E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040047 |
E.1.2 | Term | Sepsis |
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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 primary objectives of this study are to identify the optimal dosing regimen and to demonstrate that TAK-242 reduces 28-day all-cause mortality in subjects with severe sepsis. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are: - To evaluate the effects of TAK-242 on organ function as measured by the Sequential Organ Failure Assessment (SOFA) score. - To evaluate clinical improvement as measured by Systemic Inflammatory Response Syndrome (SIRS)-free days; Vasopressor-free days; Time in ICU; Discharge location status - To evaluate the safety of TAK-242 administration. - To determine the pharmacodynamic effect of TAK-242 on the level of IL-6, IL-8, IL-10, Tumor Necrosis Factor (TNF)-alpha, Procalcitonin (PCT), and C-Reactive Protein (CRP). - To further characterize the pharmacokinetic (PK) profile of TAK-242, M-I and M-III in sepsis subjects. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Clinical evidence of infection defined as the presence of a known or probable source of infection requiring the initiation of parenteral antimicrobial therapy. Examples include presence of polymorphs in a normally sterile body fluid (except blood), positive culture or Gram stain of a normally sterile body fluid, clinical focus of infection (eg, fecal peritonitis, wound with purulent discharge, pneumonia or other clinical evidence of systemic infection [eg, purpura fulminans]). 2. The subject must meet at least 3 of the following 4 criteria for systemic inflammatory response syndrome (SIRS). The events for this criterion must be related to the onset of sepsis and not attributable to an underlying disease process or the effects of concomitant therapy. 2a. A core temperature of >38°C (>100.4°F) or <36°C (<96.8°F). Core temperature is defined as rectal, central catheter, oral, tympanic or urinary temperature (oral temperature is acceptable for high temperature but not for hypothermia, which must be confirmed by a core temperature). 2b. Heart rate of >90 beats per minute. If subject has a known medical condition (eg, heart block) or is receiving treatment (eg, beta blocker) that would prevent tachycardia, only 2 of the remaining 3 criteria for SIRS must be met. 2c. Respiratory rate of >20 breaths/min or PaCO2 of <32 mmHg or mechanical ventilation for an acute process. 2d. A total white blood cell (WBC) absolute count >12,000 cells/mm3 or <4,000 cells/mm3, or a WBC differential count showing >10% immature (band) forms. 3. The subject must have sepsis with shock or respiratory failure or both. The onset of shock or respiratory failure must be manifested within 24 hours (+12 hours, ie, up to a maximum of 36 hours) prior to the initiation of study drug infusion, which should occur as soon as possible, preferably in the first 24 hours. Subjects with septic shock that have been dependant on vasopressors for > 24 hours must be discussed in more detail with Vanderbilt Coordinating Center (VCC) and documented before randomization. 3a. Septic shock is defined as requiring the use of vasopressors (eg, norepinephrine, dopamine, phenylephrine, epinephrine, vasopressin) for arterial hypotension, despite adequate fluid resuscitation for more than 1 hour, or adequate intravascular volume status. Dobutamine and dopexamine are not considered vasopressors. Arterial hypotension is defined as systolic blood pressure of <90 mm Hg (which is not the result of the subject’s underlying disease or treatment). Adequate fluid resuscitation or adequate intravascular volume status is defined as one or more of the following: (i) pulmonary arterial wedge pressure at least 12 mm Hg, (ii) central venous pressure of at least 8 mm Hg, or (iii) if an intravascular pressure monitoring catheter is not in place, vasopressor administration after unsuccessful fluid resuscitation. 3b. Respiratory failure is defined as ratio of PaO2 to FIO2 <200 while mechanically ventilated. 4. The subject or the subject’s legally authorized representative has provided a written informed consent, or is able to understand verbal English or a language for which a certified translation of the approved informed consent is available. |
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E.4 | Principal exclusion criteria |
1. The subject is less than 18 years of age. 2. If female, the subject is pregnant, nursing and the milk is to be ingested by the infant, or the subject plans to become pregnant or nurse and the milk is to be ingested by the infant. 3. The subject is receiving immunosuppressive therapy such as cyclosporine, azathioprine, or cancer-related chemotherapy. 4. The subject has a granulocyte count of less than 1000/mm3 except if the decreased count is believed to be due to sepsis. 5. The subject has documented or suspected acute myocardial infarction within the last 6 weeks prior to Pre-treatment Period. 6. The subject has a documented history of moderate to severe chronic heart failure as defined by New York Heart Association (NYHA) Functional Classification III or IV (Appendix G). 7. The subject is known to be HIV positive with known CD4 count ≤50/mm3 or has known end-stage processes (eg, progressive multifocal leukoencephalopathy, systemic mycobacterium avium complex infection). 8. The subject has known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency. 9. The subject has methemoglobin level of >5% at Pre-treatment Period or has known history of methemoglobinemia. 10. The subject is moribund and death is considered imminent 11. The subject is classified as “Do Not Resuscitate” (DNR) or “Do Not Treat” or the subject’s family has not committed to aggressive management of the subject’s condition. 12. The subject is not expected to survive for 28 days and will not likely be given life support due to a pre-existing, uncorrectable medical condition. This would include subjects with, or suspected to have, poorly controlled neoplasm or other end-stage processes (eg, end-stage cardiac disease, end-stage lung disease, requiring chronic home oxygen, end-stage liver disease, end-stage renal disease). Enrollment of subjects with known or suspected metastatic cancer, as well as subjects with an acute event (ie, cardiac arrest, viral encephalitis, ischemic or haemorrhagic cerebral event) within 2 weeks prior to Pre-treatment Period must be discussed with Vanderbilt Coordinating Center (VCC) and documented before randomization. 13. The subject has known esophageal varices, chronic jaundice, cirrhosis, or chronic ascites. 14. The subject is in a chronic vegetative state or has a similar long-term neurological condition. 15. The subject has known portal hypertension or Child-Pugh hepatic impairment class C (Appendix H). 16. The subject has had acute third degree burns involving more than 30% of body surface within 120 hours prior to Pre-treatment Period. 17. The subject has known hypersensitivity to sulfonamides. 18. The subject has known hypersensitivity to components of TAK-242; eg, is allergic to eggs, egg products, or soybeans. 19. The subject has participated in any other investigational study (drug or device) and/or taken any investigational drug within 30 days or 5 half-lives of the drug, whichever is longer, before initiation of the study drug infusion. 20. The subject is unwilling or the investigator feels the subject will be unable to be fully evaluated during the 28-day study period. 21. The subject is a study site employee, or is an immediate family member (eg, spouse, parent, child, sibling) of a study site employee, directly involved in the conduct of the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy end point is 28-day all-cause mortality.
The secondary efficacy endpoints of the study include the following:
To evaluate the effects of TAK-242 on organ function (cardiovascular, respiratory, central nervous sytem, renal, coagulation and hepatic) as measured by the Sequential Organ Failure Assessment (SOFA) score.
To evaluate clinical improvement as measured by Systemic Inflammatory Response Syndrome (SIRS)-free, vasopressor-free days, ventilator-free days, time in ICU, and discharge location status.
To evaluate the safety of TAK-242 administration.
To determine the pharmacodynamic effect of TAK-242 on the level of Tumour necrosis Factor (TNF)-alpha, IL-6, IL-8, IL-10, Procalcitonin (PCT) and C-Reactive Protein (CRP).
To further characterise the pharmacokinetic profile of TAK-242, M-I and M-III.
Exploratory endpoints include quality of life and health economic impact of TAK-242 administration.
The safety endpoints include adverse events, laboratory test results, vital signs and ECG data. |
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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 | 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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
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 | 95 |
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 | Information not present in EudraCT |
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 |
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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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Last visit of the last subject |
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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 months | 27 |