Metabolic Acidosis
Conditions
Keywords
blood bicarbonate, kidney disease
Brief summary
This is a multicenter, double-blind, placebo-controlled, parallel-design study. The study will enroll approximately 210 adult male and female subjects with stage 3 or 4 chronic kidney disease and metabolic acidosis. The study dosing (TRC101 or placebo) will continue for 12 weeks once daily. The maximum study duration is anticipated to be up to 16 weeks.
Interventions
DRUGTRC101
Oral suspension
DRUGPlacebo
Oral suspension
Sponsors
Tricida, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Blood bicarbonate level of 12 to 20 mEq/L. * Estimated glomerular filtration rate (eGFR) of 20 to 40 mL/min/1.73m2. * Stable kidney function defined as \<=20% variability in eGFR during screening period. Key
Exclusion criteria
* Any level of low blood bicarbonate during the screening period that in the opinion of the Investigator, requires emergency intervention or evaluation for an acute acidotic process. * Anuria, dialysis, acute kidney injury, or history of acute kidney insufficiency within 3 months prior to screening. * Heart failure with maximum New York Heart Association (NYHA) Class IV symptoms or that required hospitalization during the preceding 6 months. * Heart or kidney transplant. * Chronic obstructive pulmonary disease (COPD) that is treated with chronic oral steroids, that requires the subject to be on oxygen, or that required hospitalization within the previous 6 months. * Change in doses to alkali therapy in the 4 weeks prior to screening. * History or current diagnosis of diabetic gastroparesis, bowel obstruction, swallowing disorders, inflammatory bowel disease, major gastrointestinal surgery, frequent diarrhea or active gastric/duodenal ulcers. * Serum calcium \<= 8.0 mg/dL at screening. * Planned initiation of renal replacement therapy within 12 weeks following randomization. * Use of polymeric binder drugs within 14 days prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | Baseline to Week 12 | Composite endpoint of the percentage of subjects having a change from baseline in serum bicarbonate ≥ 4 mEq/L or having serum bicarbonate in the normal range (22 - 29 mEq/L) at the end of treatment (Week 12 Visit). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Treatment in Serum Bicarbonate | Baseline to Week 12 | Mean change from baseline to end of treatment (Week 12 Visit) in serum bicarbonate |
Countries
Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TRC101 Treatment Arm The first dose of blinded study drug (2 packets for a total of 6 g TRC101) was given at the study site on Day 1 in the morning with food. For the remainder of the Treatment Period, TRC101 was self-administered orally as an aqueous suspension, QD with lunch, for 12 weeks. Beginning at the Week 4 Visit, subjects could have had a blinded dose adjustment to 0, 3 or 9 g (0, 1 or 3 packets, respectively) of TRC101 QD in accordance with a protocol-specified titration algorithm. The last dose of study drug was to be taken the day before the Week 12 Visit, unless the subject was enrolled in the extension Study TRCA-301E. | 124 |
| Placebo Treatment Arm The first dose of blinded study drug (2 packets of placebo) was given at the study site on Day 1 in the morning with food. For the remainder of the Treatment Period, placebo was self-administered orally as an aqueous suspension, QD with lunch, for 12 weeks. Beginning at the Week 4 Visit, subjects could have had a blinded dose adjustment to 0, 1 or 3 packets of placebo QD in accordance with a protocol-specified titration algorithm. The last dose of study drug was to be taken the day before the Week 12 Visit, unless the subject was enrolled in the extension Study TRCA-301E. | 93 |
| Total | 217 |
Baseline characteristics
| Characteristic | TRC101 Treatment Arm | Placebo Treatment Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 65 Participants | 49 Participants | 114 Participants |
| Age, Categorical Between 18 and 65 years | 59 Participants | 44 Participants | 103 Participants |
| Age, Continuous | 62.9 years STANDARD_DEVIATION 12.64 | 63.3 years STANDARD_DEVIATION 12.08 | 63.1 years STANDARD_DEVIATION 12.38 |
| Baseline Bicarbonate | 17.27 mEq/L STANDARD_DEVIATION 1.429 | 17.30 mEq/L STANDARD_DEVIATION 1.504 | 17.28 mEq/L STANDARD_DEVIATION 1.458 |
