Metabolic Acidosis
Conditions
Keywords
blood bicarbonate, kidney disease
Brief summary
This study is a 40-week, blinded, placebo-controlled extension of Study TRCA-301 (NCT03317444). Eligible subjects who complete the 12-week treatment period in Study TRCA-301 have the option to participate in this extension study evaluating the long-term safety and durability of effect of TRC101 in subjects with non-dialysis dependent chronic kidney disease and metabolic acidosis. Eligible subjects will be treated with TRC101 or placebo once daily (QD) on an out-patient basis for the subsequent 40 weeks. Subjects will continue to receive the same blinded treatment (TRC101 or placebo) that they received in Study TRCA-301.
Interventions
DRUGTRC101
Oral suspension
DRUGPlacebo
Oral suspension
Sponsors
Tricida, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Completed the 12-week treatment period and attended the Week 12 Visit in the parent study TRCA-301. * Blood bicarbonate level of \>= 12 mEq/L at the Week 12 Visit in the parent study TRCA-301. Key
Exclusion criteria
* Any level of low blood bicarbonate at the Week 12 Visit that, in the opinion of the Investigator, requires emergency intervention or evaluation for an acute acidotic process. * Required dialysis for acute kidney injury or worsening CKD during the parent study TRCA-301. * Planned initiation of renal replacement therapy within 6 months following study entry. * History or current diagnosis of diabetic gastroparesis, bowel obstruction, swallowing disorders, severe gastrointestinal disorders, inflammatory bowel disease, major gastrointestinal surgery, or active gastric/duodenal ulcers. * Serum calcium \<= 8.0 mg/dL at the Week 10 in the parent study TRCA-301.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events, Serious Adverse Events, and Adverse Events Leading to Withdrawal. | Week 12 Visit in the parent study, TRCA-301, to the Week 54 Visit in the extension study, TRCA-301E. | The incidence of adverse events (AEs), serious adverse events (SAEs) and AEs leading to withdrawal. For incidence of AEs and SAEs, see Adverse Events Section. For incidence of AEs leading to withdrawal, see endpoint values below. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E. | Percent of subjects having a change from baseline in serum bicarbonate of at least 4 mEq/L or bicarbonate in the normal range (22 - 29 mEq/L) at the end of treatment (Week 52). |
| Change From Baseline in Serum Bicarbonate at the End of Treatment | Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E. | Change from baseline in serum bicarbonate at the end of treatment (Week 52). |
| Change From Baseline in the Total Score of the KDQOL-PFD at the End of Treatment | Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E. | Change from baseline in the total score of the Kidney Disease Quality of Life Physical Function Domain (KDQOL-PFD) at the end of treatment. The KDQOL is a validated, kidney disease-specific measure of health-related quality of life. For study TRCA-301E, and the parent study TRCA-301, the 10-question Item 3 of the KDQOL, also known as the SF-36 Physical Function subscale, was selected to measure physical functioning and is referenced herein as the KDQOL-PFD. The KDQOL-PFD was chosen as a patient-reported outcome measurement to evaluate the effects of TRC101 on daily activities that may be adversely affected by loss of muscle caused by metabolic acidosis. The minimum score for each of the 10 questions is 0 (physical activity highly limited) and the maximum is 100 (physical activity not limited). The total KDQOL-PFD score is calculated by adding the scores for all 10 questions, for a minimum and maximum possible total KDQOL-PFD score of 0 or 100, respectively. |
| Change From Baseline in the Duration of Repeated Chair Stand Test at the End of Treatment | Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E. | Change from baseline in the duration of repeated chair stand test at the end of treatment (Week 52). The five-times repeated chair stand test was used as a measure of lower extremity muscle strength. In this test, the time it took for a subject to repeatedly stand from a chair five times was recorded. This test is among the group of measures (gait speed, chair stand, and balance tests) comprising the Short Physical Performance Battery (SPPB), which has been used as a predictive tool for possible disability and for monitoring physical functioning in older people. |
Countries
Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TRC101 Treatment Arm TRC101 was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded TRC101 dose they were receiving in the parent study, TRCA-301, as follows: 0, 3, 6 or 9 g TRC101 QD (0, 1, 2 or 3 packets, respectively). Subjects could have had a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm at each study visit. | 114 |
