Chronic Kidney Disease, Cognitive Dysfunction, Metabolic Acidosis
Conditions
Brief summary
This is a pilot, randomized, double-blinded, placebo-controlled, 12-month trial of 50 patients with CKD stage 3b-4 with metabolic acidosis to examine the effect of sodium bicarbonate therapy on cognitive and cerebrovascular function.
Interventions
DRUGSodium Bicarbonate Tablets
Participants will be given sodium bicarbonate at 0.5 mEq/kg-LBW/day for 12 months
DRUGPlacebo
Participants will be given placebo at 0.5 mEq/kg-LBW/day for 12 months
Sponsors
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age 50-75 years old * Serum bicarbonate 16-22 mEq/L on 2 separate measurements (at least 1 day apart) * CKD stage 3b or 4 at time of screening (eGFR 15-44 ml/min/1.73m2) * Blood pressure \<130/80 mm Hg prior to randomization * Use of angiotensin converting enzyme inhibitor or angiotensin receptor blocker * Stable anti-hypertensive regimen for at least one month prior to randomization * Montreal Cognitive Assessment Score \> 24 * No history of stroke * No history of dementia * No history of neurologic disease * Able to provide consent
Exclusion criteria
• Significant comorbid conditions that lead the investigator to conclude that life expectancy is less than 1 year * Use of chronic daily oral alkali within the last 3 months (including sodium bicarbonate, calcium carbonate or baking soda) * Uncontrolled hypertension * Serum potassium \< 3.3 or ≥ 5.5 mEq/L at screening * New York Heart Association Class 3 or 4 heart failure symptoms, known EF ≤30%, or hospital admission for heart failure within the past 3 months * Factors judged to limit adherence to interventions * Anticipated initiation of dialysis or kidney transplantation within 12 months * Current participation in another research study * Pregnancy or planning to become pregnant or currently breastfeeding * Chronic use of supplemental oxygen
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognitive Function Composite Score at 12 Months | Baseline and 12 months | Cognitive function will be determined using the NIH Toolbox-Cognition Battery computerized tests. The Cognitive function composite score is based on the average of the Fluid and Crystallized composites. It is derived by averaging the Fluid and Crystallized standard scores, then deriving standard scores based on this new distribution. Fully Corrected T-scores are adjusted for for age, gender, race/ethnicity, and educational attainment. The score compares the score of the participant to those in the NIH Toolbox nationally representative normative sampling. The T-score has a mean of 50 in the general population and a SD of 10. Scores higher than the mean indicate better performance. |
| Change in Fluid Cognition Composite Score at 12 Months | baseline and 12 months | NIH Toolbox will be used to assess fluid cognition composite score. This score includes all the tests that are measuring fluid ability: Flanker, Dimensional Change, Picture sequence memory, list sorting and pattern comparison. The composite score is derived by averaging the standard scores of each of the measures. Fully Corrected T-scores are adjusted for age, gender, race/ethnicity, and educational attainment. The score compares the score of the participant to those in the NIH Toolbox nationally representative normative sampling. A fully corrected T-score at or near 50 (population mean with standard deviation of 10) indicates ability that is average compared with others nationally and one below 40 suggests the possibility of cognitive impairment. N |
| Change in Crystallized Cognition Composite Score at 12 Months | baseline and 12 months | NIH Toolbox will be used to assess crystallized cognition composite score. This composite score includes the picture vocabulary and reading tests. The composite score is derived by averaging the standard scores of each of the measure, and then driving standard scores based on this new distribution. Fully Corrected T-scores are adjusted for age, gender, race/ethnicity, and educational attainment. The score compares the score of the participant to those in the NIH Toolbox nationally representative normative sampling. A fully corrected T-score at or near 50 (population mean with standard deviation of 10) indicates ability that is average compared with others nationally as the mean T-score is 50 nationally. A score higher than 50 indicates better crystallized cognition. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebrovascular Reactivity at 12 Months | Baseline and 12 months | Relative cerebrovascular reactivity was calculated as % change in mean blood flow velocity of the middle cerebral artery/(hypercapnia breath-by-breath end-tidal partial pressure of CO2 (ETCO2) minus resting ETCO2). |
| Percent Change in Mean Blood Flow Velocity of the Middle Cerebral Artery at 12 Months | Baseline and 12 months | Measured using Transcranial Doppler Ultrasonography in response to a vasodilatory hypercapnic challenge.The change in mean blood flow velocity of the middle cerebral artery (MVMCA) was computed as the difference between hypercapnic MVMCA and normocapnic MVMCA |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo medication will be used at a dose of 0.5 mEq/kg-lean body weight/day
Placebo: Participants will be given placebo at 0.5 mEq/kg-LBW/day for 12 months | 16 |
| Sodium Bicarbonate Sodium bicarbonate will be used at a dose of 0.5 mEq/kg-lean body weight/day.
Sodium Bicarbonate Tablets: Participants will be given sodium bicarbonate at 0.5 mEq/kg-LBW/day for 12 months | 18 |
| Total | 34 |
Baseline characteristics
| Characteristic | Total | Placebo | Sodium Bicarbonate |
|---|---|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 6.8 | 60.6 years STANDARD_DEVIATION 5.9 | 62.0 years STANDARD_DEVIATION 7.5 |
| Bicarbonate (mEq/L) | 22.7 mEq/L STANDARD_DEVIATION 2.3 | 21.8 mEq/L STANDARD_DEVIATION 1.9 | 23.0 mEq/L STANDARD_DEVIATION 1.5 |
| Diabetes | 22 Participants | 10 Participants | 12 Participants |
| GFR (ml/min/1.73m2) | 34.8 ml/min/1.73m2 STANDARD_DEVIATION 13.9 | 32.8 ml/min/1.73m2 STANDARD_DEVIATION 10.9 | 36.9 ml/min/1.73m2 STANDARD_DEVIATION 16.7 |
| Hypertension | 32 Participants | 16 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 16 Participants | 16 Participants |
| Region of Enrollment United States | 34 participants | 16 participants | 18 participants |
| Sex: Female, Male Female | 11 Participants | 6 Participants | 5 Participants |
| Sex: Female, Male Male | 23 Participants | 10 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 18 |
| other Total, other adverse events | 6 / 16 | 13 / 18 |
| serious Total, serious adverse events | 7 / 16 | 6 / 18 |
Outcome results
Primary
Change in Cognitive Function Composite Score at 12 Months
Cognitive function will be determined using the NIH Toolbox-Cognition Battery computerized tests. The Cognitive function composite score is based on the average of the Fluid and Crystallized composites. It is derived by averaging the Fluid and Crystallized standard scores, then deriving standard scores based on this new distribution. Fully Corrected T-scores are adjusted for for age, gender, race/ethnicity, and educational attainment. The score compares the score of the participant to those in the NIH Toolbox nationally representative normative sampling. The T-score has a mean of 50 in the general population and a SD of 10. Scores higher than the mean indicate better performance.
Time frame: Baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Cognitive Function Composite Score at 12 Months | Baseline | 52.3 T-score | Standard Deviation 8.8 |
| Placebo | Change in Cognitive Function Composite Score at 12 Months | 12 months | 53.5 T-score | Standard Deviation 8.5 |
| Sodium Bicarbonate | Change in Cognitive Function Composite Score at 12 Months | Baseline | 47.3 T-score | Standard Deviation 8.5 |
| Sodium Bicarbonate | Change in Cognitive Function Composite Score at 12 Months | 12 months | 49.3 T-score | Standard Deviation 11 |
Primary
Change in Crystallized Cognition Composite Score at 12 Months
NIH Toolbox will be used to assess crystallized cognition composite score. This composite score includes the picture vocabulary and reading tests. The composite score is derived by averaging the standard scores of each of the measure, and then driving standard scores based on this new distribution. Fully Corrected T-scores are adjusted for age, gender, race/ethnicity, and educational attainment. The score compares the score of the participant to those in the NIH Toolbox nationally representative normative sampling. A fully corrected T-score at or near 50 (population mean with standard deviation of 10) indicates ability that is average compared with others nationally as the mean T-score is 50 nationally. A score higher than 50 indicates better crystallized cognition.