| Baseline Estimated Glomerular Filtration Rate (eGFR) | 29.2 mL/min/1.73m^2 STANDARD_DEVIATION 6.29 | 27.8 mL/min/1.73m^2 STANDARD_DEVIATION 5.45 | 28.6 mL/min/1.73m^2 STANDARD_DEVIATION 5.97 |
| History of Congestive Heart Failure | 36 Participants | 31 Participants | 67 Participants |
| History of Diabetes Mellitus | 76 Participants | 65 Participants | 141 Participants |
| History of Hypertension | 120 Participants | 90 Participants | 210 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 | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 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 | 121 Participants | 89 Participants | 210 Participants |
| Sex: Female, Male Female | 50 Participants | 33 Participants | 83 Participants |
| Sex: Female, Male Male | 74 Participants | 60 Participants | 134 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 124 | 2 / 93 |
| other Total, other adverse events | 31 / 124 | 13 / 93 |
| serious Total, serious adverse events | 3 / 124 | 2 / 93 |
Outcome results
Primary
Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range
Composite endpoint of the percentage of subjects having a change from baseline in serum bicarbonate ≥ 4 mEq/L or having serum bicarbonate in the normal range (22 - 29 mEq/L) at the end of treatment (Week 12 Visit).
Time frame: Baseline to Week 12
Population: The Modified Intent-to-Treat (MITT) Analysis Set was defined as all randomized subjects who had both baseline and at least one postbaseline serum bicarbonate value measured using an i-STAT device. The MITT Analysis Set was used for evaluation of efficacy, based on planned treatment assignment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TRC101 Treatment Arm | Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | Subjects with change from baseline serum bicarbonate ≥ 4 mEq/L or serum bicarbonate in normal range | 59.2 percentage of participants |
| TRC101 Treatment Arm | Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | Subjects with change from baseline serum bicarbonate ≥ 4 mEq/L | 55.8 percentage of participants |
| TRC101 Treatment Arm | Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | Subjects with serum bicarbonate in normal range | 50.0 percentage of participants |
| Placebo Treatment Arm | Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | Subjects with change from baseline serum bicarbonate ≥ 4 mEq/L or serum bicarbonate in normal range | 22.5 percentage of participants |
| Placebo Treatment Arm | Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | Subjects with change from baseline serum bicarbonate ≥ 4 mEq/L | 21.3 percentage of participants |
| Placebo Treatment Arm | Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | Subjects with serum bicarbonate in normal range | 16.9 percentage of participants |
Comparison: % Subjects Who Met Endpoint (≥ 4 mEq/L Change from Baseline Serum Bicarbonate or Serum Bicarbonate in the Normal Range \[22 - 29 mEq/L\]): TRC101-Placebop-value: <0.000195% CI: [23.5, 48.9]Fisher Exact
Comparison: % Subjects with ≥ 4 mEq/L Change from Baseline in Serum Bicarbonate: TRC101-Placebop-value: <0.000195% CI: [21.2, 46.8]Fisher Exact
Comparison: % Subjects with Serum Bicarbonate in the Normal Range (22 - 29 mEq/L): TRC101-Placebop-value: <0.000195% CI: [19.7, 45.6]Fisher Exact
Secondary
Change From Baseline to End of Treatment in Serum Bicarbonate
Mean change from baseline to end of treatment (Week 12 Visit) in serum bicarbonate
Time frame: Baseline to Week 12
Population: The Modified Intent-to-Treat (MITT) Analysis Set was defined as all randomized subjects who had both baseline and at least one postbaseline serum bicarbonate value measured using an i-STAT device. The MITT Analysis Set was used for evaluation of efficacy, based on planned treatment assignment. For this outcome measure, the analysis was done using a mixed model.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TRC101 Treatment Arm | Change From Baseline to End of Treatment in Serum Bicarbonate | 4.42 mEq/L |
| Placebo Treatment Arm | Change From Baseline to End of Treatment in Serum Bicarbonate | 1.78 mEq/L |
Comparison: Least Squares (LS) Mean Change from Baseline: TRC101-Placebop-value: <0.000195% CI: [1.77, 3.5]Mixed-effect repeated measures model