| Placebo Treatment Arm Placebo was self-administered orally as an aqueous suspension, QD with food, at approximately the same time each day for 40 weeks. Subjects entered the study on the same blinded placebo dose they were receiving in the parent study, TRCA-301, as follows: 0, 1, 2 or 3 placebo packets QD. Subjects could have had a blinded dose adjustment using these same doses in accordance with a protocol-specified titration algorithm at each study visit. | 82 |
| Total | 196 |
Baseline characteristics
| Characteristic | TRC101 Treatment Arm | Placebo Treatment Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 58 Participants | 38 Participants | 96 Participants |
| Age, Categorical Between 18 and 65 years | 56 Participants | 44 Participants | 100 Participants |
| Age, Continuous | 62.9 years STANDARD_DEVIATION 12.07 | 61.7 years STANDARD_DEVIATION 11.88 | 62.4 years STANDARD_DEVIATION 11.98 |
| Baseline Bicarbonate | 17.21 mEq/L STANDARD_DEVIATION 1.429 | 17.13 mEq/L STANDARD_DEVIATION 1.501 | 17.17 mEq/L STANDARD_DEVIATION 1.457 |
| Baseline eGFR | 29.4 mL/min/1.73m^2 STANDARD_DEVIATION 6.41 | 27.9 mL/min/1.73m^2 STANDARD_DEVIATION 5.42 | 28.8 mL/min/1.73m^2 STANDARD_DEVIATION 6.05 |
| History of Congestive Heart Failure | 34 Participants | 28 Participants | 62 Participants |
| History of Diabetes Mellitus | 70 Participants | 57 Participants | 127 Participants |
| History of Hypertension | 110 Participants | 79 Participants | 189 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 | 1 Participants | 3 Participants | 4 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 | 113 Participants | 79 Participants | 192 Participants |
| Sex: Female, Male Female | 46 Participants | 31 Participants | 77 Participants |
| Sex: Female, Male Male | 68 Participants | 51 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 112 | 2 / 81 |
| other Total, other adverse events | 78 / 112 | 39 / 81 |
| serious Total, serious adverse events | 2 / 112 | 4 / 81 |
Outcome results
Primary
Incidence of Adverse Events, Serious Adverse Events, and Adverse Events Leading to Withdrawal.
The incidence of adverse events (AEs), serious adverse events (SAEs) and AEs leading to withdrawal. For incidence of AEs and SAEs, see Adverse Events Section. For incidence of AEs leading to withdrawal, see endpoint values below.
Time frame: Week 12 Visit in the parent study, TRCA-301, to the Week 54 Visit in the extension study, TRCA-301E.
Population: The TRCA-301E Safety Analysis Set included all subjects who received any amount of study drug (TRC101 or placebo) in Study TRCA-301E.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TRC101 Treatment Arm | Incidence of Adverse Events, Serious Adverse Events, and Adverse Events Leading to Withdrawal. | 0 percentage of participants |
| Placebo Treatment Arm | Incidence of Adverse Events, Serious Adverse Events, and Adverse Events Leading to Withdrawal. | 1.2 percentage of participants |
Secondary
Change From Baseline in Serum Bicarbonate at the End of Treatment
Change from baseline in serum bicarbonate at the end of treatment (Week 52).
Time frame: Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E.
Population: The TRCA-301E Modified Intent-to-Treat (MITT) Analysis Set included all randomized subjects who had both baseline and at least one postbaseline serum bicarbonate value measured using the i-STAT device in the parent study, TRCA-301, and at least one serum bicarbonate value after the Week 12 Visit in Study TRCA-301E.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TRC101 Treatment Arm | Change From Baseline in Serum Bicarbonate at the End of Treatment | 4.70 mEq/L | Standard Error 0.335 |
| Placebo Treatment Arm | Change From Baseline in Serum Bicarbonate at the End of Treatment | 2.71 mEq/L | Standard Error 0.403 |
Comparison: Least Squares Mean Change from Baseline: TRC101-Placebop-value: =0.000295% CI: [0.96, 3.03]Mixed-effect repeated measures model
Secondary
Change From Baseline in the Duration of Repeated Chair Stand Test at the End of Treatment
Change from baseline in the duration of repeated chair stand test at the end of treatment (Week 52). The five-times repeated chair stand test was used as a measure of lower extremity muscle strength. In this test, the time it took for a subject to repeatedly stand from a chair five times was recorded. This test is among the group of measures (gait speed, chair stand, and balance tests) comprising the Short Physical Performance Battery (SPPB), which has been used as a predictive tool for possible disability and for monitoring physical functioning in older people.