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Crystallized Cognition Composite Score at 12 Months | Baseline | 52.8 T-score | Standard Deviation 8.3 |
| Placebo | Change in Crystallized Cognition Composite Score at 12 Months | 12 months | 53.5 T-score | Standard Deviation 7.6 |
| Sodium Bicarbonate | Change in Crystallized Cognition Composite Score at 12 Months | Baseline | 49.6 T-score | Standard Deviation 8 |
| Sodium Bicarbonate | Change in Crystallized Cognition Composite Score at 12 Months | 12 months | 50.6 T-score | Standard Deviation 9 |
Primary
Change in Fluid Cognition Composite Score at 12 Months
NIH Toolbox will be used to assess fluid cognition composite score. This score includes all the tests that are measuring fluid ability: Flanker, Dimensional Change, Picture sequence memory, list sorting and pattern comparison. The composite score is derived by averaging the standard scores of each of the measures. Fully Corrected T-scores are adjusted for age, gender, race/ethnicity, and educational attainment. The score compares the score of the participant to those in the NIH Toolbox nationally representative normative sampling. A fully corrected T-score at or near 50 (population mean with standard deviation of 10) indicates ability that is average compared with others nationally and one below 40 suggests the possibility of cognitive impairment. N
Time frame: baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Fluid Cognition Composite Score at 12 Months | Baseline | 52.1 T-score | Standard Deviation 10.8 |
| Placebo | Change in Fluid Cognition Composite Score at 12 Months | 12 months | 53.0 T-score | Standard Deviation 9.4 |
| Sodium Bicarbonate | Change in Fluid Cognition Composite Score at 12 Months | Baseline | 44.7 T-score | Standard Deviation 8.7 |
| Sodium Bicarbonate | Change in Fluid Cognition Composite Score at 12 Months | 12 months | 46.9 T-score | Standard Deviation 11.7 |
Secondary
Change in Cerebrovascular Reactivity at 12 Months
Relative cerebrovascular reactivity was calculated as % change in mean blood flow velocity of the middle cerebral artery/(hypercapnia breath-by-breath end-tidal partial pressure of CO2 (ETCO2) minus resting ETCO2).
Time frame: Baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Cerebrovascular Reactivity at 12 Months | Baseline | 2.5 percent change/mmHg | Standard Deviation 1.4 |
| Placebo | Change in Cerebrovascular Reactivity at 12 Months | 12 months | 2.7 percent change/mmHg | Standard Deviation 1.3 |
| Sodium Bicarbonate | Change in Cerebrovascular Reactivity at 12 Months | Baseline | 2.4 percent change/mmHg | Standard Deviation 1.2 |
| Sodium Bicarbonate | Change in Cerebrovascular Reactivity at 12 Months | 12 months | 2.5 percent change/mmHg | Standard Deviation 1.1 |
Secondary
Percent Change in Mean Blood Flow Velocity of the Middle Cerebral Artery at 12 Months
Measured using Transcranial Doppler Ultrasonography in response to a vasodilatory hypercapnic challenge.The change in mean blood flow velocity of the middle cerebral artery (MVMCA) was computed as the difference between hypercapnic MVMCA and normocapnic MVMCA
Time frame: Baseline and 12 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change in Mean Blood Flow Velocity of the Middle Cerebral Artery at 12 Months | Baseline | 26.2 percent change | Standard Deviation 17 |
| Placebo | Percent Change in Mean Blood Flow Velocity of the Middle Cerebral Artery at 12 Months | 12 months | 32.3 percent change | Standard Deviation 21.7 |
| Sodium Bicarbonate | Percent Change in Mean Blood Flow Velocity of the Middle Cerebral Artery at 12 Months | Baseline | 22.6 percent change | Standard Deviation 13.1 |
| Sodium Bicarbonate | Percent Change in Mean Blood Flow Velocity of the Middle Cerebral Artery at 12 Months | 12 months | 25.0 percent change | Standard Deviation 12.4 |