Ultraprotective Ventilation Without Extracorporeal Circulation During COVID 19 Pneumonia (VT4COVID)

• ClinicalTrials.gov Identifier: NCT04349618
• Recruitment Status: Not yet recruiting
• First Posted: April 16, 2020
• Last Update Posted: April 16, 2020
• Sponsor: Hospices Civils de Lyon
• Information provided by (Responsible Party): Hospices Civils de Lyon

Tracking Information

• First Submitted Date: April 8, 2020
• First Posted Date: April 16, 2020
• Last Update Posted Date: April 16, 2020
• Estimated Study Start Date: April 14, 2020
• Estimated Primary Completion Date: July 14, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2020)

A composite score based on all-cause mortality and the number of ventilator free-days (VFD) [ Time Frame: Day 90 ]

For an alive patient at day 90, the score will be built as follow: a value +1 will be given for comparisons to dead patients and alive patients with a lower number of VFD. For comparisons to alive patients with a higher number of VFD a value -1 will be given and in case of identical number of VFD a value 0 will be given. For a dead patient a value -1 will be given for comparisons to alive patients and 0 for comparisons to dead patients. For a given patients the score will correspond to the sum of values resulting to the comparison to all patients of the other group. A higher score indicates a more favorable result.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: April 14, 2020)

• All-cause mortality (intention to treat) [ Time Frame: 90-day after inclusion ]
  All-cause mortality with analysis in intention to treat, i.e. each patient will be analyzed in his initial randomization group regardless of whether the allocated strategy was effectively applied or not.
• Ventilator-free days (VFD) [ Time Frame: day 60 after inclusion ]
  VFD will be computed as follows from the day of inclusion: VFD= 0 if the patient dies between inclusion and day 60 VFD = 60-x if the patient is successfully weaned from invasive mechanical ventilation x days after inclusion. Successful weaning from mechanical ventilation is defined by extubation without reintubation within at least 48 hours (or weaning from mechanical ventilation for at least 48 hours in patients with tracheostomy) VFD= 0 if the patient is mechanically ventilated for more than 60 days after inclusion
• All-cause mortality with per protocol analysis [ Time Frame: 90-day ]
  Per protocol analysis will be carried out by comparing the group of patients in whom median daily tidal volume from inclusion to weaning of deep sedation will be lower of equal to 4.2 ml/kg of predicted body weight to the group of patients in whom median tidal volume from inclusion to weaning of deep sedation will be greater than 4.2 ml/kg of predicted body weight, whatever the patients' initial randomization group. Weaning of deep sedation is defined by a Richmond Agitation Sedation (RASS) score greater than -3 for at least 48 hours.
• Time to successful extubation [ Time Frame: 60 days ]
  Successful extubation is defined by extubation without reintubation within at least 48 hours (or weaning from mechanical ventilation for at least 48 hours in patients with tracheostomy) Data will be right censored at 60 days and death will be taken into account as a competing risk.
• Length of hospital stay [ Time Frame: 90 days ]
  Data will be right censored at 90 days and death will be taken into account as a competing risk.
• Respiratory parameters assessed daily from inclusion to weaning of deep sedation or 14 days whichever comes first [ Time Frame: 14 days ]
  Weaning of deep sedation is defined by a Richmond Agitation Sedation (RASS) score greater than -3 for at least 48 hours.
• Daily sedation dose during the first 14 days of the study [ Time Frame: 14 days ]
  Doses of the following drugs used for deep sedation will be assessed daily: midazolam, propofol and opioid. Opioid dose will be expressed as morphine equivalent with the following conversion factor: 1µg of sufentanil = 10 µg of fentanyl = 1 mg of morphine
• Rate of use of rescue therapies [ Time Frame: 14 days ]
  Rescue therapies are any therapy among the following ones: neuromuscular blocking agents, prone position, nitric oxide, recruitment maneuvers, ECMO
• Incidence density rate of severe mixed acidosis [ Time Frame: ICU stay ]
  Severe mixed acidosis is defined by the association of pH<7.15 and PaCO2>45 mm Hg.
• Incidence density rate of ventilator associated pneumonia [ Time Frame: ICU stay ]
  Ventilator associated pneumonia will be defined as any pneumonia acquired under mechanical ventilation after inclusion.
• Incidence density rate of acute cor pulmonale [ Time Frame: ICU stay ]
  Acute cor pulmonale is defined by the association of right ventricle dilatation (right ventricle surface / left ventricle surface >0,6) and septal dyskinesia assessed by echocardiography
• Incidence density rate of barotrauma [ Time Frame: ICU stay ]
  Barotrauma is defined by any pneumothorax OR pneumomediastinum OR subcutaneous emphysema, OR pneumatocele of more than 2 cm detected on image examinations.
• Incidence density rate of any serious adverse events [ Time Frame: ICU stay ]
  Serious adverse event is any life threatening event OR any event resulting in death.
• Cognitive impairment assessed by phone call using the Telephone Montreal Cognitive Assessment (T-MoCA) test [ Time Frame: Day 365 after inclusion ]
  The Telephone Montreal Cognitive Assessment score will be assessed by phone call. The total score ranges from 0 to 30; higher scores being associated to a better outcome.
• Quality of life assessed by the RAND 36-Item Health Survey (SF-36) score [ Time Frame: Day 365 after inclusion ]
  The RAND 36-Item Health Survey (SF-36) score will be assessed by phone call. The score ranges from 0 to 100; higher scores being associated to a better outcome.
• Post-traumatic stress disorder assessed by the Impact of Event Scale - revised (IES-R) score by phone call [ Time Frame: Day 365 after inclusion ]
  The Impact of Event Scale - revised (IES-R) score will be assessed by phone call. The total score ranges from 0 to 88; higher scores being associated to a worse outcome.
• Cost-efficacy ratio of the innovative strategy compared to the reference strategy [ Time Frame: Day 90 after inclusion ]
  The cost-efficacy ratio will be computed as the ratio of cost difference on efficacy difference between the intervention arm and the reference arm. The costs taken into account will be the direct hospitalized costs. The efficacy will be assessed as the number of days alive free from mechanical ventilation.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ultraprotective Ventilation Without Extracorporeal Circulation During COVID 19 Pneumonia
• Official Title: Open Label Randomized Controlled Trial of Ultraprotective Ventilation Without Extracorporeal Circulation in Patients With COVID 19 Pneumonia and Moderate to Severe ARDS

Brief Summary

Mortality of COVID-19 pneumonia with acute respiratory distress syndrome (ARDS) is extremely high in preliminary reports amounting to 50-60%. Duration of mechanical ventilation in these patients appears to exceed standard duration of mechanical ventilation in non-COVID-19 ARDS patients, suggesting that COVID-19 patients may be particularly at risk for ventilator-induced lung injury. Treatment of COVID-19 ARDS patients is to date mainly supportive with protective mechanical ventilation (ventilation with low tidal volume (VT) i.e. 6 ml/kg of predicted body weight (PBW) and plateau pressure control below 30 cm H2O).

Mechanical ventilation with VT reduction below 6 ml/kg PBW in ARDS may reduce alveolar strain, driving pressure and hence ventilator-induced lung injury. Investigators recently performed a multicenter pilot study on 34 moderately severe to severe ARDS patients. This study demonstrated that ultraprotective ventilation with ultra-low VT (≤4.2 ml/kg PBW) without extracorporeal circulation may be applied in approximately 2/3 of the patients, with a 4 cmH2O median reduction in driving pressure, at the price of transient episodes of severe acidosis in approximately 1/3 of the patients. Investigators hypothesized that ultraprotective ventilation without extracorporeal circulation may reduce the mortality at day-90 and increase the number of days free from mechanical ventilation (VFD) at day-60, as compared to protective ventilation.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Respiratory Distress Syndrome
• COVID19
• Sars-CoV2
• Pneumonia

Intervention

• Other: PROTECTIVE VENTILATION
  Protective ventilation with tidal volume 6 mL/kg of predicted body weight further adjusted to keep plateau pressure below 30 cm H2O and pH above 7.20, and PEEP set using the PEEP FiO2 table of the ARMA trial
• Other: ULTRAPROTECTIVE VENTILATION
  Ultraprotective ventilation with tidal volume reduction down to 4 mL/kg further adjusted to keep plateau pressure below 30 cm H2O and pH above 7.20, and PEEP set using the PEEP FiO2 table of the ARMA trial

Study Arms

• Active Comparator: PROTECTIVE VENTILATION
  Protective ventilation with tidal volume 6 mL/kg of predicted body weight
  Intervention: Other: PROTECTIVE VENTILATION
• Experimental: ULTRAPROTECTIVE VENTILATION
  Ultraprotective ventilation with tidal volume reduction down to 4 mL/kg further adjusted to keep plateau pressure below 30 cm H2O and pH above 7.20
  Intervention: Other: ULTRAPROTECTIVE VENTILATION

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: April 14, 2020): 200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 14, 2022
• Estimated Primary Completion Date: July 14, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adults aged 18 years or older
• ARDS according to the Berlin definition
• COVID-19 pneumonia confirmed by RT-PCR
• Acute respiratory failure not fully explained by left ventricular failure or sodium overload
• Bilateral pulmonary radiological opacities not fully explained by pleural effusions or atelectasis or nodules
• Invasive mechanical ventilation with PaO2/FiO2 ≤ 150 mm Hg and PEEP ≥ 5 cm H2O with a tidal volume below or equal to 6 ml per kilogram of predicted body weight
• Continuous intravenous sedation as part of ARDS treatment

Exclusion Criteria:

• Exclusion criteria related to ARDS history

  • ARDS onset more than 48 hours before inclusion
  • previous inclusion in present study

• Exclusion criteria related to ARDS severity or complications

  • arterial pH < 7.21 despite respiratory rate set to 35/min at the time of inclusion
  • patient under any extracorporeal CO2 removal technique or ECMO
  • pneumothorax or bronchopleural fistula

• Exclusion criteria related to comorbidities

  • suspected intracranial hypertension
  • severe chronic obstructive pulmonary disease defined by a GOLD score ≥ 3
  • chronic respiratory failure under home oxygen or non-invasive ventilation
  • chronic respiratory failure requiring long term oxygen or non-invasive ventilation
  • obesity with body weight over height ratio greater than 1 kg/cm
  • sickle cell disease
  • bone marrow transplant < 6 months
  • burn injury with extension greater than 30% of body surface area
  • cirrhosis with Child-Pugh score C
  • advance directives to withhold or withdraw life sustaining treatment

• Exclusion criteria related to legislation

  • Patient under an exclusion period relative to participation to another clinical trial, or inclusion into a clinical trial interfering with the ventilatory strategies
  • pregnancy, lactating women
  • patient under a legal protective measure.
  • lack of affiliation to social security as required by French regulation
  • lack of written informed consent by patient or next of kin (unless if recourse to the emergency procedure in the absence of a loved one)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jean-Christophe RICHARD, Pr; 04 26 10 92 72 ext +33; j-christophe.richard@chu-lyon.fr

Contact: Loredana BABOI; loredana.baboi@chu-lyon.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT04349618
• Other Study ID Numbers: 69HCL20_0322
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Hospices Civils de Lyon
• Study Sponsor: Hospices Civils de Lyon
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Hospices Civils de Lyon
• Verification Date: April 2020