ITHACA: A phase 2, randomized, single-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of the complement C3 inhibitor, AMY-101, in COVID-19 patients with acute respiratory distress syndrome (ARDS).

INTERVENTION: Product Name: AMY‐101 acetate (also known as Cp40 and Cp‐14 in the scientific literature/ documentation) Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: Not available yet CAS Number: 1427001‐89‐5 Current Sponsor code: AMY‐101 acetate Other descriptive name: S3,S13‐CYCLO(D‐TYROLSYL‐L‐ISOLEUCYL‐L‐CYSTEINYL‐L‐VALYL‐1‐METHYL‐L‐TRYPTOPHYL‐L‐GLUTAMINYL‐L‐ASPARTYL‐L‐TRYPTOPHYL‐N‐METHYL‐L‐GLYCYL‐L‐ALANYL‐L‐HISTIDYL‐L‐ARGINYL‐L‐CYSTEINYL‐N‐METHYL‐L‐ISOLEUCINAMIDE) ACETATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Solution for infusion Route of administration of the placebo: Intravenous drip use (Noncurrent) CONDITION: Severe COVID‐19, with Acute Respiratory Distress Syndrome (ARDS). ; MedDRA version: 23.0 Level: LLT Classification code 10084270 Term: SARS‐CoV‐2 acute respiratory disease System Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Respiratory Tract Diseases [C08] PRIMARY OUTCOME: Main Objective: The primary objective is to assess the impact of AMY‐101 on the survival without ARDS and without oxygen requirement at day 14 in patients with severe COVID‐19. Primary end point(s): The primary endpoint of the study is the proportion of patients who are alive, without evidence of ARDS (as denoted by PaO2/FIO2 >300 mm Hg), who do not require any oxygen support (in room air), at day 14. Secondary Objective: The secondary objectives are to assess the safety, further measures of clinical efficacy and PK/PD of AMY‐101 in patients. Timepoint(s) of evaluation of this end point: Day 14 INCLUSION CRITERIA: 1.Adult (age = 18), of any gender. 2.Diagnosed with Acute Respiratory Distress Syndrome due to SARS‐CoV‐2 infection (severe COVID‐19), according to the following criteria: a)Demonstration of SARS‐CoV‐2 RNAemia in nasopharyngeal swab or bronchio‐alveolar lavage (BAL) (note: the test that will be used for SARS‐CoV‐2 RNAemia is certified with the CE mark and will be used within the scope of its intended purpose) b)A ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2), PaO2/FIO2, =300 mmHg c)Pulmonary infiltrates suggestive of SARS‐COV‐2‐related ARDS: e.g., bilateral infiltrates at chest X‐ray or B‐lines at lung US scan 3.Dated and signed informed consent from patient or legal represantatives. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of s SECONDARY OUTCOME: Secondary end point(s): ‐Clinical status will be assessed on a six‐category ordinal scale, looking to the proportion of patients assigned to each category at day 7, 14, 21 and 44.; Six‐category ordinal scale in accordance to Wang Y, et al., Lancet 2020:; •1: not hospitalized; ; •2: hospitalized, not requiring supplemental oxygen; ; •3: hospitalized, requiring supplemental oxygen; ; •4: hospitalized, requiring nasal high‐flow oxygen therapy, non‐invasive mechanical ventilation, or both; ; •5: hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and ; •6: death; ; ‐Proportion of patients surviving on day 44.; ; ‐Respiratory failure‐free survival, at day 44, with respiratory failure defined as any of the following (Nava S and Hill N, 2009): ; 1)Worsening of severe gas transfer deficit, accounting for a shift in ARDS disease category (PaO2/FiO2 =200 for patients with PaO2/FiO2 >200 at baseline; PaO2/FiO2 =100 for patients with PaO2/FiO2 >100 at baseline), ; 2)Persistent respiratory distress while receiving oxygen (persistent marked dyspnea, use of accessory respiratory muscles, paradoxical respiratory movements), ; 3)?ransfer to the intensive care unit for intubation, ; 4)Death.; ; ‐Cumulative incidence of resolution of ARDS (defined as PaO2/FiO2 =300 in room air) through day 44; ; ‐Cumulative incidence of freedom from O2 requirement through day 44; ; ‐Proportion of patients requiring invasive mechanical ventilation due to worsening of ARDS within 14 days after inclusion in the study ; ; ‐Proportion of patients requiring non‐invasive mechanical ventilation (NIV) due to worsening of ARDS within 14 days after inclusion in the study ; ; ‐Proportion of patients developing thrombotic complications (thrombotic macro‐ or/and micro‐angiopathy or/and thromboembolism) through day 44; ; ‐Changes in PaO2 and PaO2/FIO2 ; ; ‐Changes in respiratory rate ; ; ‐Changes in quick Sequential Organ Failure Assessment Score (qSOFA: respiratory rate, systolic blood pressure, Glasgow Coma Scale (GCS) ; ; ‐Changes in maximal and minimal cardiovascular parameters (RR, HR) per day; ; ‐Changes in biomarkers of thromboinflammation (CBC, CRP, LDH, Ferritin, D‐dimers, markers of NETosis) on day 0, 1, 2, 4, 7, 10, 14, 21 and 44; ; ‐Length of stay in ICU (days); ; ‐Cumulative incidence of discharge from hospital ; ; ; Safety:; ‐All severe adverse events through day 44; ‐All adverse events through day 44; ‐All infectious events through day 44; ‐Anti‐drug antibodies on day 0, 21 and 44; ; ; PK/PD on day 0, 1, 2, 4, 7, 10, 14, 21 and 44.; ; Timepoint(s) of evaluation of this end point: Up to day 44