E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Vasodilatory hypotension in early septic shock |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
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 establish Proof-of-Concept for specific V1a agonism in patients with vasodilatory hypotension in early septic shock (stabilisation of adequate blood pressure)
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E.2.2 | Secondary objectives of the trial |
a) To assess the pharmacokinetics of FE 202158 in patients with vasodilatory hypotension in early septic shock
b) To assess the pharmacodynamic effects of FE 202158 with special focus on blood pressure, vascular leakage and inflammatory response.
c) To detect early signals suggestive of clinical efficacy of FE 202158 (morbidity and mortality)
d) To assess the safety and tolerability of FE 202158 in patients with vasodilatory hypotension in early septic shock
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All of the following inclusion criteria must be met before the subject can enter into the trial:
1. Signed informed consent form by the patient or a legal representative according to local regulations
2. Man or woman 18 years of age or older
3. Proven or suspected infection
4. Vasodilatory hypotension (systolic blood pressure less than 90 mmHg or decrease in systolic blood pressure by at least 40 mmHg for more than one hour) that has not responded to fluid (20 ml/kg of crystalloid or 10 ml/kg of colloid), requiring norepinephrine at a dose of at least 0.1 µg/kg/min, or a minimal dose of 11.5 µg/min (males) and 10.0 µg/min (females) for patients with a body weight above 115 kg (men) or 100 kg (women) for at least 2 hours
5. Signs of tissue hypoperfusion (at least one of the following criteria): Oliguria (< 0.5 ml/kg/hr for 1 hour), decreased Glasgow Coma Score (< 13) if fully assessable, i.e. only in non-sedated and non-ventilated patients, decreased PaO2/FiO2 ratio (≤ 300 in the presence of other dysfunctional organs or systems than the lung or ≤ 200 if the lung is the only dysfunctional organ), increased arterial blood lactate (≥ 2.5 mmol/L).
6. Willing to use an adequate barrier method or hormonal method of contraception, if not abstinent, from informed consent to one week after the end of infusion of study medication. |
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E.4 | Principal exclusion criteria |
Any subject meeting one or more of the following exclusion criteria can not be included in the trial:
1. Present or a history (within the last 5 years) of acute coronary syndrome (myocardial infarction or unstable angina). Patients who have been asymptomatic for 6 months after coronary revascularisation are eligible. Known or suspected coronary ischemia.
2. Hypovolaemia suspected on clinical grounds, e.g. cold extremities with delayed capillary filling, low cardiac filling pressure, marked systolic or pulse pressure variation or positive leg raising test
3. Known or suspected cardiac failure, e.g. CI < 3 l/min/ m2, left ventricular ejection fraction (LVEF) ≤ 40 %, bilateral pulmonary edema/congestion and cardiomegaly, ScvO2 (superior vena cava) < 64 %, known or suspected coronary ischemia, cold extremities with delayed capillary filling, distended neck veins.
4. Pregnancy or breastfeeding
5. Any cause of hypotension other than early septic shock
6. Use of vasopressin or terlipressin for blood pressure support during the current hospital admission
7. Proven or suspected acute mesenteric ischemia, as judged by the investigator
8. Known episode of septic shock within 1 month prior to randomisation
9. Death anticipated within 24 hours
10. Underlying chronic heart disease, including heart failure NYHA class III or IV
11. Known past or current 2nd and 3rd degree AV-block without a well functioning pacemaker
12. Hyponatremia (serum/plasma sodium <130 mmol/L)
13. Traumatic brain injury (Glasgow Coma Score <8 prior to onset of sepsis)
14. Present hospitalisation with burn injury
15. Symptomatic peripheral vascular disease including Raynaud’s syndrome
16. Previously randomised in this trial
17. Intake of an IMP within the last 3 months (or longer if judged by the Investigator to possibly influence the outcome of the current study)
18. Known participation in another clinical trial
19. Considered by the investigator to be unsuitable to participate in the trial for any other reason |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints:
Stabilisation of blood pressure
a) Proportion of patients maintaining target MAP with no open label NE at 12 hours, 24 hours, 48 hours, 96 hours and Day 7
b) Proportion of patients maintaining target MAP at 12 hours, 24 hours, 48 hours, 96 hours and Day 7
c) Cumulative dose and infusion rates of open label NE (every 12 hours for 3 days, then daily) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 96 hours and Day 7 |
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E.5.2 | Secondary end point(s) |
Pharmacokinetics, Pharmacodynamics, Effect on vascular leakage, safety and tolerability, morbidity, mortality |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Several - please refer to protocol |
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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 | No |
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 | 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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Belgium |
Canada |
Denmark |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |