E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients in ICU with septic shock who remain tachycardic (HR ≥95 bpm) and require vasopressor therapy to maintain a Mean arterial pressure (MAP) of ≥65 mmHg after a hemodynamic optimization period (at least 12 hours and up to 36 hours). |
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E.1.1.1 | Medical condition in easily understood language |
Septic shock / Tachycardia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10043071 |
E.1.2 | Term | Tachycardia |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.1 |
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 compare the rate of patients with heart rate response (80-94 bpm) and maintenance thereof without increase in vasopressor requirements in the first 24 hours in a septic shock population with persistent tachycardia (≥95bpm) randomized to either Group L or Group C.
Group L: will receive standard treatment according to SSCG 2016 and treatment with LDLL300 for the duration of vasopressor treatment And Group C: will receive standard treatment according to SSCG 2016 which is not specifically targeted to the HR control |
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E.2.2 | Secondary objectives of the trial |
To further assess efficacy and safety in the two treatment arms. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Informed consent (signed informed consent by the patient or a legal representative or other country-specific documentation, as required) 2) Age ≥18 years 3) Confirmed septic shock: a. Confirmed or suspected infection b. Acute increase of ≥2 points on SOFA Score c. Need for continuous vasopressor therapy to maintain a mean arterial pressure (MAP) of >65 mmHg despite adequate fluid resuscitation d. Blood lactate >2mmol/L (18mg/dl) Presence of blood lactate >2mmol/L (18mg/dl) and increase of ≥2 points on SOFA Score are only necessary for the diagnosis of septic shock but not at time of study inclusion 4) Tachycardia and/or tachyarrhythmia with heart rate ≥95 beats/min 5) Norepinephrine infusion (any dose) at the time of study inclusion 6) Patients must have undergone a haemodynamic optimization period of at least 12 hours but a maximum of 36 hours, during which period they received continuous vasopressor treatment and standard treatment for septic shock according to the SSCG 2016 guidelines |
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E.4 | Principal exclusion criteria |
1. Any form of compensatory tachycardia 2. β-blocker treatment after septic shock diagnosis 3. Sick Sinus syndrome 4. Severe atrioventricular (AV) nodal conductance disorders (without pacemaker); 2nd or 3rd degree AV block 5. A known serious cardiovascular condition such as ischemic stroke or transient ischaemic attack within last 6 months, or preexisting heart failure New York Heart Association Class IV 6. Cardiogenic shock 7. MAP <65 mmHg 8. Known pulmonary hypertension 9. Known terminal illness other than septic shock with expected patient’s survival <28 days 10. Known presence of an advanced condition to withhold life-sustaining treatment 11. Patients for whom a “Do Not Resuscitate” (DNR) exists 12. Known sensitivity to any component of the study medication (e.g. Landiolol, mannitol) 13. Participation in a clinical drug trial within 30 days prior randomization or prior participation in the LANDI-SEP trial 14. Any condition that, in the Investigator’s opinion, makes the subject unsuitable for study participation (to be documented) 15. Pregnant or breast feeding patients 16. Untreated Pheochromocytoma 17. Anticipated to be in need of beta-blocker therapy prior to vasopressor discontinuation due to their prior medication/ medical history (Investigator ́s opinion) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Heart rate response (80-94 bpm) and maintenance thereof and no increase in vasopressor requirements during the first 24 hours |
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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) |
1) Change in vasopressor requirements over the study period (dose and duration). 2) Heart rate response (80-94bpm) during the first 24 hours. 3) 28 day mortality (all cause). 4) ICU mortality (all cause). 5) Duration of ICU stay in (survivors/non-survivors). 6) Duration of hospital stay (survivors/non-survivors). 7) SOFA score (as long as the patient is treated with vasopressors) on day 1, 2, 3, 4, 7, 10, 13, 16, 19, 22, 25 and 28. 8) Daily inotropic requirements (as long as the patient is treated with vasopressors). Secondary Safety Endpoints: 1) Incidence rate of bradycardic episodes requiring intervention. 2) Incidence of Adverse Events (AE). 3) Incidence of Serious Adverse Events (SAE) |
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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 | 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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
standard treatment for septic shock according to the SSCG 2016 guidelines |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
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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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |