E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Catecholamine-resistant distributive shock |
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E.1.1.1 | Medical condition in easily understood language |
Catecholamine-resistant distributive shock |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040070 |
E.1.2 | Term | Septic shock |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 compare the effectiveness of continuous infusion PHP plus conventional vasopressor therapy to that of placebo (normal saline) plus conventional vasopressor therapy in patients with catecholamine-resistant distributive shock. Efficacy will be demonstrated by PHP significantly reducing 28-day all-cause mortality.
· To compare over 28 days the safety and tolerability of continuous infusion PHP plus conventional vasopressor therapy to the safety and tolerability of placebo plus conventional vasopressor therapy by evaluating mortality, morbidity measured by indicators of organ failure, and the frequency and duration of adverse effects.
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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 |
SIRS Inclusion Criteria Patients with SIRS as characterized by two or more of the following conditions (worst values in a 24 hour period): a) Either respiratory rate ≥ 20 breaths/minute, or partial pressure of arterial carbon dioxide (PaCO2) ≤ 32 torr, or mechanical ventilation b) Heart rate ≥ 90 beats/minute c) Either hyperthermia ≥ 38°C, or hypothermia ≤ 36°C d) Either white blood cell (WBC) ≥ 12,000 cells/mm3, ≤ 4,000 cells/mm3, or ≥ 10% immature (band) forms
Shock Inclusion Criteria Patients with adequate fluid resuscitation (see guidelines in Section IV.G.) and requiring a norepinephrine dose of ≥0.3 mcg/kg/min for at least one hour to maintain a MAP ≥ 65 mmHg but ≤ 80 mmHg within the first 24 hours of the initiation of norepinephrine treatment.
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E.4 | Principal exclusion criteria |
Exclusion Criteria · Patients who lack documented Informed Consent signed by the patient or his/her legally authorized representative · Patients that are pregnant · Patients less than 18 years old · Patients with suspicion of or active treatment for coronary artery disease within 60 days of enrollment defined as any of the following: - Acute myocardial infarction with an abnormal ECG indicative for myocardial infarction or abnormal regional wall motion (echocardiography) - Unstable angina with abnormal regional wall motion (echocardiography) and/or EF < 35% -Coronary revascularization (angioplasty, stenting, coronary bypass graft) if EF < 35 % - Patients who have received a stent within the last 12 months · Patients with suspicion of or active treatment for malignant arrhythmia within 60 days of enrollment defined as any of the following: - Ventricular Tachycardia - Ventricular Fibrillation - Appropriate defibrillator firing in patient with AICD Note: A pacemaker is not an exclusion criterion. · Patients with suspicion of or active treatment for congestive heart failure within 60 days of enrollment defined as any of the following: -Ejection fraction < 35% and LV end-diastolic dimension > 6.0 cm demonstrated by echocardiography or MUGA -Hospitalization primarily for congestive heart failure -NYHA Class IV congestive heart failure · Patients with suspicion of or active treatment for aortic valve heart disease within 60 days of enrollment defined as any of the following: - Aortic valve stenosis with area < 1.0 cm2 - Severe aortic insufficiency - After aortic valve replacement if EF < 35% (If there is no history of coronary artery disease, malignant arrhythmia, congestive heart failure, or aortic valve heart disease, the patient may be enrolled without further cardiac evaluation. If history is ambiguous, an echocardiogram may be performed to exclude suspected diagnosis (e.g. to assess ejection fraction or aortic valve performance). Patients successfully treated for any of the above conditions earlier than 60 days before enrollment, who are asymptomatic and in stable clinical condition, may be enrolled (e.g. CABG 1 year before with no ongoing angina). This rule is not applied in patients with stents. Prior to randomization, the cardiac status of the subject, from the perspective of study eligibility, must be documented in the medical or research record, and be supported by the baseline medical history. · Patients with stage 3 or 4 solid tumors (TMN classification, group staging), hematologic malignancies with high tumor burden, CNS cancer (WHO stage 3 and 4)unless significant tumor mass was removed near occurence of shock. · Patients with dead bowel likely to result in death. After surgical removal of dead bowel the patient can be enrolled. · Patients receiving/scheduled to receive another investigational drug or have received an investigational drug in the previous 30 days · Patients with known hypersensitivity to blood products · Patients with hypovolemic shock from bleeding or other volume loss . Patients with anaphylactic shock · Patients who are likely to die within days for diseases or conditions other than catecholamine-dependent shock (e.g. multiple organ failure that is irreversible as distinct from multiple organ dysfunction that may resolve) · Patients with Glasgow Coma Score ≤ 7 at the time of admission and prior to the administration of confounding medications such as narcotics, sedatives or neuromuscular blockers · Patients that experienced trauma within the past 48 hours · Patients that experienced burns within the past 48 hours ·
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be 28 day all-cause mortality |
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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) |
- All-cause mortality at days 3, 7, 14, and 21; - Survival time; - Survivor days in the ICU censored at 28 days; - Survivors' hospital length of stay censored at 28 days; - Time on mechanical ventilation, - Time on pressors. - All-cause mortality at days 60 and 90 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3,7,14, 21, 28, 60 and 90 days |
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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 | 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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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End of the trial will be the 90 day follow up contact with the patient (last visit). |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |