E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metabolic acidosis associated with Chronic Kidney Disease |
|
E.1.1.1 | Medical condition in easily understood language |
Low blood bicarbonate levels in patients with chronic kidney disease (CKD) |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027417 |
E.1.2 | Term | Metabolic acidosis |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety of administration of TRC101 in CKD patients with metabolic acidosis (blood bicarbonate 12 to 20 mEq/L) To evaluate the efficacy of TRC101 in CKD patients with metabolic acidosis (blood bicarbonate 12 to 20 mEq/L) |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have provided written informed consent prior to participation in the study. 2. Male or female subjects 18 to 85 years of age at Screening 1 Visit. 3. Have a blood bicarbonate value of 12 to 20 mEq/L at Screening 1 and Screening 2 Visits AND an average value for Screening 1, Screening 2, and Baseline Visits (i.e., baseline blood bicarbonate) within the range 12 to 20 mEq/L based on onsite measurement using an i-STAT point of care device. Screening 1 and Screening 2 Visits must be at least 5 days apart. Note: Subjects with baseline blood bicarbonate values of 12 to 18 mEq/L are eligible without restriction. Once 105 subjects with baseline blood bicarbonate values of > 18 to 20 mEq/L have been enrolled, randomization may be closed to additional subjects with baseline blood bicarbonate in this range. 4. At both Screening Visits have an eGFR value of 20 to 40 mL/min/1.73m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation as reported by the central laboratory. If a central laboratory eGFR value from Screening 2 Visit is not available, eGFR can be calculated using CKD-EPI equation based on onsite serum creatinine measurement at the Baseline Visit to establish subject’s eligibility. Screening 1 and Screening 2 Visits must be at least 5 days apart. 5. Have stable renal function as defined by eGFR values at both Screening Visits that are not different by more than 20% (the higher of the two Screening eGFR values will be used as the denominator to calculate the 20% allowable difference). 6. At both Screening Visits have systolic blood pressure < 170 mmHg (all three replicates). 7. Have a hemoglobin A1c (HbA1c) value of ≤ 9.0% at the Screening 1 Visit based on central laboratory measurement. 8. Have adequate peripheral venous access for blood draws. 9. Women who are of childbearing potential must have negative pregnancy tests at the Screening 1 Visit and Day 1 and be willing to use an acceptable method of birth control from the Screening 1 Visit until 1 month after study completion. Acceptable methods include hormonal contraception (oral contraceptives, patch, implant, and injection), intrauterine devices, double barrier methods (e.g., vaginal diaphragm, vaginal sponge, condom, spermicidal jelly), sexual abstinence or a vasectomized partner. Women who are surgically sterile with documentation of such, or who are at least 1-year post-last menstrual period and > 55 years of age, are considered not to be of childbearing potential. |
|
E.4 | Principal exclusion criteria |
1. Have any level of low blood bicarbonate at either Screening Visit that, in the opinion of the Investigator, requires emergency intervention or evaluation for an acute acidotic process. 2. Have had anuria, dialysis, acute kidney injury, history of acute renal insufficiency or known ≥ 30% increase in serum creatinine or known ≥ 30% acute or chronic decrease in eGFR in the 3 months prior to the Screening 1 Visit. 3. Have 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. 4. Had heart failure with maximum New York Heart Association (NYHA) Class IV symptoms, or that required hospitalization with a primary cause of heart failure, during the preceding 6 months. 5. Have had a heart or kidney transplant. Note: Patients on the cadaveric transplant list or being evaluated for a future living donor transplant may be enrolled. 6. Planned initiation of renal replacement therapy (dialysis or transplantation) within 12 weeks following randomization. 7. Have had a stroke or transient ischemic attack (TIA) within the 6 months prior to randomization. 8. Have had a cardiac event within 12 weeks prior to randomization, including: myocardial infarction, acute coronary syndrome, coronary bypass grafting, percutaneous coronary intervention, valve procedure, inpatient or outpatient treatment for acute decompensated heart failure. 9. Have been hospitalized for any reason during the 2 months prior to the Screening 1 Visit, other than for pre-planned diagnostic or minor invasive procedures. Note: Subjects who had major cardiovascular procedures or percutaneous cardiac procedures during this time frame are excluded, even if the procedures were pre-planned. 10. Have a history or current diagnosis of clinically significant diabetic gastroparesis (based on Investigator’s judgment) or a history of bariatric surgery. 11. Have a history or current diagnosis of bowel obstruction, swallowing disorders, severe gastrointestinal (GI) disorders, inflammatory bowel disease, major GI surgery, frequent diarrhea or active gastric/duodenal ulcers. 12. Have liver enzyme (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) or total bilirubin values > 3 × the upper limit of normal (ULN) at Screening based on central laboratory measurements. 13. Have a serum calcium ≤ 8.0 mg/dL at the Screening 1 Visit based on central laboratory measurement. 14. Have a serum potassium value < 3.8 mEq/L or > 5.9 mEq/L at the Screening 1 or Screening 2 Visit. 15. Have active cancer during the 1 year prior to Screening, other than non-melanoma skin cancer, or cancer that is currently being treated or will be treated during the study. Subjects with cancers that are being treated with hormonal therapy only may be permitted with approval of the Medical Monitor. 16. Have received any investigational medication during the last month (28 days or ≥ 5 half-lives [if known], whichever is longer) preceding the Screening 1 Visit. 17. Have used any of the following in the 14 days prior to the Screening 1 Visit: lanthanum carbonate, colesevelam, cholestyramine, sodium or calcium polystyrene sulfonate, calcium acetate, sevelamer, bixalomer, patiromer, and other polymeric binder drugs. 18. Have had a change in doses (including starting or stopping treatment) in the 2 weeks prior to the Screening 1 Visit or during Screening Period to the following: calcium-containing supplements, such as calcium carbonate and calcium citrate; antacids; H2-blockers; proton pump inhibitors. 19. Have had a change in doses (including starting or stopping treatment) in the 4 weeks prior to the Screening 1 Visit or during Screening Period to the following: sodium bicarbonate, potassium citrate, sodium citrate or other alkali therapy; diuretics; renin-angiotensinaldosterone system [RAAS] inhbitors, such as angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs], aldosterone antagonists [AAs], mineralocorticoid receptor antagonists [MRAs]; non-ophthalmic carbonic anhydrase inhibitors. Note: For diuretics, dose changes of up to ± 50% relative to the average dose during the Screening Period are considered “stable”, and a dose change up to ± 50% between the Screening 1 Visit and the Baseline Visit is considered “stable”. 20. Have a known allergy to placebo (microcrystalline cellulose). 21. Inability to consume the study drug or otherwise comply with the protocol. 22. Have, in the opinion of the Investigator, any medical condition, uncontrolled systemic disease or serious concurrent illness that would significantly decrease study compliance or jeopardize the safety of the subject or affect the validity of the study results. 23. Have participated in a previous clinical study of TRC101. 24. Currently breastfeeding. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy: Having a change from baseline (CFB) in blood bicarbonate ≥ 4 mEq/L or having blood bicarbonate in the normal range (22 to 29 mEq/L).
Safety: 1. AEs, SAEs and withdrawal of study treatment due to AE. 2. Having met the high bicarbonate dose interruption criterion (confirmed > 30 mEq/L) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy: At the end of treatment (Week 12 Visit).
Safety: 1. At any time during the Treatment Period. |
|
E.5.2 | Secondary end point(s) |
Secondary Efficacy: CFB in blood bicarbonate.
Exploratory Efficacy: 1. CFB in the total score of the Kidney Disease and Quality of Life (KDQOL) Question 3 items (daily activities). 2. CFB in repeated chair stand test duration. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of treatment (Week 12 Visit). |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Croatia |
Georgia |
Hungary |
Serbia |
Slovenia |
Ukraine |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |