E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
QPI-1002 is being developed for prevention of acute kidney injury (AKI) in patients at risk for AKI following cardiac surgery and for reduction in the incidence and severity of delayed graft function after kidney transplantation. |
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E.1.1.1 | Medical condition in easily understood language |
The investigational compound shall minimize the risk of patients after cardiac surgery with high likelyhood to induce a problematic medical situation with the kidneys |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10069339 |
E.1.2 | Term | Acute kidney injury |
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 assess the efficacy of a single intravenous (IV) infusion of QPI-1002 in preventing Major Adverse Kidney Events (MAKE) in subjects at high risk for acute kidney injury (AKI) following cardiac surgery. • To assess the safety and tolerability of an IV infusion of QPI-1002 in comparison to placebo when administered to subjects at high risk for AKI following cardiac surgery. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have the ability to understand the requirements of the study, are able to provide written informed consent (including consent for the use and disclosure of research related health information) and are willing and able to comply with the requirements of the study (including required study visits) 2. Adult male or female, age ≥ 18 years old 3. Have stable pre-operative renal function per Investigator assessment and no known increase in Serum creatinine (SCr) of ≥ 0.3 mg/dL (≥ 26.4 μmol/L) during preceding 28 days as assessed by the site's local laboratory using standard assay methodology. 4. At risk for AKI following cardiac surgery on the basis of at least one of the following pre-operatively assessed risk factors: a) eGFR (defined using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) SCr formula) of < 60 mL/min/1.73 m2 b) Diabetes with ongoing insulin treatment (defined as known type 2 or type 1 diabetes requiring prescribed insulin usage prior to hospitalization for cardiac surgery) c) Albuminuria defined as Urine Albumin/Creatinine ratio > 30 mcg/mg or screening urine dipstick of 1+ Note: If albuminuria is the only possible risk factor (i.e. eGFR is ≥ 60 mL/min/1.73 m2 and subject does not have a history of diabetes requiring prescribed insulin usage), a dipstick must be confirmed by urinalysis as > 30 mcg albumin/mg creatinine. If the urine albumin creatinine ratio is not available, and albuminuria is the only possible risk factor, a dipstick value of ≥ 2+ for protein or equivalent may be considered as meeting the albuminuria definition (> 30 mcg albumin/mg creatinine). 5. Undergoes non-emergent open chest cavity cardiovascular surgeries, with use of cardiopulmonary bypass (CPB) pump, with or without hypothermic circulatory arrest: a) Combined coronary artery bypass grafting (CABG) surgery and surgery of one or more cardiac valve (valve(s) surgery) b) Only CABG or single valve surgery that is a "redo" surgery (i.e. subject had any previous open chest cavity cardiovascular surgery) c) Surgery of more than one cardiac valve (valve surgery) d) Surgery of the aortic root or ascending part of the aorta in combination with CABG and/or valve(s) surgery e) If only CABG or single valve surgery and that surgery is not a "redo" surgery (i.e. not the surgery described in Inclusion Criteria #5b), subjects are required to have at least one additional risk factor for AKI: either one additional risk factor from Inclusion Criterion #4 above (for a total of two risk factors from Inclusion Criterion #4 above), OR age ≥ 65 years old, OR history of congestive heart failure requiring hospitalization, OR type 2 diabetes requiring at least 1 oral hypoglycemic agent but not requiring insulin Note: Transcatheter aortic valve implantation (TAVI) or transcatheter aortic valve replacement (TAVR) are allowed only if performed in combination with surgeries defined in Inclusion Criterion #5. *Note: "Non-emergent surgery" would denote an operation that does not require prompt and immediate surgery (within a few hours or the same day) and is scheduled in advance. 6. No known cancer as identified by cancer screening according to sitespecific pre-operative standard of care 7. Past medical history must be negative for malignancy within 5 years of randomization, with the exception of adequately treated basal cell or squamous cell carcinoma, or cervical carcinoma in situ 8. A female subject is eligible to enter the study if she is: a) Not pregnant or nursing b) Of non-childbearing potential (i.e., post-menopausal defined as having been amenorrheic for at least 1 year prior to screening, or has had a bilateral tubal ligation at least 6 months prior to administration of study drug or bilateral oophorectomy or complete hysterectomy) c) If of childbearing potential, must have a negative urine or serum pregnancy test within 48 hours prior to cardiac surgery and be using a highly effective means of contraception (per site-specific guidelines or use 2 methods of birth control concurrently, whichever is more stringent), which will be continued until the Day 90 visit 9. Male subjects with female partners of childbearing potential must agree to use an effective means of contraception (per site-specific guidelines or use 2 methods of birth control concurrently, whichever is more stringent), which will be continued until the Day 90 visit
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E.4 | Principal exclusion criteria |
1. Have an eGFR ≤ 20 mL/min/1.73 m2 (defined using CKD-EPI SCr formula) 2. Subjects with an eGFR < 60 mL/min/1.73 m2 (defined using CKD-EPI SCr formula) requiring intravascular iodinated contrast within 48 hours of surgery initiation as defined by the planned skin incision. However, subjects may be included if the post contrast increase in SCr is < 0.3 mg/dL (< 26.4 μmol/L) in at least 2 SCr evaluations performed not less than 36 hours (post final dose of contrast) apart 3. Have a history of any organ or cellular transplant which requires active immunosuppressive treatment which can interfere with kidney function 4. Emergent surgeries, including aortic dissection, and major congenital heart defects *Note: See Inclusion #5. Also, "emergent surgeries" are defined as cardiac operations that are not elective and must be done promptly to address an immediately life-threatening condition. 5. Undergoes cardiac surgery off CPB for subjects ≥ 45 years old.(Cardiac Surgery off CPB for subjects < 45 years old is allowed.) 6. Undergoes TAVI or TAVR only* or single vessel, minimally invasive direct coronary artery bypass (MIDCAB) off-pump surgeries or left ventricular assist device (LVAD) implantation *Note: See Inclusion Criterion #5 7. Have participated in an investigational drug study in the last 30 days 8. Have a known allergy to or had participated in a prior study with small interfering ribonucleic acid (siRNA) or prior treatment with QPI-1002 9. Have a known history of human immunodeficiency virus (HIV) infection 10. Have known active Hepatitis B (HBV) (Note: Subjects with a serological profile suggestive of clearance, or prior antiviral treatment of HBV infection may be enrolled) 11. Have known active Hepatitis C (HCV) (Note: Subjects at least 24 weeks from completion of treatment with an antiviral regimen and who remain free of HCV as determined by HCV RNA testing may be enrolled.) 12. Cardiogenic shock or hemodynamic instability within the 24 hours prior to surgery, requiring inotropes or vasopressors or other mechanical devices such as intra-aortic balloon counter-pulsation (IABP) 13. Post cardiac surgery, have hemodynamic instability despite increasing doses of three types of vasopressors and/or inotropes (see Appendix 1) 14. Perioperative or post cardiac surgery, an LVAD is inserted or anticipated (Note: Unplanned intraoperative LVAD that is removed before the end of surgery (i.e. skin closure) is allowed.) 15. Post cardiac surgery, have bleeding > 300 mL/hr requiring return to surgery or ≥ 3 units of packed Red Blood Cells (RBC) in the first 2 hours post-surgery 16. Have required any of the following within 7 days prior to cardiac surgery: defibrillator, mechanical ventilation, IABP, LVAD, other forms of mechanical circulatory support (MCS) (Note: The prophylactic insertion of an IABP preoperatively for reasons not related to existing LV pump function is not exclusionary.) 17. Have required cardiopulmonary resuscitation (CPR) within 14 days prior to cardiac surgery 18. Have ongoing sepsis or history of sepsis within the past 2 weeks or untreated diagnosed infection prior to Screening visit. Sepsis is defined as presence of a confirmed pathogen, along with fever or hypothermia, and hypoperfusion or hypotension 19. Have total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN) at time of screening 20. Have a history of chronic liver disease (i.e. cirrhosis) and Child Pugh Class A liver disease with ALT/AST above the upper limit of normal, or Class B or higher 21. Have a history or presence of a medical condition or disease or psychiatric condition that in the Investigator's assessment would render the subject ineligible for study participation 22. Have planned or actual administration of methylene blue from 24 hours prior to surgery through the time of planned randomization
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint 1. Proportion of subjects who develop any of the components of MAKE90, defined as either: • Death through day 90 • Initiation of Renal Replacement Therapy (RRT) through day 90, or • A ≥ 25% reduction in eGFR at the Day 90 visit Note: For the primary analysis, eGFR will be based on serum cystatin C (eGFRcys). Estimated GFR based on serum creatinine (eGFRcreat) will be used in a sensitivity analysis
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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) |
Key Secondary Efficacy Endpoints 1. Proportion of subjects developing AKI overall by modified Acute Kidney Injury Network (AKIN) criteria within 5 days post-surgery by SCr 2. Proportion of subjects who develop any of the components of MAKE90, defined as either: • Death through day 90 • Initiation of RRT through day 90, or • A ≥ 25% reduction in eGFR at the Day 90 visit Note: This secondary analysis is identical to the primary efficacy analysis except that it will include all subjects regardless of age. Thus, eGFRcys will be used for this analysis. eGFRcreat will be used in a sensitivity analysis. 3. Proportion of subjects developing AKI within 5 days post-surgery as defined by modified AKIN criteria stage 2 and stage 3 combined by SCr 4. Proportion of subjects who develop either or both of the following: • Death through day 90 • Initiation of RRT through day 90
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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 | Yes |
E.6.3 | Therapy | No |
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 |
NGAL-Biomarker-Assessment and Optional Assessment of mGFR |
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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 | No |
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 | 47 |
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 |
Australia |
Austria |
Belgium |
Canada |
Czech Republic |
France |
Germany |
New Zealand |
Spain |
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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The study ends when the last data element is available from the last subject to complete the Day 90 visit. However, there will be a Day 365 interaction to determine renal function, subject survival and malignancy status. |
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |