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 |
Type 2 Diabetes and Nephropathy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
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 | 10061835 |
E.1.2 | Term | Diabetic nephropathy |
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 |
The study objective is to evaluate the effect of atrasentan compared with placebo on time to doubling of serum creatinine or the onset of end stage renal disease (ESRD) in type 2 diabetic subjects with nephropathy who are treated with the maximum tolerated labeled daily dose (MTLDD) of a Renin Angiotensin System (RAS) inhibitor. |
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E.2.2 | Secondary objectives of the trial |
The study will additionally assess the effects of atrasentan compared with placebo on cardiovascular morbidity and mortality, urine albumin excretion, changes in estimated glomerular filtration rate (eGFR), as well as on the impact on quality of life in type 2 diabetic subjects with nephropathy. |
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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 |
- pharmacogenetic study
- 24 hour urine study |
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E.3 | Principal inclusion criteria |
1. Subject has type 2 diabetes (including patients with latent autoimmune diabetes or insulin-treated patients without a history of diabetic ketoacidosis who also have a negative anti-glutamic acid decarboxylase test AND an elevated post-prandial serum C-peptide level) and has been treated with at least one anti-hyperglycemic medication and ACEi/or ARB (RAS inhibitor) for at least 4 weeks prior to the Screening S2 visit.
2. For entry into the Run-In Period the subject must satisfy the following criteria based on the Screening laboratory values:
• Estimated GFR 25 to 75 mL/min/1.73 m2 [until the eGFR cap on subjects (approximately 300) with a baseline of > 60 mL/min/1.73 m2 is reached] and a UACR ≥ 300 and < 5,000 mg/g (≥ 34 mg/mmol and < 565 mg/mmol);
• Serum albumin ≥ 2.5 g/dL (25 g/L);
• BNP ≤ 200 pg/mL (200 ng/L);
• Serum Potassium ≥ 3.5 (3.5 mmol/L) and ≤ 6.0 mEq/L (6.0 mmol/L);
• SBP ≥ 110 and ≤ 180 mmHg at any time during the Screening Period;
Subjects on a MTLDD of a RAS inhibitor for ≥ 4 weeks and on a diuretic at the time of screening and who satisfy the above criteria may proceed directly to the last visit in Run-In Period (R6 visit);
Subjects on a MTLDD of a RAS inhibitor for ≥ 4 weeks and not on a diuretic (unless medically contraindicated) at the time of Screening will start with a diuretic and participate in Run-In for at least 2 weeks.
4. For entry into the Enrichment Period the subject must satisfy the following criteria based on the last visit of the Run-In Period:
• RAS inhibitor at the MTLDD for the previous 4 weeks with no adjustments of the dose;
• Subjects that were on a MTLDD RAS inhibitor and not on a diuretic (unless medically contraindicated) at the time of Screening must have been in Run-In for at least 2 weeks.
5. For entry into the Double-Blind Treatment Period, the subject must satisfy the following criteria based on the last visit of the Enrichment Period:
• Subject has taken a RAS inhibitor at the MTLDD for the previous 6 weeks during the Enrichment Period with no adjustments of the dose;
• Subject has taken a diuretic at any dose unless medically contraindicated or clinically intolerable in the investigator's judgement (i.e., hypotension or hypokalemia);
• Subject must not have a weight change ≥ 3 kg from the beginning of Enrichment (E1) to the end of the Enrichment Period and absolute serum BNP ≥ 300 pg/mL (300 ng/L) at the last Enrichment visit;
• Subject must not have an increase in serum creatinine > 0.5 mg/dL and > 20% increase from the beginning of Enrichment (E1) to the end of the Enrichment Period. |
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E.4 | Principal exclusion criteria |
• Subject has a history of severe peripheral edema or facial edema requiring diuretics unrelated to trauma or a history of myxedema in the prior 4 weeks to the initial Screening S1 visit.
• Subject has a history of pulmonary hypertension, pulmonary fibrosis or any lung disease requiring oxygen therapy (e.g., chronic obstructive pulmonary disease, emphysema).
• Subject has a documented diagnosis of heart failure, previous hospitalization for heart failure or current constellation of symptoms (dyspnea on exertion, pedal edema, orthopnea, paroxysmal nocturnal dyspnea) felt to be compatible with heart failure, that was not explained by other causes, and for which there was a change in medication or other management directed at heart failure.
• Subject has known non-diabetic kidney disease (other than kidney stones).
• Subject has elevated liver enzymes (serum alanine aminotransaminase [ALT] and/or serum aspartate aminotransaminase [AST]) > 3 × the upper limit of normal (ULN).
• Subject is currently receiving rosiglitazone, moxonidine, aldosterone blockers, aliskiren, or a combination of ACEi and ARB. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to the first occurrence of a component of the composite renal endpoint: doubling of serum creatinine (confirmed by a 30-day serum creatinine) or the onset of ESRD (confirmed eGFR < 15 ml/min/1.73 m2 confirmed by a 90-day eGFR, receiving chronic dialysis, renal transplantation or renal death). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End points are monitored throughout the study |
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E.5.2 | Secondary end point(s) |
•Time to a 50% eGFR reduction.
•Time to cardio-renal composite endpoint: confirmed doubling of serum creatinine, ESRD, CV death, nonfatal myocardial infarction, nonfatal stroke.
•Time to first occurrence of a component of composite renal end-point: confirmed doubling of serum creatinine, or the onset of ESRD for all randomized subjects (pooled).
•Time to the CV composite endpoint: CV death, nonfatal myocardial infarction and nonfatal stroke.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End points are monitored throughout the study |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 340 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Hong Kong |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Peru |
Poland |
Portugal |
Puerto Rico |
Romania |
Russian Federation |
Singapore |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |