E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Respiratory Distress Syndrome (ARDS)
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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] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003083 |
E.1.2 | Term | ARDS |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10085269 |
E.1.2 | Term | ARDS disease progression |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
The primary objective is to demonstrate a difference in the time to initial unassisted breathing (UAB) in patients receiving FX06 compared to patients receiving placebo until day 28.
• Time to initial unassisted breathing (UAB) until day 28 in both treatment groups Unassisted breathing is defined as: Without invasive ventilation for 48h consecutively for patients with invasive ventilation at BL and neither invasive nor non-invasive ventilation (including HFNO) for 48h consecutively for patients with non-invasive ventilation (including HFNO) at BL. Continuous or bilevel positive airway pressure (CPAP, BIPAP) solely for sleep-disordered breathing management is not defined as assisted breathing. Also, non-mechanical oxygen supplementation will not be defined as assisted breathing.
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E.2.2 | Secondary objectives of the trial |
- Disease progression/improvement based on Berlin Definition - Proportion of patients with respiratory support - days with ventilation and ventialtor-free days - days on ECMO - patients alive and UAB - patients that achieved initial UAB - patients achieving extubation - patients that needed intubation - patients returning to assisted breathing or mechanical ventilation - patients needing catecholamine hemodynamic support - patients receiving kinetic therapy - Lung function (e.g. PaO2, FiO2, Horowitz Index, pCO2, LPEEP, Pinsp, FiO2, vasodilator use, high-flow oxygen, oxygen saturation) - inflammation markers and their change and normalization - Mortality rate - Survival censored - normal and pathological capillary refill time - Length of hospital and ICU stay - Location where patients have been discharged to - Subgroup analysis by concomitant medication, age, sex, and ARDS cause - AEs/SAEs, type, severity and their relatedness to IMP - injection-related AEs |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Hospitalised patients with mild to moderate ARDS according to the Berlin Definition of ARDS or patients with assisted breathing (without the use of PEEP) and high oxygen demand (e.g., HFNO ≥ 30 L/min) who fulfil the other criteria of the Berlin Definition of ARDS (modified Berlin criteria) (for clarification see Table 1) 2. Patients ≥ 18 years 3. Randomization within 48h of ARDS diagnosis 4. Written informed consent obtained prior to the initiation of any protocol-required procedures by the patient or his/her legal representative 5. Patients or their legal representatives able to understand the requirements of the study and give written informed consent
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E.4 | Principal exclusion criteria |
1. >48 hours of invasive mechanical ventilation before randomization 2. Severe ARDS according to the Berlin Definition 3. Evidence of other significant uncontrolled concomitant diseases or serious and/or uncontrolled diseases with a bad prognosis that are likely to interfere with the evaluation of the patient’s safety and with the study outcome as judged by the treating physician, e.g.: o Other severe advanced or chronic lung diseases (e.g., COPD Gold ≥ 3, severe silicosis) o Acute respiratory failure due to cardiac failure (NYHA ≥ III) or fluid overload o Advanced hepatic insufficiency or severe liver disease (e.g., liver cirrhosis CHILD C) o Use of chronic (> 3 months) long-term oxygen therapy before randomization o Exacerbation of asthma o Septic shock 4. Any contraindications to use the IMP (e.g., allergy or intolerance against the IMP or its ingredients) 5. Is currently being detained in an institution by a governmental or judicial order 6. Do not intubate order 7. Women pregnant or breastfeeding 8. Males or females of reproductive potential not willing to use effective contraception for the duration of the study period (defined as PEARL index –1 - e.g., contraceptive pill, IUD or true sexual abstinence, bilateral tubal occlusion or male partner with vasectomy; also see chapter 19.2 for guidance) 9. Current participation in another interventional clinical trial with IMP or participation within the last 30 days
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective is to demonstrate a difference in the time to initial unassisted breathing (UAB) in patients receiving FX06 compared to patients receiving placebo until day 28.
• Time to initial unassisted breathing (UAB) until day 28 in both treatment groups Unassisted breathing is defined as: Without invasive ventilation for 48h consecutively for patients with invasive ventilation at BL and neither invasive nor non-invasive ventilation (including HFNO) for 48h consecutively for patients with non-invasive ventilation (including HFNO) at BL. Continuous or bilevel positive airway pressure (CPAP, BIPAP) solely for sleep-disordered breathing management is not defined as assisted breathing. Also, non-mechanical oxygen supplementation will not be defined as assisted breathing.
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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) |
Secondary objectives and endpoints: Assessment and treatment comparison of the following objectives at all available visits and time points between the FX06 and placebo group:
• Disease progression/improvement - Proportion of patients with improved or worsened disease state compared to baseline based on Berlin Definition (mild, moderate, severe, or no ARDS) - Proportion of patients with each Berlin Definition classification (mild, moderate, severe, or no ARDS) - Proportion of patients with respiratory support (non-invasive, invasive, ECMO, HFNO, low flow oxygen, non-mechanical oxygen supplementation) - Number of days with ventilation (invasive vs non-invasive ventilation (incl. HFNO)) until day 28 and day 60 - Number of days on ECMO unitl day 28 and day 60 - Number of ventilator-free days until day 28 - Number and proportion of patients alive and breathing without assistance at day 28 and day 60 - Proportion of patients that achieved initial UAB within 28 days -Proportion of patients achieving extubation until day 28 and day 60 (for those patients intubated at BL) - Proportion of patients that needed intubation (invasive ventilation) until day 28 (for those patients that were not intubated at BL) - Proportion of patients returning to assisted breathing or mechanical ventilation (after achievement of initial UAB as defined above) - Proportion of patients needing catecholamine hemodynamic support to achieve target blood pressure and cumulative dosage of catecholamine drugs - Proportion of patients receiving kinetic therapy to improve pulmonary function and cumulative duration of prone positioning up to day 28
• Lung function (partial oxygen pressure in the blood, fraction of inspired oxygen, Horowitz index) at BL, D3, D6, D10 and D28 - Absolute PaO2 (mmHg) values - Absolute FiO2 (mmHg, fraction of inspired oxygen) - Horowitz Index (mmHg) and change to BL - pCO2 value and change to baseline - Lung compliance (ml/cm H2O) and change to BL - Respiratory minute volume and change to baseline - Absolute and relative change in applied Positive-End-Expiratory Pressure (PEEP) - Absolute and relative change in applied inspiratory pressure support (Pinsp) - Absolute and relative change in applied flow-rate and FiO2 when using high-flow oxygen therapy -Proportion of patients using pulmonary vasodilators (eg. nitric oxide or prostaglandin) - Proportion of patients reaching > 92% oxygen saturation under room air
For respiratory parameters the worst value over 24h at the respective day will be documented for the study
• Systemic inflammation (changes and normalisation in troponin, procalcitonin, CRP, leukocyte count, ferritin, D-dimers, lactate, lactate dehydrogenase, albumin, IL-6) - Concentration of blood parameters and their change to BL - Proportion of patients with normalized systemic inflammation (for each inflammation parameter)
• Survival / Mortality - Mortality rate at day 28 and day 60 - Survival censored at day 28 and day 60
• Capillary refill time - Proportion of patients with normal and pathological capillary refill time at baseline (as pathological: ≥2 s or normal: <2 s) and change to BL
• Duration of hospital and ICU stay - Length of hospital and ICU stay until day 28 or until day 60 - Proportion of patients that have been discharged from the hospital and/or the ICU until day 28 and day 60 - Location where patients have been discharged to (if applicable; e.g. home, rehabilitation centre)
• Subgroup analysis by concomitant medication, age, sex, and ARDS cause - Proportion of patients with a specific type of concomitant medication (e.g., antibiotics, corticosteroids, antibody therapy, etc.), by age group, by sex, and by ARDS cause - Comparison of patients with different concomitant medications, age groups, sex, and ARDS cause in terms of safety events and efficacy parameters Safety • Safety parameters (evaluated for safety set) - Number of adverse events and serious adverse events - Type and severity (mild, moderate, severe) of all adverse events - (s)AEs and their relatedness to treatment - Mean number per patient and total number of injection-related (s)AEs within 1 h after injection of IMP |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
BL, day 28, day 60 and day 3, day 6 and day 10 |
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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 | 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
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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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data base hard lock In order to fulfil sponsor obligations (ICH E6[R2]) by monitoring and source data verification at site to confirm data integrity and patient safety the definition LVLS/LPLV cannot be used as end of trial. The access to hospitals and isolated departments as ICUs are hindered to avoid spreading of various potential infections. Therefore, site monitoring visits and site data corrections within eCRF may only be performed significantly after LVLS/LPLV. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |