 
 
a. Reduce and/or discontinue treatment for safety reasons 
b. Reduce and/or discontinue treatment because of medication intolerance or pill burden 
c. Have ≥ 80% pill count compliance. 
 
These three endpoints will respectively address the safety, medication intolerance/pill burden, 
and compliance for each dose group during the 28-week intervention period. In contrast to the 
co-primary endpoints, each of these endpoints will be treated as missing if they cannot be 
ascertained due to loss-to-follow-up or missing data. Exact 90% binomial confidence intervals 
will also be constructed for the differences between the proportions of subjects reaching these 
endpoints in the active dose groups and the proportion who reach these endpoints in the 
placebo group.   
 
Additional Analyses of Pill Counts.  Pill counts will be expressed as a percent of the number of 
pills prescribed for a particular participant under the protocol and summarized by treatment 
group at each follow-up visit using box plots and histograms. 90% confidence bounds will be 
constructed for the average pill count as a percent of prescribed pills as well as for the 
proportion of participants whose counts meet a target of ≥80% compliance for each treatment 
group and each follow-up visit during the 28-week intervention period.  
 
Additional analyses of binary safety endpoints.  Frequencies and proportions of subjects 
developing each AE (as described in Section 8.1) and SAE (as described in Section 8.4) during 
the 28 week intervention period will be tabulated for each of the three treatment groups. For 
each AE or SAE category, these tabulations will be provided for the frequencies and proportions 
of subjects who are required to a) reduce the dose of the study drug, b) who are required to 
either temporarily or permanently discontinue the study drug, and c) who are required to 
permanently discontinue the study drug. Because the proportions of subjects developing side 
effects in this Pilot Clinical Trial are expected to be relatively low, the tabulations of side effect 
frequencies will be primarily descriptive. However, exact 90% confidence limits will be 
constructed for each proportion tabulated, and additional exact 90% confidence limits will be 
constructed for the differences in the proportions in the two active treatment groups and the 
placebo group.   
 
Additional safety analyses will be performed to compare the proportion of participants who: 
 
Increase the number of antihypertensive medications, including diuretics, by ≥ 2  
 
Have an increase in leg circumference by ≥ 5 cm in either leg 
 
Start a proton-pump inhibitor or H2 blocker. 
 
Assessment of continuous safety-related endpoints. Box plots will be constructed to display the 
distributions of systolic and diastolic blood pressure, serum potassium, serum bicarbonate, and 


 
BASE Protocol Version 1.2–December 12, 2016 
 
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participant weight by treatment group at baseline and each follow-up visit during the 28 week 
intervention period. Mixed-effect analyses will also be used to compare the mean systolic and 
diastolic blood pressure, serum potassium, serum bicarbonate, and participant weight between 
the 0.8, 0.5 mEq/kg-LBW/day and placebo groups at each of the follow-up visits while assuming 
equal mean levels for each randomized group at baseline to increase the statistical power of the 
treatment comparisons.  The covariance structure of the mixed models will be determined 
based on likelihood ratio tests comparing the fit of nested covariance models and by 
comparisons of the Bayes Information Criterion for non-nested models.  
9.2.3  Statistical Power for Aim 1 Analyses 
 
Primary Analysis of Achievement of Benchmarks.  Chance variation may lead to two types of 
errors in our application of the 66.7% and 80% benchmarks for the percent of participants in 
each group who complete the intervention period prescribed either the full dose or at least 25% 
of the full dose. First, chance variation may lead to a higher percent of subjects successfully 
completing an intervention in the study sample than the true percent in the study population, in 
which case we may falsely conclude that an intervention is suitable for evaluation in a Phase 3 
trial when it is not, representing a Type 1 error. Second, chance variation may lead to a lower 
percent of subjects attaining the benchmarks in the study sample than in the study population, 
in which case we may falsely conclude that an intervention is not suitable for evaluation in a 
Phase 3 trial when in fact it is suitable.  
 
Using exact binomial calculations, the Type 1 error for falsely concluding suitability based on the 
66.7% benchmark will be ≤0.035 for the higher dose group (with N = 88) and ≤0.085 for the 
lower dose group (with N = 52) if the true percent prescribed the full randomized dose is ≤57%. 
The statistical power for attaining the 66.7% benchmark will be at least 0.87 in the higher dose 
group and 0.82 in the lower dose group if the true percent prescribed the randomized dose is at 
least 72%.  For the 80% benchmark, the Type 1 error will be ≤0.018 for the higher dose group 
and ≤0.057 for the lower dose group if the true percent prescribed at least 25% of the 
randomized dose is ≤70%. The statistical power for attaining the 80% benchmark will be at least 
0.84 in the higher dose group and 0.80 in the lower dose group if the true percent prescribed at 
least 25% of the randomized dose is ≥84%.   
 
Precision of 90% Confidence Limits. The expected margin of error (expressed as ½ the width of 
a 90% exact confidence interval) for estimates of a proportion of participants meeting a binary 
endpoint in the high dose group will be 0.075 if the true proportion is 0.20 and 0.093 if the true 
proportion is 0.50 when the proportion can be evaluated in all 88 subjects. If the endpoint is 
missing in 15% of subjects, the corresponding margins of error are 0.083 if the true proportion is 
0.20 and 0.101 if the true proportion is 0.50.   
 
The margin of error for estimates of a proportion of participants meeting a binary endpoint in the 
placebo or lower dose groups will be 0.100 if the true proportion is 0.20 and 0.122 if the true 
proportion if 0.50 when the proportion can be evaluated in all 52 subjects. If the endpoint is 
missing in 15% of subjects, the corresponding margins of error are 0.109 if the true proportion is 
0.20 and 0.132 if the true proportion is 0.50.   
 
9.3  Analysis plan for Specific Aim 2 
 
Specific Aim 2: To determine the effect of the 0.5 and 0.8 mEq/kg-LBW/day sodium 
bicarbonate doses on renal NH4+ excretion, compared to placebo, as a pharmacodynamics 
assessment.   
 


 
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Renal NH3 production is central to the pathogenic mechanism of acid-induced kidney injury, and 
urinary NH4+ is a reflection of renal NH3 production [17].  To this end, urinary NH4+ will be used 
as the main pharmacodynamics outcome parameter of oral bicarbonate therapy in this Pilot 
Clinical Trial.  
 
The effect of the treatment intervention on urinary NH4+ excretion will be investigated from two 
perspectives.  The first perspective will characterize the distributions of NH4+ standardized by 
body weight in the respective treatment groups, as weight-standardized NH4+ is expected to 
best reflect the biological effect of the bicarbonate intervention on long-term clinical outcomes. 
These analyses will focus on the W28 measurements, which are more likely to reflect the 
participant’s long-term kidney exposure to NH4+ in the Phase 3 trial.  
 
The second perspective will investigate the pharmacodynamics response of NH4+ excretion to 
the administered dose of bicarbonate.  The pharmacodynamics analyses will evaluate the 
differences in the mean NH4+ measurements at the W12 and W28 follow-up assessments 
compared to the baseline assessment, without standardizing for weight as the 
pharmacodynamics dose-response is not expected to be modified by the participant’s weight.  
 
9.3.1  Distributions of weight-standardized urinary NH4+ excretion 
 
Comparison of mean weight standardized NH4+ excretion levels by treatment group. A linear 
mixed effects model with an unstructured covariance matrix and separate fixed effect indicator 
variables for each treatment group at each follow-up time will be used to compare mean weight-
standardized NH4+ excretion levels between the randomized treatment groups at weeks 12 and 
28, with primary emphasis being given to the week 28 comparisons as noted above. The mixed 
model will assume a common mean NH4+ excretion level for each treatment group at baseline to 
increase the statistical power of between group comparisons.    
 
Overlap of the distributions of urinary NH4+ excretion between the treatment groups at week 28. 
The full distributions of weight-standardized NH4+ will be summarized using box plots and 
histograms for each of the three randomized groups at week 28.  The amount of overlap in the 
weight-standardized NH4+ will be described by computing Mahalanobis distances between the 
mean values for each pair of treatments (e.g., 0.5 mEq/kg-LBW/day vs. placebo, 0.8 mEq/kg-
LBW/day vs. placebo, and 0.8 vs. 0.5 mEq/kg-LBW/day), and by reporting the proportion of 
pairs of participants in the respective treatment groups for whom the weight-standardized NH4+ 
measurements are lower for the participants in the higher of the two dose groups being 
compared. The same approach will be used to summarize the changes in weight-standardized 
NH4+ excretion from baseline to W28. 
 
9.3.2  Pharmacodynamics analyses of NH4+ excretion 
 
The main pharmacodynamics analyses will relate the changes in urinary NH4+ (without weight 
standardization) from the baseline NH4+ measurement to the W12 and W28 NH4+ 
measurements to the actual prescribed bicarbonate dose based on the number of pills assigned 
to the participant.  
 
Two sets of analyses will be performed.  The first set will relate the mean changes in 
unstandardized NH4+ from baseline to weeks 12 and 28 to the average dose (defined by 
multiplying 12 mEq/pill by the average number of pills administered) in each of the three dose 
groups (placebo, 0.5, and 0.8 mEq/kg-LBW per day) preceding each of the two follow-up 
assessments. As in the weight standardized analyses in Section 9.3.1, the adjusted mean 
changes in NH4+ will be obtained for each of the 3 dose groups at each assessment by using a 


 
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linear mixed model with unstructured covariance matrix and indicator variables for the three 
dose groups at each of the two follow-up measurements, with a common mean NH4+ level 
assumed for each randomized group at baseline. The adjusted mean changes in NH4+ will be 
plotted against the average bicarbonate dose (defined as 12 mEq/pill x the number of pills 
prescribed) to summarize the dose-response relationships at both the week 12 and week 28 
visits.  
 
The second set of analyses will relate the mean change in NH4+ to the actual prescribed dose of 
bicarbonate given by multiplying 12 mEq/pill by the actual number of bicarbonate pills 
prescribed to the participant.  Thus in this analysis there will be a total of 7 dose groups, 
corresponding to 0, 1, 2, 3, 4, 5, and 6 bicarbonate pills, where the number of pills is prescribed 
based on the participant's randomized dose group and the participant's LBW.  We will use a 
linear mixed model with indicator variables for number of pills at each of the week 12 and week 
28 visits to relate the change in NH4+ to the number of bicarbonate pills prescribed (as a 
categorical variable). In contrast to the mixed models used for direct comparisons of 
randomized groups, in this case different mean NH4+ levels will be assumed in the different dose 
groups at baseline since the dose groups are defined in part by the participant's weight rather 
than randomized assignment. We will test if the dose-response relationship of the mean change 
in NH4+ vs. dose deviates from linearity at each of the week 12 and week 28 visits by modifying 
the mixed effects model to compare the slope of the relationships between 2.1 and 6 pills to the 
slope between 0 and 2.1 pills using a 2-slope linear spline in the estimated mean NH4+ values 
with a knot at 25.2 mEq, corresponding to 2.1 pills.  Subsequently, a smooth nonparametric 
estimate of the dose-response curve will be estimated by fitting a cubic spline to relate the 
adjusted mean change in NH4+ to the number of pills administered. In subsequent analyses, the 
mixed models will be modified to relate the change in NH4+ to the average of the two follow-up 
assessments to the average of the two dose levels preceding the two assessments.  
 
In further secondary analyses, both approaches for evaluating the dose response relationship 
will be repeated after adjusting the dose levels downwards to account for any pills not 
consumed as indicated by pill counts. 
 
9.3.3  Power calculations for comparisons of change in NH4+ between dose groups 
 
Oster et al. report a pooled standard deviation of the percent change in NH4+ excretion over a 5 
day period of 21.8% in 20 subjects [31]. Because Oster et al. used averages of two 24-hour 
urine assessments at both the baseline and follow-up time points, and because the time interval 
of 5 days in that study is shorter than the 12 week or 28 week intervals planned for the BASE 
study, we consider possible standard deviations for percent change of 24% or 30%. Allowing for 
10% missing follow-up measurements, the Pilot Clinical Trial will provide 80% power with 2-
sided α=0.05 to detect a mean difference of 12.5% for the high dose vs. placebo and high dose 
vs. low dose comparisons, and of 14.0% for the low dose vs. placebo comparison if the 
standard deviation for the percent change is 24%. If a mean baseline NH4+ excretion of 30 
mEq/24 hr is assumed [32], these differences represent 3.75 and 4.20 mEq/24 hr, respectively. 
If the standard deviation of the per cent change is 30%, the minimum detectable effects are 
increased to 15.6% and 17.2%, respectively, corresponding to differences of 4.68 and 5.16 
mEq/24 hr, respectively.  
 
9.4  Analysis of the relationship between bicarbonate dose and serum bicarbonate level 
 
In a prior study, the 0.5 mEq/kg-LBW/day dose of sodium bicarbonate did not raise serum 
bicarbonate concentration [13].  While we expect that this will also be the case with this dose in 
the Pilot Clinical Trial, it is possible that serum bicarbonate may increase above baseline values 


 
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in the 0.8 mEq/kg-LBW/day sodium bicarbonate dose group.  It would, therefore, be important to 
monitor the serum bicarbonate levels in relationship to the oral dose, i.e., assessing the 
pharmacokinetics of oral bicarbonate.  Mixed-effect analyses will be used to compare the mean 
serum bicarbonate levels between the 0.8, 0.5 mEq/kg-LBW/day and placebo groups at the 
week 4, 8, 12, 20, 28 and 32 visits while controlling for the baseline serum bicarbonate values.  
Additional analyses using quantile regression will be used to compare the upper tails of the 
serum bicarbonate distributions between the treatment groups.  Since the ability of the kidney to 
eliminate bicarbonate may be affected by eGFR, we will examine the pharmacokinetics of the 
two oral bicarbonate doses according to eGFR levels (20-44 and 45-59 ml/min/1.73m2).  The 
interaction between eGFR and oral bicarbonate dose on pharmacokinetics will also be 
examined.  We do not anticipate that the degree of albuminuria would appreciably affect the 
renal excretion of bicarbonate, however, we may consider this interaction in additional 
exploratory analyses. 
 
9.5  Exploratory Analyses of Treatment Effects on albuminuria and eGFR 
 
Fixed acid presumably exerts its detrimental effects on the kidney tubules, instead of the 
glomerulus.  Urinary albumin excretion is, therefore, not expected to be substantially increased 
in acid-induced kidney damage, as in most types of interstitial-tubular diseases.  Nonetheless, 
glomerulo-tubular balance occurs, and the glomerulus often undergoes fibrosis over time even 
when the injury is initiated in the tubules.  We will compare the effect of lower-dose and higher-
dose sodium bicarbonate on urinary ACR and eGFR.  Importantly, these analyses will be 
interpreted as exploratory only, and will not be incorporated in the evaluation of the 
appropriateness of conducting a Phase 3 trial of oral bicarbonate intervention. The rationales for 
designating the analysis of eGFR also as exploratory are as follows.  Previous small 
randomized trials over 2-5 years in somewhat different CKD populations have already shown 
that oral bicarbonate therapy attenuates eGFR decline, as discussed above.  Because of its 
short duration and limited sample size, this Pilot Clinical Trial will have very limited statistical 
power to detect significant differences in eGFR changes between the arms. 
 
It is likely that urinary ACR will be positively skewed.   If this skewed distribution is confirmed, 
ACR will be log-transformed.  Mixed-effects models will be applied to relate the changes from 
baseline to W12 and W28 in log-transformed urinary ACR to indicator variables for the 
randomized treatments.  The mixed models will assume the same baseline mean in the study 
population for each treatment group (placebo, lower-dose, and higher-dose), so that the 
analysis will have the structure of an ANCOVA to increase power.  The primary treatment 
comparisons will contrast the low-dose and high-dose bicarbonate groups to placebo; the head-
to-head comparisons between the two bicarbonate groups will be a secondary analysis. A 
similar mixed-effect model will be used to compare the mean change in eGFR between the 
treatment groups, but in this case only the mean change in eGFR from baseline to 28 weeks, 
after controlling for baseline eGFR, will be evaluated. 
 