Time frame: Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E.
Population: The TRCA-301E Modified Intent-to-Treat (MITT) Analysis Set included all randomized subjects who had both baseline and at least one postbaseline serum bicarbonate value measured using the i-STAT device in the parent study, TRCA-301, and at least one serum bicarbonate value after the Week 12 Visit in Study TRCA-301E.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TRC101 Treatment Arm | Change From Baseline in the Duration of Repeated Chair Stand Test at the End of Treatment | -4.28 seconds | Standard Error 1.24 |
| Placebo Treatment Arm | Change From Baseline in the Duration of Repeated Chair Stand Test at the End of Treatment | -1.42 seconds | Standard Error 1.248 |
Comparison: Change from Baseline for Repeated Chair Stand Test: TRC101-Placebop-value: <0.0001ANCOVA
Secondary
Change From Baseline in the Total Score of the KDQOL-PFD at the End of Treatment
Change from baseline in the total score of the Kidney Disease Quality of Life Physical Function Domain (KDQOL-PFD) at the end of treatment. The KDQOL is a validated, kidney disease-specific measure of health-related quality of life. For study TRCA-301E, and the parent study TRCA-301, the 10-question Item 3 of the KDQOL, also known as the SF-36 Physical Function subscale, was selected to measure physical functioning and is referenced herein as the KDQOL-PFD. The KDQOL-PFD was chosen as a patient-reported outcome measurement to evaluate the effects of TRC101 on daily activities that may be adversely affected by loss of muscle caused by metabolic acidosis. The minimum score for each of the 10 questions is 0 (physical activity highly limited) and the maximum is 100 (physical activity not limited). The total KDQOL-PFD score is calculated by adding the scores for all 10 questions, for a minimum and maximum possible total KDQOL-PFD score of 0 or 100, respectively.
Time frame: Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E.
Population: The TRCA-301E Modified Intent-to-Treat (MITT) Analysis Set included all randomized subjects who had both baseline and at least one postbaseline serum bicarbonate value measured using the i-STAT device in the parent study, TRCA-301, and at least one serum bicarbonate value after the Week 12 Visit in Study TRCA-301E.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TRC101 Treatment Arm | Change From Baseline in the Total Score of the KDQOL-PFD at the End of Treatment | 11.42 KDQOL-PFD total score | Standard Error 2.201 |
| Placebo Treatment Arm | Change From Baseline in the Total Score of the KDQOL-PFD at the End of Treatment | -0.71 KDQOL-PFD total score | Standard Error 2.268 |
Comparison: Mean Change from Baseline in KDQOL-PFD: TRC101-Placebop-value: <0.0001ANCOVA
Secondary
Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range
Percent of subjects having a change from baseline in serum bicarbonate of at least 4 mEq/L or bicarbonate in the normal range (22 - 29 mEq/L) at the end of treatment (Week 52).
Time frame: Baseline in the parent study, TRCA-301, to the Week 52 Visit in the extension study, TRCA-301E.
Population: The TRCA-301E Modified Intent-to-Treat (MITT) Analysis Set included all randomized subjects who had both baseline and at least one postbaseline serum bicarbonate value measured using the i-STAT device in the parent study, TRCA-301, and at least one serum bicarbonate value after the Week 12 Visit in Study TRCA-301E.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TRC101 Treatment Arm | Subjects With Change From Baseline in Serum Bicarbonate of ≥ 4 mEq/L or Serum Bicarbonate Within the Normal Range | 62.7 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 | 37.8 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: =0.001595% CI: [10.2, 38.7]Fisher Exact
Comparison: % Subjects with ≥ 4mEq/L Change from Baseline in Serum Bicarbonate: TRC101-Placebop-value: =0.001595% CI: [9.7, 38.2]Fisher Exact
Comparison: % Subjects with Serum Bicarbonate in Normal Range (22 - 29 mEq/L): TRC101-Placebop-value: <0.000195% CI: [15.6, 43.7]Fisher Exact