Clinical trial NCT01574157
Conditions: Chronic Renal Insufficiency Diabetes Mellitus
Sponsor: VA Office of Research and Development
Start date: 2012-11-05; Completion date: 2018-05-01
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to see if treatment with sodium bicarbonate will lower urine levels of proteins that are indicators of kidney damage in people with diabetes who also have chronic kidney disease.

Detailed description:
Diabetic chronic kidney disease (CKD) is a common problem in Veterans and progresses to end-stage renal disease in many people. It is important to identify treatment strategies that will help prevent the progression of CKD to overt kidney failure. The purpose of this study is to see if sodium bicarbonate reduces urinary markers of kidney damage in Veterans with diabetic CKD and normal serum bicarbonate levels.

Arms: arm 1: Participants were prescribed 0.5 meq of sodium bicarbonate per 1 kilogram of lean body weight daily for six months arm 2: Participants were prescribed an identical number of placebo tablets had they been assigned to the intervention, and took this daily for six months.
Interventions: intervention 1: Sodium bicarbonate intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 0.5 meq of sodium bicarbonate per 1 kilogram of lean body weight daily. The total amount will be divided into twice daily doses. intervention 2: Participants will receive an identical number of placebo tablets had they been assigned to the intervention. Placebo will be divided into twice daily doses and receive this for six months.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Summary (ERICA) 
 
IRB_00055487 
Page 1 of 9 
 
IRB Approval 10/17/2018 
 
 
Investigations of the optimum serum bicarbonate level in 
renal disease (placebo) 
 
Protocol Summary 
 
 
 
IRB Approval 
Date of 
Current 
Version: 
3/22/2019 
University of 
Utah IRB #: 
IRB_00055487 
Sponsor: VA CLINICAL SCIENCE RESEARCH & DVLPMT 
  
Principal 
Investigator: 
Kalani Raphael 
Internal Staff 
and  Sub-
Investigators: 
Site Name 
Staff Names 
Veterans Affairs SLC Health Care 
System (VAMC) 
Kalani Raphael 
 
Hayden Bush 
 
Kunani Tuttle 
 
John Gardner 
 
Guo Wei 
 
 
 
This document was created using the ERICA Online System at the University of Utah. The document is created 
from study information approved by the IRB on the date listed above.  Any alteration to the original content of this 
document may not be considered to represent the study as approved by the IRB.  
 
 


Protocol Summary (ERICA) 
 
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Background and Introduction 
 
Chronic kidney disease (CKD) is a common complication of diabetes and can progress to end-
stage renal disease (ESRD) in many people.  Given the high mortality, morbidity, and costs 
associated with ESRD 1-3, it is important to identify treatment strategies that will slow CKD 
progression in people with diabetes. 
Treatment with a medication called sodium bicarbonate is a promising strategy to slow CKD 
progression.  Sodium bicarbonate is typically prescribed to people with CKD when the serum 
bicarbonate is low (<22 mmol/L) because of the adverse effects of metabolic acidosis on 
muscle and bone. 
However, a recent study in people with hypertensive CKD with normal serum bicarbonate 
levels also found that sodium bicarbonate treatment might slow CKD progression 4. It is 
unknown whether the administration of sodium bicarbonate to people with diabetic CKD with 
normal serum bicarbonate levels might protect long-term renal function. 
One means by which sodium bicarbonate might slow CKD progression is by reducing renal 
ammonia production, intrarenal activation of the complement cascade, and subsequent renal 
fibrosis 5.  Previous studies have shown that short-term administration of sodium bicarbonate 
lowers urinary excretion of the complement pathway activation products Bb and membrane 
attack complex (MAC) 6.  Also, the administration of a different alkalinizing agent, sodium 
citrate, was also found to reduce urinary excretion of transforming growth factor-β1 (TGF-β1) 
7, which is considered to be a marker of renal fibrosis in diabetic CKD. 
Furthermore, frailty is a common finding in CKD patients.  Limited data suggests that sodium 
bicarbonate may improve muscle mass, but it's effects on physical function has not been 
thoroughly investigated. 
This study will investigate whether sodium bicarbonate reduces intrarenal complement 
activation and fibrosis in people with diabetic CKD with normal serum bicarbonate levels, as 
well as explore whether it improves physical function.  Such findings would add insight into 
our understanding of the mechanisms that accelerate diabetic CKD progression as well as 
influence the design of future definitive trials of alkaline treatment to slow CKD progression 
and improve frailty in CKD patients. 
  
 
 
 
Purpose and Objectives 
 
The objective of this double-blind randomized placebo-controlled study is to investigate 
whether sodium bicarbonate treatment will reduce kidney damage in people with diabetic 
CKD who have normal serum bicarbonate levels. 


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Hypothesis. Chronic oral alkaline therapy in people with diabetic CKD and normal serum 
bicarbonate levels reduces renal fibrosis via the inhibition of intrarenal complement activation. 
Specific Aim:  To determine in a randomized placebo-controlled study of 74 people with 
diabetic CKD and normal serum bicarbonate levels, the effect of a 6-month oral sodium 
bicarbonate intervention on: 
1. Urinary excretion of TGF-β1, a mediator of renal fibrosis, as the primary outcome; and 
2. Urinary excretion of Bb (a product of alternative pathway of complement activation) 
and MAC (a product of common pathway of complement activation) as secondary 
outcomes. 
3. Physical function. 
 
 
 
Study Population 
 
Age of Participants: 18+ 
 
Sample Size: 
At Utah: 
74  
All Centers: 
74 
 
Inclusion Criteria: 
1. Age older than 18 years 
2. Type I and Type II diabetes mellitus 
3. Serum bicarbonate 22 - 28 mmol/L on the most recent measurement within the past 
six months 
4. Stage 2, 3, or 4 CKD  (defined as eGFR 15 - 89 ml/min/1.73m2 using the MDRD 
equation) 
5. Urinary albumin:creatinine ratio > 30 mg/gm or urinary protein:creatinine ratio > 
300 mg/gm on the most recent sample within the past 12 months. 
  
 
 
Exclusion Criteria: 
1. Lean body weight > 100 kg 
2. Use of oral medications typically prescribed to raise serum low serum bicarbonate 
levels (i.e. sodium bicarbonate, sodium citrate, potassium citrate). 
3. Serum potassium < 3.5 meq/L at enrollment visit 
4. Use of 5 or more antihypertensive agents, regardless of the indications of each agent 
5. Systolic blood pressure  > 140 mmHg or diastolic blood pressure > 90 mmHg at the 
enrollment or baseline visit 
6. Diagnosis of congestive heart failure with current, active Class III or IV New York Heart 
Association  symptoms. 


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7. Significant fluid overload such that it is unsafe in the opinion of the PI for the patient 
to participate in the trial 
8. chronic gastrointestinal disorder or any other factors judged to be likely to limit 
adherence to interventions (i.e. alcoholism, a history of missing clinic visits) 
9. Chronic immunosuppressive therapy for transplanted organs or other indications 
10. Individuals who are currently a member of a vulnerable population (I.e. incarcerated, 
pregnant). 
11. Currently participating in another interventional research study 
 
 
 
Design  
 
Prospective Clinical Research 
Double Blind 
Placebo Controlled 
Randomized 
 
 
 
 
 
Study Procedures 
 
Recruitment/Participant Identification Process: 
Participants will be recruited from clinics at the VA Salt Lake City Healthcare System.  The 
study coordinator and/or PI will screen the medical records of patients with an upcoming 
clinic appointment.  Those who preliminarily meet entry criteria will be approached during the 
clinic visit and informed of the nature and purpose of the study.  If the patient meets 
enrollment criteria and agrees to participate in the study, after written informed consent, they 
will be scheduled for the baseline visit and given supplies and instructions to collect the 
baseline 24-hour urine collection.  
If a member of the study team is unable to speak with a patient during their clinic visit, a letter 
of invitation  will be mailed to the patient and followed up with a phone call. 
The study team will also utilize the VINCI serivces. This program will provide a list of 
potential participants that meet our inclusion/exclusion criteria. Once the study team has the 
list of patients the study coordinator will approach them at their next clinic appointment or 
send an opt-out letter.  
Also see the attached VINCI document located in the "other"document section.  
  
 
 
Informed Consent: 
Description of location(s) where consent will be obtained:  


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Consent will be obtained in private outpatient clinic rooms at the Salt Lake City VA. 
 
Description of the consent process(es), including the timing of consent:  
Consent will be obtained at the time of the clinic visit. If a patient asks for additional time to 
consider participation, then consent will be obtained at a mutually convenient time for the 
participant and study team.  
 
Requested Waivers/Alterations of Consent: 
Waiver of Informed 
Consent 
VA Waiver of Consent for Recruitment Purposes Only 
 
Procedures: 
Enrollment: Consented participants who meet entry criteria will be provided with urine 
collection supplies and instructions on how to collect a 24-hour urine sample and scheduled 
for the baseline visit.  
Baseline/Randomization Visit: Participants will be seen at the VHASLC Dialysis 
Clinic.  Participants will bring in the 24-hour urine collection to the baseline visit.  A medical 
questionnaire will be reviewed with participants and a medication history will be 
obtained.  Height, weight, blood pressure, and heart rate will be measured.  Lower extremities 
will be assessed for edema.  Ten mL of blood will be collected in serum separator tubes and 5 
mL of blood will be collected in an EDTA tube.  Participants will also provide another urine 
sample at the time of the visit.  Participants will be randomized during this visit and be 
provided with the assigned intervention and instructions on how to take the 
intervention.  Participants will be counseled regarding possible side effects of the active 
drug.  A low sodium diet brochure will be provided for participants. Urine collection supplies 
and instructions on how to collect a 24-hour urine sample will be provided.  The study 
coordinator will  lead the participant through the physical activity assessment tests and 
administer the physical activity questionnaire. Participants will be scheduled for their 3-month 
visit. 
Intervention: Participants will be randomly assigned to either the active (sodium bicarbonate) 
or placebo arm of the study.  The number of tablets is determined by the participant's weight 
and height and will not change during the study.  The maximum number of tablets a 
participant might take each day would be 6.  Participants will split the total number of tablets 
such that half the daily dose is taking twice each day.  For an odd number of tablets, the larger 
number of tablets will be taken in the morning.   Participants will be encouraged to monitor 
blood pressure at home and to contact the study team if there are any questions about the blood 
pressure measurements. 
3-month visit: Participants will be seen at the SLCVHA Dialysis Clinic.  Participants will 
bring in the 24-hour urine collection and their assigned medication.  A medical questionnaire 
will be reviewed and a medication history will be obtained.  Participants will be asked about 
any perceived side effects of the intervention. Height, weight, blood pressure, and heart rate 
will be measured.  Lower extremities will be assessed for edema.  Ten mL of blood will be 
collected in serum separator tubes.  Participants will also provide another urine sample. Pill 
counts will be performed to assess for compliance.  Participants will again be counseled 
regarding possible side effects of the active drug.  A low sodium diet brochure will again be 


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provided for participants. Urine collection supplies and instructions on how to collect a 24-
hour urine sample will be provided.  The study coordinator will  lead the participant through 
the physical activity assessment tests and administer the physical activity 
questionnaire.  Participants will be scheduled for their 6-month visit.  The assigned 
intervention will be dispensed by the Investigational Pharmacy.  
6-month visit: Participants will be seen at the SLCVHA Dialysis Clinic.  Participants will 
bring in the 24-hour urine collection and their assigned medication.  A medical questionnaire 
will be reviewed  and a medication history will be obtained.  Participants will be asked about 
any perceived side effects of the intervention. Height, weight, blood pressure, and heart rate 
will be measured.  Lower extremities will be assessed for edema.  Ten mL of blood will be 
collected in serum separator tubes.  Participants will also provide another urine sample. The 
study coordinator will  lead the participant through the physical activity assessment tests and 
administer the physical activity questionnaire.  Pill counts will be performed to assess for 
compliance. This is the final visit. 
Medical management during the study. Participants will be provided with handouts regarding 
a low-sodium diet to help prevent weight gain and increases in blood pressure.  They will also 
be asked to contact the study team if worsening edema is noted or if there are concerns about 
home blood pressure readings.  All general medical care, including the management of blood 
pressure, will be coordinated with the primary physicians.  In order to avoid a potential effect 
of blood pressure changes on the outcomes, blood pressure will be kept as constant as possible 
during follow-up.  Therefore, blood pressure will be targeted to keep it < 140/90 mm Hg. 
Changes to antihypertensive agents and diuretics will be at the discretion of the 
investigator.  Weight will be monitored at follow-up visits. If weight gain is > 5 pounds and is 
clinically felt to be due to fluid retention, a diuretic will be added or the dose adjusted. 
Because the administration of sodium bicarbonate sometimes causes hypokalemia, serum 
potassium will be monitored and maintained ≥ 3.5 meq/L in all study participants.  If 
hypokalemia requires intervention, additional measurements of serum potassium will be 
obtained at the discretion of the research team. Serum bicarbonate levels will be monitored 
during follow-up visits. If the serum bicarbonate is > 32 mmol/L, the medication will be 
held.  Additional measurements of serum bicarbonate will be per the discretion of the research 
team with reinstitution of study drug when serum bicarbonate returns into the enrollment 
range.  If abdominal discomfort occurs, addition of a proton-pump inhibitor may be 
recommended to alleviate discomfort allowing the participant to continue taking study 
medication.  Any changes in medications and the rationale for the changes will be recorded for 
safety monitoring and for comparison between the two randomized groups.  Since one follow-
up visit will occur between the baseline and the closeout visits, it is not expected that many 
changes in medications will occur during the course of the study.  Thus, patient medications 
and characteristics (such as blood pressure) are anticipated to remain relatively stable during 
this short study. 
Venous blood gas  
Venous blood gas measurements will be obtained in participants at all three study visits to evaluate the effect of sodium bicarbonate 
on acid-base status indicators.  All active and new participants at Salt Lake City VA will be included.  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, 


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total CO2, HCO3- (calculated), base excess, oxygen saturation, ionized calcium, sodium, potassium, glucose, hematocrit, and 
hemoglobin.  
  
Participants will be called by the study team at months 1, 2, 4, and 5 to monitor safety (AEs, 
SAEs), compliance, and medication changes. 
Treatment Endpoints: Since the primary and secondary outcomes are biomarkers, rather than 
hard clinical end-points, we do not anticipate having to stop the study based on the biomarker 
results.  Temporary cessation of therapy will occur if SBP is > 180 mmHg or DBP is > 120 
mmHg.  If SBP is > 180 mmHg or DBP is > 120 mmHg, the study medication will be held in 
addition to adjusting anti-hypertensive medications.  Reinstitution of the assigned intervention 
will be determined at twice-monthly intervals and restarted only if blood pressure returns to 
the enrollment range.  If the serum bicarbonate level is > 32 mmol/L at the 3-month follow-up 
visit, the medication will be held.  Follow-up serum bicarbonate values will be measured at the 
discretion of the study team and drug reinstituted when the serum bicarbonate falls back into 
the enrollment range. 
 
 
Procedures performed for research purposes only:  
 
 
 
Statistical Methods, Data Analysis and Interpretation 
 
I.  Sample size. The primary outcome in this study is the change in log-transformed urinary 
TGF-β1.  Sample size calculations are based on prior data (7) in which sodium citrate (another 
oral alkaline treatment) reduced urinary TGF-β1 by 16.3 ng/g Cr, or 17.3%, from the mean 
baseline level of 94.0 (SD 28.7) ng/g Cr. We were not able to find data from the literature on 
the standard deviation of changes over time in log-transformed TGF-β1. However, Song et al 
reported a pooled standard deviation of 24.7% in the percent change in urinary TGF-β1 over 
16 weeks in 21 subjects, allowing us to apply a first-order approximation to estimate the 
required sample size based on the approximate relationships between standard deviations of 
percent change and standard deviations of the log-transformed values (12). If the average 
correlation among the percent changes in the urinary TGF-β1 levels from baseline to the two 
follow-up assessments does not exceed 0.90, the estimated standard deviation of the average 
percent change over the two assessments would not exceed 24.1%. Under these assumptions, 
32 patients with complete follow-up in each treatment group will provide 81% power at a 2-
sided α = 0.05 in the primary analysis to detect a 17.3% difference in the average percent 
change between the treatment groups. In order to allow for loss to follow-up, we have 
designated a sample size of 37 enrolled patients in each group, allowing for a loss to follow-up 
of up to 13.5%. Thirty-two patients with complete data in each group will also provide 79% 
power to detect treatment effects in secondary analyses of the change in urinary TGF-β1 of 
17.3% to each individual follow-up visit, although the primary analysis will compare the mean 
values across both the 3-month and 6-month assessments between the treatment groups.  


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Power calculations for the secondary outcomes of urinary Bb/Cr and urinary MAC/Cr are 
based on data from Morita et al in which the coefficients of variation (CVs) for 17 proteinuric 
diabetic CKD patients were 0.794 for Bb/Cr and 0.705 for MAC/Cr (6). After adjustment for 
the baseline levels, 32 patients per group will provide ≥ 80% power at a 2-sided α = 0.05 to 
detect 33% and 30% greater reductions in the geometric means over the two follow-up visits 
of Bb/Cr and MAC/Cr, respectively, for the sodium bicarbonate vs. placebo groups assuming 
approximately lognormal data and equal Pearson correlations among the baseline and follow-
up measurements of 0.50 or greater. 
  
II. STATISTICAL METHODS 
The statistical methods will address the hypothesis that compared to placebo, the sodium 
bicarbonate intervention reduces urinary TGF-β1 (as the primary outcome) and urinary Bb and 
MAC (each as secondary outcomes). 
A. Descriptive analyses: Descriptive summaries will be presented according to the 
randomized group. Between groups comparisons will be done using t-test or Fisherʻs exact test 
as appropriate.  Standard descriptive summaries, such as box plots, will be performed on the 
baseline and follow-up levels of each outcome in the study. Outcomes exhibiting substantial 
skewness may be transformed prior to subsequent statistical analyses to better approximate 
normality. 
B. Analytic strategy for primary and secondary outcomes: The primary treatment 
comparison will be performed using a mixed effects model to relate the change in log-
transformed TGF-β1 from baseline to 3 and 6 months to the randomized treatment groups 
while controlling for the baseline value of TGF-β1. This analysis will have the structure of an 
analysis of covariance (ANCOVA) in which the effect of the sodium bicarbonate intervention 
on TGF-β1 will be estimated after controlling for the baseline TGF-β1 value in order to 
increase statistical power. The primary analysis will estimate the average of the treatment 
effects across the 3-month and 6-month assessments.  We have selected the average of the 
treatment effects at months 3 and 6 as the contrast for our primary analysis because this 
contrast maximizes statistical power among all possible linear contrasts under our hypothesis 
that the treatment effect will occur by 3 months and persist to 6 months.    Further secondary 
contrasts will be constructed to compare the change in TGF-β1 between months 3 and 6 
between the treatment groups to evaluate the persistence in any treatment effects after 3 
months, and to estimate the treatment effect at both individual follow-up assessments. In the 
event of a linear pattern of change in log-transformed TGF-β1 over the follow-up period, an 
additional secondary contrast will be constructed to compare slopes from baseline to 6 
months.  An unstructured covariance matrix (13) will be used to account for correlations in the 
baseline and two follow-up outcome measurements within the same participants. The same 
analytic approach will be used to estimate effects of the secondary outcomes of log-
transformed urinary Bb/Cr and log-transformed urinary MAC/Cr. Secondary analyses will be 
performed on a comparison-wise basis without formal adjustment for multiple comparisons. 


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C. Sensitivity analyses to address missing data: Under the intent-to-treat analysis plan, all 
efforts will be made to continue to obtain planned follow-up measurements for any patients 
who cease taking study medications. Although it is highly unlikely that a participant with stage 
3 CKD will develop ESRD requiring dialysis or transplantation during the 6-month follow-up 
period, if this occurs, the participant will be censored at that time because of the complex 
nature of acid-base balance with dialysis or immunosuppressive therapy. The mixed-effect 
model results of the primary analysis will remain valid in the presence of missing data if data 
are missing at random, i.e., if values of missing responses are independent of the missing data 
mechanism after taking into account non-missing measurements. Informative-censoring 
models or multiple-imputation procedures may be used to further address the sensitivity of the 
results to missing data (14, 15). In the event that sensitivity analyses indicate that the 
conclusions are heavily influenced by the missing observations, the pre-specified mixed effects 
analyses will be retained for the primary presentation of results, but the results of sensitivity 
analyses will also be presented, and the conclusions will be appropriately tempered in the 
discussion section of the manuscript. 
D. Other analytic issues: Intent-to-treat strategy where all patients are analyzed according to 
their randomized assignment, regardless of whether they continue to take the study medication 
will be the primary methodology used to examine the effects of sodium bicarbonate.  Percent 
pill count compliance will be summarized to characterize adherence to the intervention.