E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Longstanding kidney disease |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 effect of TRC101 on the progression of chronic kidney disease and to evaluate the safety profile of TRC101 in CKD patients with metabolic acidosis. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
DXA sub-study
Dual energy x-ray absorptiometery (DXA) scans will be performed in a
subset of subjects (approximately 100 to 300) to evaluate bone mineral
density, trabecular bone score, lean body mass and appendicular muscle
mass. These subjects will be enrolled from a subset of sites who have
qualified DXA facilities if they consent to undergo the scans.
Interview sub-study (US only)
To facilitate the interpretation of results pertaining to physical
functioning, as well as to support the content validity of the KDQOL-PFD,
qualitative interviews will be conducted with approximately 40 subjects
at selected sites following the completion of their Month 12 Visit
assessments |
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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, inclusive, at Screening 1 Visit.
3. The mean of two Screening eGFR measurements, drawn at least 2 weeks apart and both within 6 weeks of the first day of Part A, is 20 to 40 mL/min/1.73m2, inclusive, calculated using the CKD-EPI equation as reported by the central laboratory.
• Note: If more than two eGFR values were measured at the central laboratory during the Screening Period, the Screening eGFR will be based on the most recent two values that are at least 2 weeks apart and within 6 weeks of the first day of Part A.
Enrollment of patients with Screening eGFR in the range 15 to 20 mL/min/1.73m2 may be allowed in the future with notification to the sites by Tricida and will not require a protocol amendment. Subjects with a Screening eGFR value in the range of 15 to <20 mL/min/1.73m2 may not be enrolled until Tricida has authorized this change in writing.
4. Have stable renal function as defined by eGFR Screening values that are not different by > 20% (the higher of the two Screening eGFR values will be used as the denominator to calculate the 20% allowable difference).
• Note: If more than two eGFR values were measured at the central laboratory during the Screening Period, the first and last values must be used for calculation of the allowable eGFR difference.
5. Based on onsite measurement using an i STAT point of care device, have three serum bicarbonate values, each ≥ 2 weeks apart from each other and all within 6 weeks of the A1 Visit, in the range from 12 to 20 mEq/L, inclusive. One of these three values must be from the A1 Visit, pre-dose.
One retest (which can be performed on the same day as the test being repeated) using the i-STAT point of care device is allowed from
Screening 1 Visit through the A1 Visit.
Subjects with Baseline Bicarbonate (defined as the average of the serum bicarbonate values at Screening 1, Screening 2 and the A1 Visit [predose]) values of 12 to 18 mEq/L are eligible without restriction. Once approximately half of study subjects have been randomized with Baseline Bicarbonate > 18 to 20 mEq/L, randomization may be closed to additional subjects with Baseline Bicarbonate in this range.
6. Mean systolic and diastolic blood pressure (determined as the average of three replicates) must be < 160/92 mmHg at the Screening 2 Visit.
7. Receiving treatment with an ACE inhibitor and/or ARB at the maximum tolerated (for the individual subject) dose within the country-specific labeled dose range, without adjustments, for ≥ 4 weeks prior to the Screening 1 Visit and during the Screening Period. The maximum tolerated dose for an individual subject may be less than the maximum labeled dose or may be zero if the medical reason is documented.
Subjects not treated with an ACE inhibitor or ARB must be approved by the Medical Monitor following a review of the medical justification.
Non-diabetic subjects with urine ACR < 30 mg/g (< 3.39 mg/mmol) are not required to be receiving treatment with an ACE inhibitor and/or ARB.
8. If receiving an oral alkali supplement, the dose must be stable for ≥ 2 weeks prior to Screening 1 Visit and during the Screening Period.
If not receiving alkali treatment, there must be no such treatment within the 2 weeks prior to Screening 1 Visit or during the Screening Period.
9. Have a hemoglobin A1c (HbA1c) value of ≤ 11.0% (0.11 fraction; 97 mmol/mol) at the Screening 1 Visit (based on central laboratory measurement).
10. Have adequate peripheral venous access for blood draws.
11. Women who are of childbearing potential must have negative pregnancy tests at the Screening 1 and Part B Day 1 Visits and be willing to use an acceptable method of birth control from the Screening 1 Visit until 1 week after study drug 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.
Inclusion Criterion for Randomization:
1. Have an increase from Baseline Bicarbonate of ≥ 4 mEq/L or have a serum bicarbonate value that is ≥ 22 mEq/L based on an i-STAT point of care measurement during Part A.
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E.4 | Principal exclusion criteria |
1. Have any level of low serum 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, or acute kidney injury/acute renal failure in
the 3 months prior to the Screening 1 Visit.
3. Had heart failure with maximum New York Heart Association (NYHA)
Class IV symptoms during the 3 months prior to the Screening 1 Visit.
4. Had a heart, liver or kidney transplant.
5. Have a corrected serum calcium < 8.0 mg/dL (80 mg/L; 2 mmol/L) at
the Screening 1 Visit, based on central laboratory measurement. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression of chronic kidney disease, defined by time to first occurrence of any event in the composite endpoint consisting of the following as adjudicated by the independent blinded Clinical Endpoint Adjudication Committee (CEAC):
• A confirmed ≥ 40% reduction in eGFR
• End-stage renal disease (ESRD)
• Renal death |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The time to first occurrence of any component of the composite endpoint as adjudicated by an independent blinded CEAC. |
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E.5.2 | Secondary end point(s) |
1. Time to first occurrence of any event in the composite of death (all cause), ESRD or a confirmed ≥ 50% reduction in eGFR
2. Change from baseline (i.e., A1 Visit) to Month 12 in the total score of the KDQOL-PFD
3. Change from baseline (i.e., A1 Visit) to Month 12 in the time to complete the repeated chair stand test
4. Time to ESRD or renal death
5. Time to first occurrence of the primary composite endpoint or
cardiovascular (CV) death
6. Time to first occurrence of a confirmed doubling of serum creatinine
7. Time to first occurrence of a confirmed ≥ 50% reduction in eGFR
8. Time to first occurrence of a confirmed ≥ 40% reduction in eGFR
9. Frequency of all-cause hospitalization
10. Time to CV death
11. Time to all-cause mortality
With the exception of endpoints #2, #3, #6 and #9, all secondary endpoint events will be adjudicated by the CEAC. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Time to first occurrence of any event in the composite of death (all cause), ESRD or a confirmed ≥ 50% reduction in eGFR
2. At Month 12
3. At Month 12
4. Time to occurrence of ESRD or renal death
5. Time to first occurrence of primary composite endpoint or CV death
6. Time to first occurrence of a confirmed doubling of serum creatinine
7. Time to first occurrence of a confirmed ≥ 50% reduction in eGFR
8. Time to first occurrence of a confirmed ≥ 40% reduction in eGFR
9. At the end of treatment
10. Time to CV death
11. Time to all-cause mortality |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
This study includes a single-blind period of 4-8 weeks and a double-blind period for up to 6 years |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 135 |
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 |
Albania |
Armenia |
Australia |
Belarus |
Brazil |
Canada |
Chile |
Colombia |
Georgia |
Hong Kong |
Israel |
Korea, Republic of |
North Macedonia |
Malaysia |
Mexico |
Serbia |
Singapore |
Taiwan |
Ukraine |
United States |
Belgium |
Bulgaria |
France |
Hungary |
Italy |
Netherlands |
Poland |
Portugal |
Romania |
Slovakia |
Spain |
United Kingdom |
Czechia |
Argentina |
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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
|
The point in time when all subjects who are required to complete and
likely to complete the 2-Week Post-Treatment Visit have done so. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |