E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate to Severe Chronic Kidney Disease |
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E.1.1.1 | Medical condition in easily understood language |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
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 demonstrate AST-120, added to standard-of-care therapy in moderate to severe CKD, reduces the risk of progression of CKD as assessed by the development of a component of a triple composite endpoint (initiation of dialysis, kidney transplant, or doubling of sCr), when compared with placebo; and
• To demonstrate the general safety and tolerability of long-term AST-120 therapy in CKD patients. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are as follows:
• To evaluate the efficacy of AST-120 in reducing the risk of developing a component of a quadruple composite endpoint (initiation of dialysis, kidney transplant, doubling of sCr, or death) compared with placebo;
• To evaluate the effects of AST-120 versus placebo, on other measures of renal function i.e. sCr, 24 hr urinary protein excretion, creatinine clearance, urea clearance, and 24 hr urinary creatinine excretion; and
• To assess the effects of AST-120 versus placebo, on fat-soluble vitamin levels (A, D, E, and K), vitamin B-12, and folate levels.
Exploratory objective of this study is;
• To assess quality of life by KDQOL ™-36 questionnaire. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients that meet all of the following Inclusion Criteria may be enrolled into the study:
1) Age 18 years or older;
2) Moderate to severe CKD (in men: sCr ≥ 2.0 mg/dL[≥ 177 µmol/L] and ≤ 5.0 mg/dL[≤ 442 µmol/L]); in women: sCr ≥ 1.5 mg/dL[≥ 133 µmol/L] and ≤ 5.0 mg/dL[≤ 442 µmol/L]); , not anticipated to require dialysis or renal transplant within the next 6 months;
3) Patient survival expected to be no less than one year;
4) Serum creatinine in men ≥ 2.0 mg/dL [≥ 177 µmol/L] and ≤ 5.0 mg/dL [≤ 442 µmol/L] and in women ≥ 1.5 mg/dL [≥ 133 µmol/L] and ≤ 5.0 mg/dL [≤ 442 µmol/L] at the initial Screening visit;
5) Proteinuria / Progressive deterioration in renal function:
Urinary total protein to urinary total creatinine ratio (both values measured as mg/dL, or other like units) must be ≥ 0.5 on a spot void obtained at the Screening visit
OR
If the urinary total protein to urinary total creatinine ratio is <0.5, then the patient may return for a second Screening visit 3 months later. If the sCr value at the second Screening visit is >10% higher than the first Screening visit but not > 5.0 mg/dL [≤ 442 µmol/L] or if the urinary total protein to urinary total creatinine ratio is ≥ 0.5, then the patient may be enrolled (See Appendix E of the Protocol for a listing of qualifying sCr values based on initial and second Screening visit values).
6) Sitting blood pressure ≤160/90 mmHg at both Screening and Baseline visits. In addition, blood pressure, if measured, must have been stable in hypertensive patients over the 3 months prior to Screening, with no more than 1 blood pressure reading > 160/90 mmHg;
7) In patients being treated for hypertension, they should be on a stable anti-hypertensive regimen, defined as no changes in anti-hypertensive medications or doses in the last 3 months prior to the Baseline visit, and to include, a stable dose of either an ACEI or ARB unless contraindicated;
8) Stable nutritional status; and
9) Willingness to comply with the study and sign a written informed consent. |
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E.4 | Principal exclusion criteria |
Patients that meet any of the following Exclusion Criteria must not be enrolled into the study:
1) Obstructive or reversible cause of kidney disease;
2) Nephrotic syndrome defined as a ratio of urinary total protein to urinary creatinine (both components measured as mg/dL or other like units) of > 6.0 as measured on a spot void;
3) Adult polycystic kidney disease;
4) History of previous kidney transplant;
5) History of alcohol or drug abuse within the past 12 months;
6) Known human immunodeficiency virus (HIV) infection;
7) Received immunosuppressive therapy (including systemic corticosteroids for more than 5 days at a daily dose in excess of 0.1 mg/kg, prednisone equivalent) in the past 3 months, or anticipated to require such treatment during the study course;
8) History of recent (within the past 6 months) accelerated or malignant hypertension;
9) Patients who are likely to require changes in ACEI or ARB regimens during the course of this study;
10) Uncontrolled arrhythmia or severe cardiac disease (New York Heart Association Class III - IV), including myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, cerebrovascular accident, or transient ischemic attack within the past 6 months;
11) History of malabsorption, inflammatory bowel disease, hiatal hernia, active peptic ulcer, or severe GI dysmotility, not attributable to the use of a phosphate binder;
12) History of cancer within the past 5 years (cervical carcinoma in situ, low-grade cutaneous malignancy, or other low grade malignancy are exemptions);
13) Alanine transaminase (ALT) or aspartate transaminase (AST) values > 2.5 times the upper limit of normal (ULN);
14) Received any investigational agent or participated in a clinical study within the previous 3 months;
15) Presence of any significant medical condition that might create an undue risk with study participation, or significantly confound the collection of safety and efficacy data in this study; or
16) For women of childbearing potential, a positive pregnancy test result of serum beta human chorionic gonadotropin (βHCG) or unwillingness to use approved single barrier or oral contraception, or unwillingness to be sexually abstinent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be the occurrence of one component of a triple
composite of renal outcomes: initiation of dialysis, kidney transplantation,
or doubling of sCr from the value obtained at the Baseline visit (Visit 2).
The initial doubled (from Baseline) sCr result will be verified 5-10 days
later with another sCr sampling. If this result remains doubled, a
confirmatory measurement of sCr doubling will occur at 4-6 weeks after
the initial doubled result was reported. If the Baseline value is not
available for comparison, the value obtained at the Screening visit (Visit 1)
will be used, If a second screening visit is performed then that screening
value will be used. An Endpoint Adjudication Committee (EAC) will review
and adjudicate all potential endpoint events. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 |
European Union |
Argentina |
Brazil |
Canada |
Mexico |
Russian Federation |
Ukraine |
United States |
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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
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When 291 renal outcome events have occured and met the criteria for an adjudicated study event, the study will be considered completed. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |