OBJECTIVES: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.
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint of the study is progression of chronic kidney
disease, defined by the time to first occurrence of any event in the composite
endpoint as adjudicated by the independent blinded CEAC:
• A confirmed >= 40% reduction in eGFR
• ESRD
• Renal death
Secondary outcome
Secondary Efficacy Endpoints
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 the A1 Visit (predose) to Month 12 in the total score of the
KDQOL-PFD
3. Change from the A1 Visit (predose) 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.
Background summary
Patients with chronic kidney disease (CKD) continue to generate acid from their
diet and metabolism but have a reduced ability to excrete acid via the kidneys.
As a result, metabolic acidosis, characterized by a reduced serum bicarbonate
concentration (i.e., below 22 mEq/L),
can develop in advanced stages of CKD. Metabolic acidosis affects 9 - 32% of
patients with CKD Stages 3 - 5. If metabolic acidosis is left untreated, the
consequences include increased mortality, progression of CKD, acceleration of
muscle breakdown, and the
development or exacerbation of bone disease.
Clinical outcomes for CKD patients with bicarbonate levels below the normal
range are significantly worse compared to patients with normal bicarbonate
(i.e., 22 - 29 mEq/L) as demonstrated in multiple large retrospective cohort
studies. As described in these reports, the relationship between decreasing
bicarbonate levels and clinical outcomes is believed to be a continuum (i.e.,
as bicarbonate decreases from normal levels the risk of adverse outcomes, such
as progression of CKD and death, progressively increases). Furthermore, the
risk of deleterious clinical outcomes for patients with bicarbonate levels in
the range required for subjects in this study (i.e., 12 - 20 mEq/L) is
significantly greater than for patients with bicarbonate levels indicative of
more mild metabolic acidosis (i.e., > 20 to 22 mEq/L). Correction of low
bicarbonate levels in patients with CKD (i.e., with oral alkali supplementation
or consumption of a less acidic diet) has been shown to result in slowing of
progression of renal disease in several small single-center studies.
Oral alkali supplements (e.g., oral sodium bicarbonate and sodium citrate) are
variably used in clinical practice to treat metabolic acidosis in patients with
CKD. However, use of these agents is often limited to use in CKD patients with
mild metabolic acidosis due to concerns
about sodium overload in patients who often have one or more conditions for
which sodium restriction is indicated. The daily doses of sodium bicarbonate
required to increase serum bicarbonate levels by 3 - 4 mEq/L in patients with
metabolic acidosis can be prohibitively high (6 - 8 g per day introducing 1.7 -
2.2 g of sodium for an 80 kg patient. Combined with the sodium intake from
diet, the sodium intake from therapeutic doses of oral sodium bicarbonate would
result in a total daily sodium load exceeding the guideline-recommended limit
of 2 g/day for CKD patients (Kidney Disease: Improving Global Outcomes (KDIGO)
Blood Pressure Work Group 2012) independent of underlying comorbidities.
Furthermore, common conditions accompanying CKD (e.g., hypertension, heart
failure, and edema) may be aggravated, and efficacy of diuretics negated, by
the sodium load that sodium-containing alkali therapies deliver. In addition,
potassiumcontaining alkali treatments can cause or aggravate hyperkalemia in
CKD patients whose ability to excrete potassium loads is reduced. Given these
considerations, there is a clear unmet medical need for new treatments with
demonstrated efficacy and safety to treat metabolic acidosis.
TRC101 is being developed as a first-in-class, orally administered,
counterion-free, insoluble, non-absorbed hydrochloric acid binder for the
treatment of metabolic acidosis associated with CKD. The mechanism of action of
TRC101 involves binding of proton (H+) and chloride (Cl-), resulting in a net
reduction and removal of hydrochloric acid (HCl) from the gastrointestinal (GI)
tract, which results in an increase in serum bicarbonate levels. TRC101 has
both high H+ and Cl- binding capacity and Cl- binding selectivity. The high
amine content of the polymer is responsible for the high H+ and Cl- binding
capacity of TRC101; the polymer*s extensive crosslinking leads to insolubility
of the polymer and
provides size exclusion properties and high selectivity over other competing
anions, such as phosphate, citrate, bile acids and short-chain and long-chain
fatty acids present in the GI tract.
This study will explore whether treatment of metabolic acidosis with TRC101
results in slowing of progression of kidney disease in patients with CKD.
Study objective
OBJECTIVES:
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.
Study design
This is a randomized, double-blind, placebo-controlled trial. Eligible subjects
will be randomized in a 1:1 ratio to TRC101 or placebo. The primary endpoint of
the study will be progression of renal disease, defined by time to first
occurrence of any event in the composite endpoint consisting of a confirmed >=
40% reduction in eGFR, end-stage renal disease (ESRD), and renal death. The
study will terminate when the independent blinded Clinical Endpoint
Adjudication Committee has positively adjudicated the targeted number of
primary efficacy endpoint events. The maximum duration of follow-up for a
randomized subject is anticipated to be 6 years in Part B of the study.
Intervention
Part A
At the A1 Visit, subjects will receive study drug QD for 4-8 weeks.
Part B
Approximately 1,600 subjects will be randomized in a 1:1 ratio to study drug.
Study drug will be self-administered orally as an aqueous suspension, QD with
food.
Study burden and risks
See attached document 'D6. Risk-Benefit Statement - 18Aug2018'.
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Listed location countries
Age
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 subjects 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.
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. 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 (see Appendix 5) during the 3 months prior to the Screening 1 Visit.
5. Had a heart, liver or kidney transplant.
Note: Subjects on the cadaveric transplant list or being evaluated for a future
living donor transplant may be enrolled.
6. Have planned initiation of renal replacement (RRT) therapy (dialysis or
transplantation) within 6 months following randomization.
7. Have had a stroke or transient ischemic attack within the 6 months prior to
Screening 1 Visit.
8. Have had a cardiac event within 3 months prior to Screening 1 Visit,
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 (e.g., placement of dialysis access).
Note 1: Subjects who had major cardiovascular procedures or percutaneous
cardiac interventional or therapeutic procedures during this time frame are
excluded, even if the procedures were pre-planned.
Note 2: Subjects hospitalized during this time frame for < 48 hours or for
self-limited conditions (e.g., hypoglycemia, hyperkalemia, nausea) may be
enrolled with approval of the Medical Monitor.
10. Have liver enzyme (alanine aminotransferase [ALT], aspartate
aminotransferase [AST]) or total bilirubin values > 3× the upper limit of
normal (ULN) at the Screening 2 Visit based on central laboratory measurements.
11. 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.
12. Have active cancer during the 1 year prior to Screening 1 Visit or cancer
that is currently being treated or will be treated during the study, other than
non-melanoma skin cancer or low-grade cervical carcinoma. Subjects with
cancers that are being treated with hormonal therapy only may be permitted with
approval of the Medical Monitor.
13. Have received any investigational drug during the last month (28 days or >=
5 half-lives [if known], whichever is longer) preceding the Screening 1 Visit
or during the Screening Period.
14. Have a known allergy to placebo (microcrystalline cellulose).
15. Have an inability to consume the study drug or otherwise comply with the
protocol.
16. Has received cytotoxic therapy, immunosuppressive therapy, or other
immunotherapy for renal disease within 6 months prior to the Screening 1 Visit
or during the Screening Period.
Note: Glucocorticoid use is allowed.
17. Have a history of alcoholism or drug/chemical abuse, as defined by The
Diagnostic and Statistical Manual of Mental Disorders (DSM-5), within 6 months
prior to the Screening 1 Visit.
18. 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 interpretability of the subject*s data.
19. Participated (i.e., was randomized) in Study TRCA-301.
20. Are pregnant or currently breastfeeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 03710291 |
| EudraCT | EUCTR2018-001303-36-NL |
| CCMO | NL66767.042.18 |