E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Type 2 Diabetes and Nephropathy |
|
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 | 16.0 |
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 |
|
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 dose (MTLD) of a Renin Angiotensin System (RAS) inhibitor. |
|
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. |
|
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 |
|
E.3 | Principal inclusion criteria |
1. Subject has type 2 diabetes and has been treated with at least one anti-hyperglycemic medication and ACEi/or ARB (RAS inhibitor) for at least 3 months prior to the Screening Period.
2. HbA1c ≤ 12%.
3. 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 and a UACR ≥ 300 and < 5,000 mg/g (The number of subjects with eGFR between 60 to 75 mL/min/1.73 m2 will be capped to 10% of the total population);
• Serum albumin ≥ 3.0 g/dL (30 g/L);
• BNP ≤ 200 pg/mL (200 ng/L);
• SBP > 110 and <160 mmHg;
• Serum Potassium > 3.5 (3.5 mmol/L) and ≤ 5.5 mEq/L (5.5 mmol/L);
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 to the last visit in Run-In Period (R6);
Subjects already 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 proceed to 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:
• RAS inhibitor at the MTLDD for the previous 6 weeks during the Enrichment Period with no adjustments of the dose;
• Diuretic at any dose unless medically contraindicated or clinically intolerable in the investigator's judgement (i.e., hypotension or hypokalemia);
• Weight change < 3 kg and absolute serum BNP < 300 pg/mL (300 ng/L) at Enrichment Week 6 from the beginning of Enrichment;
• Subjects must not have an AKI event at the end of the Enrichment period, as defined by an increase from baseline in serum Creatinine > 0.5 mg/dL and > 20% increase at Enrichment Week 6 (visit E5) from baseline. |
|
E.4 | Principal exclusion criteria |
1. Subject has a history of moderate or severe peripheral edema, pulmonary edema or facial edema unrelated to trauma or a history of myxedema in the prior 6 months to Screening.
2. Subject has a history of pulmonary hypertension requiring oxygen therapy, and/or endothelin receptor antagonist or phosphodiesterase therapy or any lung diseases requiring oxygen therapy (e.g., chronic obstructive pulmonary disease, emphysema, pulmonary fibrosis).
3. Subject has a documented diagnosis of heart failure, previous hospitalization for heart failure or current or 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.
4. Subject has known non-diabetic kidney disease (other than kidney stones).
5. Subject has a history of symptomatic hypotension within the last 6 months. |
|
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 (needing chronic dialysis or renal transplantation or renal death). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
End points are monitored throughout the study |
|
E.5.2 | Secondary end point(s) |
• Change from baseline to Month 24 post-randomization visit on UACR.
• Time to a 30% eGFR reduction after 3 months post-randomization treatment.
• Time to cardio-renal composite endpoint: doubling of serum creatinine, ESRD, CV death, nonfatal myocardial infarction, nonfatal stroke.
• Time to the CV composite endpoint: CV death, nonfatal myocardial infarction and nonfatal stroke. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
End points are monitored throughout the study |
|
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.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 200 |
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 |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Hong Kong |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Norway |
Peru |
Poland |
Portugal |
Puerto Rico |
Romania |
Russian Federation |
Singapore |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 |