E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of Staphylococcus aureus Pneumonia in Heavily Colonized, Mechanically Ventilated Subjects |
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E.1.1.1 | Medical condition in easily understood language |
Pneumonia in Mechanically Ventilated Subjects |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
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 evaluate the safety, tolerability, and efficacy of a single dose of ASN100 (administered as ASN-1 and ASN-2 components) versus placebo for the prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized with S. aureus. |
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E.2.2 | Secondary objectives of the trial |
•To compare the duration of mechanical ventilation post-treatment in subjects treated with ASN100 versus placebo; •To compare the length of stay in the intensive care unit (ICU) post-treatment for subjects treated with ASN100 versus placebo; •To determine the serum pharmacokinetics (PK) (i.e., maximum serum concentration [Cmax], time to maximum serum concentration [Tmax], area under the serum concentration-time curve [AUC], and terminal elimination half-life [t1/2]) of ASN-1 and ASN-2 in mechanically ventilated subjects heavily colonized with S. aureus; and •To compare 28-day all-cause mortality in subjects treated with ASN100 versus placebo.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Bronchoalveolar lavage (BAL) fluid pharmacokinetic sub-study Approximately 25 to 30 subjects will participate in this sub-study and will have BAL fluid collected 48 hours (±36 hours) post-dose (on Day 2 or Day 3, depending on time of study drug administration) to determine ASN-1 and ASN-2 levels and and calculate a blood to epithelial lining fluid (ELF) ratio. The version date and number are the same as the ASN100-201 study |
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E.3 | Principal inclusion criteria |
1.Subject or legally authorized representative or CIP (if applicable) has provided written informed consent; 2.Subject is 18 years of age or older at the time of enrollment; 3.Subject is currently hospitalized and is mechanically ventilated endotracheally (i.e., orotracheal or nasotracheal) and, in the Investigator’s opinion, will require ongoing ventilator support for at least 48 hours; NOTE: Subjects with a tracheostomy at the time of enrollment are not eligible. After enrollment, conversion to tracheostomy is permitted per standard of care. 4.Female subjects must not be pregnant or lactating. Female subjects of childbearing potential must have a documented negative pregnancy test at the Screening Visit. Female subjects may be enrolled on the basis of a negative urine pregnancy test, pending the result of a negative serum pregnancy test prior to randomization; and 5.Female subjects of childbearing potential and non-surgically sterile male subjects who are sexually active must agree to use an approved highly effective form of contraception from the time of informed consent until 165 days post dose. Approved forms of contraception include hormonal intrauterine devices (IUD), hormonal contraceptives (oral birth control pill, depot, patch or injectable) together with supplementary double barrier methods such as condoms or diaphragms with spermicidal gel or foam. NOTE: The following categories define women who are NOT considered to be of childbearing potential: •Premenopausal female with 1 of the following: o Documented hysterectomy, o Documented bilateral salpingectomy, or o Documented bilateral oophorectomy, or •Postmenopausal female, defined as having amenorrhea for at least 12 months without an alternative medical cause.
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E.4 | Principal exclusion criteria |
1.Subject has received intravenous (IV) immunoglobulin therapy within 4 months prior to the Screening Visit; 2.Subject has a chest X-ray or thoracic computed tomography (CT) scan that is definitive for a diagnosis of pneumonia; 3.Subject demonstrates both of the following: a.Need for acute changes in ventilator support to enhance oxygenation or to the amount of positive end-expiratory pressure; and NOTE: Changes made in ventilator support due to day to day maintenance other than those changes made to improve oxygenation will not exclude a subject from participation in the study. b.New onset of purulent suctioned respiratory secretions; 4.Subject has a known and documented ETA culture showing heavy colonization with a Gram negative organism at enrollment or at any time during the Screening period; NOTE: Randomization should not be delayed while waiting for Gram-negative results if heavy colonization with S. aureus has been confirmed. 5.Subject has been diagnosed with neutropenia (absolute neutrophil count 500/mm3); 6.Subject has a severe non-pulmonary source of infection which, in the Investigator’s opinion, would interfere with the conduct of the study or jeopardize the subject’s safety; 7.Subject is currently on either continuous veno- venous hemodialysis or extracorporeal membrane oxygenation; 8.Subject has been previously exposed to ASN100 or ASN-1 or ASN-2, individually; 9.Subject has a known hypersensitivity to ASN100 or any of its excipients; 10.Subject has received any investigational product within 30 days prior to the Screening Visit (or 5 half-lives of the investigational product, whichever is longer); 11.Subject has, in the opinion of the Investigator, a high probability of death within 72 hours of enrolment; 12.Subject is, in the opinion of the Investigator, not able or willing to comply with the protocol; 13.Any condition that, in the opinion of the Investigator, would compromise the safety of the subject, the potential activity of the study drug , or the quality of the data; or 14.Subjects with known history or current (suspected) diagnosis of cytokine release syndrome associated with the administration of peptides, proteins, and/or antibodies. NOTE: Subject with a prior history of sepsis are not excluded. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects in the Modified Intent-to-Treat (MITT) Population who develop S. aureus pneumonia as defined in the protocol Section 7.4 up to but not including Day 22. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Endotracheal aspirates will be collected for culture during the screening period to determine the degree of S. aureus. Additional respiratory specimens may be collected throughout the monitoring period if clinically indicated. Subjects will be assessed daily throughout the monitoring period for clinical signs and symptoms of pneumonia. |
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E.5.2 | Secondary end point(s) |
•Duration of mechanical ventilation during the first 21 days post-randomization for subjects in the MITT, Intent-to-Treat (ITT), and Per Protocol (PP) Populations; •Length of ICU stay during the first 21 days post-randomization for subjects in the MITT, ITT, and PP Populations; •The Cmax, Tmax, AUC, and t1/2 of ASN-1 and ASN-2 in serum following a single dose of ASN100 in the PK Population; and •28-day all-cause mortality in the MITT, ITT, and PP Population.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Microbiological and clinical assessments will be done throughout the monitoring period. |
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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 | 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) | 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 | 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 | 45 |
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 |
Austria |
Czech Republic |
France |
Georgia |
Germany |
Hungary |
Israel |
Italy |
Poland |
Portugal |
Russian Federation |
Spain |
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |