| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Septic shock and respiratory failure. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10040070 |
| E.1.2 | Term | Septic shock |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038695 |
| E.1.2 | Term | Respiratory failure |
|
| 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 objective is to evaluate the effects of TAK-242 on all-cause mortality as compared to placebo during the 28-day period from the start of study drug administration. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives include an evaluation of the safety profile of TAK-242 vs. placebo, evaluation of the effects of TAK-242 vs. placebo in vasopressor free days, ventilator free days, and ICU free days. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject is aged 18 years or older.
2. The subject has a suspected or proven bacterial or fungal infection for which he or she is receiving parenteral antimicrobial therapy.
3. The subject has developed at least 3 of the 4 following SIRS criteria within 36 hours prior to start of study drug administration:
a. A temperature from any site >38°C (>100.4°F) or a core temperature (ie, rectal or central) <36°C (<96.8°F).
b. 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.
c. Respiratory rate of >20 breaths/min or arterial partial pressure of carbon dioxide of <32 mm Hg or mechanical ventilation for an acute process.
d. 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.
4. The subject has septic shock diagnosed within 36 hours prior to study drug administration. Septic shock is defined as hypotension with a persistent requirement for vasopressors to maintain systolic blood pressure >90 mm Hg or mean arterial pressure (MAP) >60 mm Hg, despite adequate fluid resuscitation (eg, >20 mL/kg) or documentation of a central venous pressure >8 mm Hg or a pulmonary artery occlusion pressure >12 mm Hg. Vasopressor is defined as >5 µg/kg/min dopamine or any dose of norepinephrine, epinephrine, vasopressin, or phenylephrine.
5. The subject has developed respiratory failure within 36 hours prior to study drug
administration. Respiratory failure is defined as a ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FIO2) of <200 while receiving positive pressure ventilation via tracheal tube.
6. The central trial coordinating center, VCC, has approved subject eligibility.
7. The subject or the subjects legally authorized representative has provided written informed consent. |
|
| E.4 | Principal exclusion criteria |
1. The subject has received any investigational compound within 30 days (or 5 half-lives of the drug, whichever is longer) prior to the initiation of the study drug infusion or is participating in another investigational study, not including investigational compound, without prior approval from the VCC/sponsor.
2. The subject is a study site employee, or is an immediate family member (ie, spouse, parent, child, sibling) of a study site employee, involved in conduct of this study.
3. A female subject who is pregnant or nursing.
4. The subject is currently receiving any immunosuppressive therapy (excluding glucocorticoids) such as methotrexate, azathioprine, anti tumor necrosis factor α (TNF-α), or a cancer related chemotherapeutic agent.
5. The subject has a known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
6. The subject has a methemoglobin level of ≥5% at pretreatment period or has a known history of methemoglobinemia.
7. The subject is moribund and death is considered imminent.
8. Prior to the onset of sepsis, the subject would not otherwise have been expected to survive 28 days or to complete a functional recovery due to a pre-existing unstable medical condition (eg, a recent acute cerebral hemorrhage or infarct, a recent acute unstable myocardial infarction, severe traumatic injury).
9. The subject has a poorly controlled or metastatic neoplasm.
10. The subject, family, or physician is not committed to full aggressive management or the presence of an unstable medical condition makes the receipt of full aggressive management support unlikely in the view of the coordinating center. The presence of a do not resuscitate order does not automatically exclude participation.
11. The subject has severe end stage chronic respiratory failure or lung disease that significantly impairs physical functioning equivalent to that of New York Heart Association (NYHA) functional classification III or IV.
12. The subject has a documented history of moderate to severe chronic heart failure as defined by NYHA functional classification III or IV.
13. The subject has received electrocardioversion for a pulse-less rhythm or chest compressions during their current hospitalization.
14. The subject is known to be immunocompromised such as subjects with human immunodeficiency virus and a CD4 count <50 mm3, primary immune deficiency or chronic lymphocytic leukemia.
15. The subject has chronic end stage hepatic failure or significant sequelae of chronic hepatic failure (eg, esophageal varices, jaundice, chronic ascites) or Child-Pugh hepatic impairment Classification C.
16. The subject is in a chronic vegetative state or has a similar long-term neurological impairment, where continued aggressive care would be unlikely.
17. The subject has acute third degree burns involving more than 30% of body surface area within 120 hours of first qualifying organ failure.
18. The subject has known hypersensitivity to sulphonamides.
19. The subject has known hypersensitivity to components of TAK-242; for example, is allergic to eggs, egg products, or soybeans. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be 28-day all-cause mortality.
|
|
| 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 | 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 | 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.8.3 |
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 | 150 |
| 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 |
|
| 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
|
| End of the Long Term Follow-up Period for the last patient. |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 8 |
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