9.6  Other exploratory pharmacodynamics analyses 
 
Other exploratory analyses will be performed to provide further information on the 
pharmacodynamics of bicarbonate therapy.  These exploratory analyses are: 
 
 
Effect of oral bicarbonate therapy on renal acid excretion, calculated as NH4+ plus titratable 
acid (TA, calculated using urine pH and phosphate excretion) 
 
Correlation between NH4+ and urinary anion gap (UAG) and response of UAG to the dose 
interventions 


 
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 
Effect modification of dose on NH4+ by baseline level of net endogenous acid production 
(NEAP) 
 
Effect of oral bicarbonate therapy on NEAP 
 
9.7  Comparisons of the response of blood pressure, serum bicarbonate, serum 
potassium, and weight after discontinuing treatment 
 
The mixed effects models described in Section 9.2.2 for evaluating mean changes in systolic 
and diastolic blood pressure, serum bicarbonate, serum potassium, and weight will be extended 
to include the final study visit after discontinuation of treatment. Linear contrasts will be 
constructed to estimate the mean changes in each of these outcomes between the Off-
Treatment and the last On-Treatment visit, and to compare the Off-Treatment mean values to 
the baseline mean values within each treatment group. The indicated mean changes will also be 
compared between the two active treatment groups and the placebo group.  
 
9.8  How will this study be considered successful? 
 
The purpose of this Pilot Clinical Trial is to determine whether it is feasible to proceed with a 
Phase 3 trial that will test the effect of sodium bicarbonate on slowing CKD progression in 
people with advanced CKD and normal serum bicarbonate, and if so, what dose to deliver.  The 
primary analysis will be interpreted as suggesting that an intervention is suitable for evaluation 
in a Phase 3 trial if at least 80% complete the study prescribed at least 25% of the randomized 
dose and no less than 2/3 of participants in their respective arm are prescribed the full 
randomized dose at the end of the On-Treatment phase of the study.  The full assessment of 
the suitability of the lower and higher dose interventions will also consider the global results of 
this Pilot Clinical Trial, such as compliance, and other ongoing sodium bicarbonate trials.  
 
If both dose groups are successful, then comparisons of the reduction in urinary NH4+ excretion 
from baseline between the two dose levels will help determine which dose to employ in the 
Phase 3 trial.  If NH4+ excretion were significantly lower in the higher-dose group, this dose will 
be recommended for the Phase 3 trial.  If there is no substantial difference in urinary NH4+ 
excretion between the dose levels, the lower dose will be recommended in order to reduce 
excess pill burden and potential adverse events.   
 
 
10  PLANS FOR THE STUDY DESIGN OF THE PHASE 3 TRIAL 
 
The Phase 3 trial will be a well-powered, double-blinded, randomized, controlled trial with two 
parallel arms, testing the long-term safety and efficacy of oral sodium bicarbonate on kidney 
function against placebo.  The primary outcome will likely be the composite of a 50% decrease 
in eGFR and progression to ESRD.  The dose determined to be the most promising in terms of 
safety, compliance, and pharmacodynamics in this Pilot Clinical Trial will be used in the Phase 3 
trial.  
 
 
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12  Table of Abbreviations 
 
ACE-I 
Angiotensin converting enzyme inhibitor 
ACR 
Albumin to creatinine ratio (urinary) 
AE 
Adverse event 
ARB 
Angiotensin receptor blocker 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease - Epidemiology 
Cr 
Creatinine 
CRIC 
Chronic Renal Insufficiency Cohort 
DCC 
Data Coordinating Center 


 
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DSMB 
Data Safety Monitoring Board 
EDTA 
Ethylenediaminetatraacetic acid 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End stage renal disease 
ET-1 
endothelin-1 
GMP 
Good manufacturing practice 
HIPAA 
Health Insurance Portability and Accountability Act 
KIM-1 
Kidney injury marker-1 
LBW 
Lean body weight 
MDRD 
Modification of Diet in Renal Disease 
mEq 
milliequivalent 
NGAL 
neutrophil gelatinase-associated lipocalin 
NH3 
ammonia 
NH4+ 
ammonium 
NIDDK 
National Institute of Diabetes Digestive and Kidney Diseases 
RR 
Relative risk 
SAE 
Serious adverse event