| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Sepsis-Associated Acute Kidney Injury |
|
| E.1.1.1 | Medical condition in easily understood language |
| Sepsis-Associated Acute Kidney Injury |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| 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 |
1. To investigate the effect of recAP on renal function and related clinical parameters in patients with SA-AKI.
2. To determine the therapeutic dose(s) of recAP to support the pivotal Phase 3 program. |
|
| E.2.2 | Secondary objectives of the trial |
1. To investigate the safety and tolerability of recAP in patients with SA-AKI.
2. To investigate the pharmacokinetics (PK) of recAP in a subset of patients with SA-AKI (in the first 120 patients from Part 1 only).
3. To investigate the immunogenic potential of recAP in patients with SA-AKI.
4. To investigate the effect on quality of life (using the EuroQol, EQ-5D). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has informed consent form (ICF) signed by patient or legal representatives or independent investigator, according to local rules and regulations.
2. Is aged 18 to 85 years, inclusive.
3. Is admitted to the ICU or intermediate care unit.
4. Has diagnosis of sepsis (<96 hours prior to first study drug administration or < 72 hour prior to AKI diagnosis), according to criteria defined by the American College of Chest Physicians/Society of Critical Care Medicine (Bone 1992]), based on:
a. Has a proven or strongly suspected bacterial infection.
b. Have at least 2 of the following 4 SIRS criteria within a timeframe of 72 hours at time of AKI diagnosis. Note: it is not required that symptoms are present simultaneously at study randomization:
i. Has a core temperature > 38°C or < 36°C.
ii. Has a heart rate > 90 beats/minute (unless the patient has a medical condition known to increase heart rate or is receiving treatment to prevent tachycardia).
iii. Has a respiratory rate > 20 breaths/minute, PaCO2 < 32 mm Hg or the use of mechanical ventilation for an acute respiratory process.
iv. Has a white cell count > 12 000/mm3 or < 4000/mm3 or a differential count showing > 10% immature neutrophils (band cells).
5. Has first diagnosis of AKI, defined as any of the following:
AKI Stage 1 or greater, according to the following Acute Kidney Injury Network (AKIN) criteria (Note: adjusted in regards to time-window):
a. Increase (absolute) in serum creatinine > 26.2 μmol/L (0.30 mg/dL) compared with a serum creatinine value within the previous 48 hours, or presumed to have occured in the previous 48 hours when compared to a reference* creatinine value
b. Increase (relative) in serum creatinine to > 150% (> 1.5–fold) compared with a serum creatinine value in the previous 48 hours or presumed to have occured in the previous 48 hours when compared to a reference* creatinine value. *The reference creatinine value is a serum creatinine value in the following order of preference:
i. Lowest value within 3 months of the hospital admission. If not available:
ii. At hospital admission. If not available:
iii. At ICU or intermediate care unit admission. If not available:
iv. Lowest value between 3 and 12 months prior to hospital admission
c. Urinary output < 0.5 mL/kg/h for > 6 hours following adequate fluid resuscitation when applicable, in the absence of underlying primary renal disease.
6. When the diagnosis of AKI is made according to one of the AKIN serum creatinine criteria (absolute or relative increase, see inclusion criteria 5a and 5b), continuing AKI needs to be confirmed by a confirmative serum creatinine measure (that is corrected for fluid administrations), defined as no decrease in serum creatinine ≥ 26.2 µmol/L (≥ 0.30 mg/dL). The result must be available prior to randomization, within 24 hours after the primary AKI diagnosis so that administration of the first study treatment can be started within 24 hours after AKI diagnosis.
7. When the AKI diagnosis is made according to the AKIN urine output criteria (urinary output < 0.5 mL/kg/h for > 6 hours, see inclusion criterion 5c), the oliguria or anuria should still meet the AKIN urine output criteria prior to randomization and study drug administration; administration of study treatment must be started within 24 hours after first AKI diagnosis. |
|
| E.4 | Principal exclusion criteria |
1. Woman of childbearing potential with a positive pregnancy test (blood or urine), pregnant, or breastfeeding.
2. Weighs more than 115 kg (253 lb).
3. Has life support limitations (i.e., do not intubate, do not dialyze, do not resuscitate).
4. Is known to be human immunodeficiency virus positive.
5. Has urosepsis.
6. Is already on dialysis (RRT) or a decision hs been made to initiate RRT within 24 hours after planned start of study drug administration.
7. Is receiving immunosuppressant treatment or is on chronic high doses (high-dose therapy exceeding 2 weeks of treatment) of steroids equivalent to prednisone/prednisolone 0.5 mg/kg/day, including solid organ transplant patients. Patients with septic shock treated with hydrocortisone (e.g., 3 × 100 mg) can be included.
8. Is expected to have rapidly fatal outcome (within 24 hours).
9. Has known, confirmed fungal sepsis.
10. Has advanced chronic liver disease, confirmed by a Child-Pugh score of 10 to 15 (Class C).
11. Has acute pancreatitis with no established source of infection.
12. Has participated in another investigational study within 30 days prior to enrollment into the study.
13. Is not expected to survive for 28 days due to medical conditions other than SA-AKI, e.g. end-stage cancer, end-stage cardiac disease, cardiac arrest requiring cardiopulmonary resuscitation or with pulseless electrical activity or asystole within the past 30 days, end-stage lung disease, and end-stage liver disease.
14. Has known prior history of CKD with a documented sustained estimated GFR
(eGFR) < 60 mL/min by a commonly used formula such as Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), a measured GFR < 60 mL/min, or a known history of persistent creatinine level equal or greater than 150 μmol/L (1.70 mg/dL) prior to entry for reasons other than the current
sepsis condition.
15. Has diagnosis of malaria or other parasite infections.
16. Has burns on > 20% of body surface.
17. Has had AKI diagnosis according to the AKI inclusion criteria for a period longer than 24 hours prior to study drug administration.
18. Is anticipated to be treated with non-continuous RRT from Day 1 to Day 7.
19. During Day 1 to Day 7 continuous RRT is anticipated to be started or stopped not according to per protocol criteria.
20. The AKI is most likely attributable to other causes than sepsis, such as nephrotoxic drugs (NSAIDs, contrast, aminoglycosides) and renal perfusion-related (acute abdominal aortic aneurysm, dissection, renal artery stenosis).
21. Improvement in serum creatinine of at least 0.30 mg/dL or (26.2 µmol/L) prior to administration of the study drug.
22. Patients who use nephrotoxic medication (e.g. NSAIDs, angiotensin-converting enzyme inhibitors, gentamycin, tobramycin) and who fulfill the SA-AKI inclusion criteria at screening are not eligible if the use of this nephrotoxic medication is to continue when alternative, medically appropriate, non-nephrotoxic medication is available. (Note: this is according to KDIGO Clinical Practice Guideline for AKI recommendations [KDIGO Acute Kidney Working Group 2012]) to avoid nephrotoxic medication, where possible).
23. Has a history of known IV drug abuse.
24. Is an employee or family member of the investigator or study site personnel.
25. Has active hematological malignancy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be calculated from time-corrected endogenous creatinine clearance measurements on Day 1 (first measurement after treatment) to Day 7, inclusive. Time-corrected endogenous creatinine clearance is assessed on each day during a 6 ± 1 hour period and calculated in mL/min as the mean creatinine clearance over the period, which is expected to be representative of the full 24 hours for that day. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be calculated from time-corrected endogenous creatinine clearance measurements on Day 1 (first measurement after treatment) to Day 7, inclusive. Time-corrected endogenous creatinine clearance is assessed on each day during a 6 ± 1 hour period and calculated in mL/min as the mean creatinine clearance over the period, which is expected to be representative of the full 24 hours for that day. |
|
| E.5.2 | Secondary end point(s) |
| The key secondary endpoint is RRT incidence during the period Day 1 (after first treatment) to Day 28, inclusive. Should a patient die or withdraw from the study during this period without recording RRT incidence, he or she will be counted as having not required RRT. analysis of this endpoint will be repeated excluding patients who died or withdrew from the study prior to completion of this period. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The key secondary endpoint is RRT incidence during the period Day 1 (after first treatment) to Day 28, inclusive. Should a patient die or withdraw from the study during this period without recording RRT incidence, he or she will be counted as having not required RRT. analysis of this endpoint will be repeated excluding patients who died or withdrew from the study prior to completion of this period. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 4 |
| 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 | 70 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Spain |
| 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
|
| The end of the study is defined as the date on which the last patient completes the final assessments (includes follow-up assessments). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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 |
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