Ignite Creation Date:
2024-05-06 @ 10:52 AM
Last Modification Date:
2024-10-26 @ 12:37 PM
Study NCT ID:
NCT03376854
Status:
WITHDRAWN
Last Update Posted:
2021-04-30
First Post:
2017-12-07
Brief Title:
Pilot RCT of Therapeutic Hypothermia Plus Neuromuscular Blockade in COVID-19 Patients With ARDS
Sponsor:
University of Maryland Baltimore
Organization:
University of Maryland Baltimore
Study Overview
Official Title:
Pilot Randomized Clinical Trial of Therapeutic Hypothermia Plus Neuromuscular Blockade vs Standard of Care in COVID-19 Patients With Moderate to Severe ARDS - the Cooling to Help Injured Lungs CHILL Pilot Study
Status:
WITHDRAWN
Status Verified Date:
2021-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Competition from other studies and initiation of a larger multi center trial
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CHILL-pilot
Brief Summary:
Acute Respiratory Distress Syndrome ARDS is a serious condition that occurs as a complication of medical and surgical diseases has a mortality of 40 and has no known treatment other than optimization of support Data from basic research animal models and retrospective studies case series and small prospective studies suggest that therapeutic hypothermia TH similar to that used for cardiac arrest may be lung protective in patients with ARDS however shivering is a major complication of TH often requiring paralysis with neuromuscular blocking agents NMBA to control Since the recently completed NHLBI PETAL ROSE trial showed that NMBA had no effect good or bad in patients with moderate to severe ARDS the investigators sought to evaluate whether TH combined with NMBA is beneficial in patients with ARDS The investigators are scheduled to begin enrolling in a Department of Defense-funded Phase IIb multicenter RCT of TH core temperature 34-35C NMBA for 48h vs usual temperature management in patients with ARDS with time on ventilator as the primary outcome Since COVID-19 is now the most common cause of ARDS we are conducting a pilot study to examine the safety and feasibility of including patients with COVID-19-associated ARDS in our upcoming trial In this pilot we will randomize 20 patients with COVID-19 and ARDS to either THNMBA for 48h or usual temperature management The primary outcome is achieving and maintaining the target temperature Secondary outcomes include safety physiologic measures mortality hospital and ICU length of stay and serum biomarkers collected on days 0 1 2 3 4 and 7
Detailed Description:
Background
Despite recent advances in supportive care for patients with acute respiratory distress syndrome ARDS mortality remains 40 Fever worsens and hypothermia mitigates animal models of ALI and in small non-randomized in patients with ARDS Since hypothermia reduces oxygen utilization as long as shivering is blocked TH may reduce injury in part by allowing lower levels of assisted ventilation TH likely exerts additional lung protective effects by directly modifying temperature-dependent cellular processes in endothelium epithelium and leukocytes Neuromuscular blockade NMB is the ultimate treatment to block shivering and is frequently used in patients with ARDS to facilitate ventilator management Since the recently completed NHLBI PETAL ROSE trial showed that NMB caused conferred neither benefit nor harm in patients with moderate to severe ARDS the investigators have bundled TH with NMB to reduce shivering An open-label study of 8 ARDS patients showed that studying TH NMB in patients with moderate to severe ARDS was feasible Moreover the patients treated with TH NMB had more 28-day ventilator-free days VFDs ICU-free days ICU-FDs and greater hospital survival 75 vs 25 p 0027 than historical controls with ARDS and NMB but without TH Within the limits of historical comparisons these results support further study of TH in ARDS A Department of Defense-funded Phase IIb multicenter trial of THNMB in patients with moderate to severe ARDS will begin enrolling in Fall 2020 Since COVID-19 has become the most common cause of ARDS it is important to understand whether patients with COVID-19-associated ARDS can be included in the multicenter trial
Focus of Study We will conduct a single-site feasibility and safety RCT pilot of THNMB for 48h vs usual temperature management in 20 patients with COVID-19-associated ARDS We will also analyze efficacy markers to help decide whether the treatment duration 48h to be used in the multicenter trial is appropriate for patients with COVID-19-associated ARDS The results of this pilot help us decide whether to include patients with COVID-19-associated ARDS in our planned multicenter trial of THNMB in ARDS from all causes or to pursue a separate trial focused on patients with COVID-19-associated ARDS
Primary and secondary objectives The primary objective is to assess the safety and feasibility of the 48h THNMB treatment protocol The secondary objective is to compare the THNMB and control arms for efficacy markers to be used in the multicenter trial
Study design The CHILL trial is a single center RCT
Intervention The study intervention is TH to core temperature 34-35C NMB for 48h Patients in the THNMB arm will receive deep sedation continuous infusion of cisatracurium and mechanical ventilation for at least 48h Decisions about transition to unassisted breathing extubation and transfer from ICU will be based on criteria in the CHILL study protocol
THNMB Once sedation and NMB are confirmed TH to 34-35C will be initiated using surface cooling Temperature will be measured from a central probe Once target temperature is reached TH will be maintained for 48h Patients will then be rewarmed to 355C by 03Ch and the cooling devices removed Post-TH fever suppression is not part of the CHILL protocol and will be performed at the discretion of the primary ICU team THNMB will be aborted for persistent severe bradycardia uncontrolled bleeding and intractable arrhythmias
Usual temperature management Patients will receive light sedation RASS 0 to -1 During the 54h post-randomization treatment period acetaminophen will be given for core temperature 38C and surface cooling will be initiated if core temperature remains 38C within 45 minutes of receiving acetaminophen and adjusted to maintain core temperature 38C If core temperature 36C patients in this arm will receive surface warming to core temperature 37C Following the 54h treatment period temperature will be managed at the discretion of the primary ICU team
Concomitant Treatment Since prone positioning independently improves survival in ARDS starting and stopping rules for prone positioning have been protocolized
Primary and Secondary Endpoints
Primary endpoint The low and high core temperatures in each 2-hour period will be recorded for each of the first four study days The time required to reach the target temperature and the percent of readings within the target range in the THNMB arm will be determined
Secondary endpoints
Clinical a 28-day VFDs The 28-day VFDs will be calculated at day 28 b 28-day ICU-FDs The 28-day ICU-FDs will be calculated at day 28 c day 0 1 2 3 4 and 7 non-neurologic SOFA score d Glasgow coma score at hospital discharge e 60- and 90-day survival f 60- and 90-day functional status The Montreal Cognitive Assessment Tool MOCA will be administered at ICU and hospital discharge
Physiologic a day-3 and -7 driving pressure b day-3 and day-7 oxygen saturation index OSI
Plasma Biomarker Day 0 1 2 3 4 and 7 plasma IL-1ß IL-6 IL-8 IL-18 soluble-RAGE surfactant protein-D soluble ICAM-1 MMP8 and soluble TNFRI
Safety
1 For the first 54h a continuous cardiac monitoring for bradycardia with associated hypotension requiring iv fluid or vasopressors b every 6h blood glucose measurement c every 12 h potassium magnesium and phosphate d significant bleeding event requiring 2u packed red blood cells or surgical or interventional radiologic intervention
2 First 7 days a Ventilator-associated pneumonia VAP b other secondary infections c monitor for SAEs
Schedule of Clinical and Laboratory Evaluations
1 Definitions
1 Day 0 day of randomization
2 Comprehensive metabolic panel CMP includes basic electrolytes BUN creatinine ALT AST alkaline phosphatase bilirubin calcium magnesium phosphate C-reactive protein CRP
3 CBC complete blood count
4 Driving Pressure Plateau Pressure - PEEP with patient NOT making inspiratory effort on NMB or post-NMB and observed RR at set ventilator rate
5 OSI Mean airway pressure x 100 x FIO2SpO2
2 Clinical and Research laboratory testing Two purple top EDTA 14 ml blood tubes will be collected for biomarker analysis at randomization and on study days 1 2 3 4 and 7 at 800-1000 on study days 1 2 3 4 and 7 Clinical laboratory testing required for secondary clinical outcomes at enrollment and on study days 1 2 3 4 and will be performed as part of usual clinical care whenever possible at 600-1000 AM and 600-1000 PM
3 Day -2 to 0 Screening and enrollment To facilitate randomization within the inclusion window we will consent and enroll based on partial fulfillment of randomization criteria and randomize once all criteria are met Patients with COVID-19 receiving mechanical ventilation for 7 days and have bilateral pulmonary opacities not fully explained by pleural effusions atelectasis or hydrostatic pulmonary edema for 48h will be offered enrollment and will be randomized when PF ratio is 200 In patients without arterial blood gas values the PF ratio will be inferred from SpO2 readings as described by Brown et al Chest 150307 2016
1 Pregnancy testing in women of child-bearing years
2 Obtain informed consent from patient or Legally Authorized Representative LAR depending on capacity
3 Complete Screening enrollment and randomization CRFs
4 If PF200 at enrollment proceed with randomization otherwise follow until PF 200 or patient exits the 48 hr ARDS or 7 day mechanical ventilation windows
3 Day 0 Randomization day Pt identified in screen
1 Obtain baseline plasma for research testing If 8h since last CBC and CMP or 24 since last CRP send new samples to lab
2 Randomize
3 If patient does not have a central temperature probe place esophageal probe
4 For THNMB arm confirm adequate sedation RASS -4 and NMB Train of four 2 twitch and initiate TH protocol
5 Complete Randomization Worksheet and Randomization and Baseline Data CRFs
6 Note time cooling initiated and time patient first reached target temperature on Baseline CRF
4Day 1-4
a Fill out Daily CRFs b Collect plasma for research testing c Measure Driving Pressure and OSI d Make sure CBC and CMP sent every 12h and CRP every 24h e Rewarming starts after 48h cooling on day 3 f Complete Unassisted Breathing Checklist form if applicable g Assess for adverse events
5 Days 5-6
a Follow for ventilator status ICU status survival SAEs b Follow CRP daily c Complete Unassisted Breathing Checklist form if applicable d Assess for adverse events
6 Day 7
a Fill out Day 7 CRF b Collect plasma for research testing c Measure Driving Pressure and OSI d Make sure CBC CMP and CRP sent e Complete Unassisted Breathing Checklist form if applicable f Assess for adverse events
7 Day 8-27
a Follow for ventilator status ICU status survival SAEs b Complete Unassisted Breathing Checklist form if applicable
8 Day 28
1 Complete Day 28 CRF
2 Calculate 28 day VFDs and ICU-FDs
9 When patient is discharged from the ICU complete ICU discharge CRF
10 When patient is discharged from the hospital complete Hospital discharge CRF
11 Day 60 and 90 Follow up about patient status Complete phone follow-up CRF
Study population Adult patients with COVID-19 diagnosed by PCR testing within previous 2 weeks and moderate to severe ARDS based on Berlin criteria PF 200 while on PEEP 8 cm H2O 48h in duration
Data Analysis This is a pilot trial to determine whether patients with COVID-19-associated patients with ARDS should be included in a multicenter trial of THNMB in patients with ARDS from all causes The data from this pilot will not be merged with data from the planned multicenter trial The primary analysis of this pilot study will be to determine the effectiveness of the THNMB protocol in maintaining targeted temperature and to determine whether there are any safety issues with the THNMB protocol in this patient population
Data Management Data for this pilot RCT will be recorded on paper CRFs Completion of all fields will be checked in real-time The forms have been designed to be compatible with the electronic versions developed for the multicenter trial
Randomization Plan The investigators will use a randomization protocol stratified for proning status using pre-generated random assignment lists Assignments will be made using an in-house Excel-based assignment tool which blinds the observer to the assignment list
Subject Participation Duration The duration of intervention TH NMB vs usual temperature management is 48h followed by rewarming for 3-6h in the TH group NMB will be discontinued and sedation reduced when subjects are rewarmed to core temperature 355C In the control group fever and hypothermia during continuous renal replacement therapy CRRT will be treated by protocol for 54h post-randomization Physiologic and clinical parameters will be collected through study day 7 In hospital follow-up up to 90 days will include determination of 28-day VFDs and ICU-FDs and day of hospital discharge When the patient regains competence consent for continued participation will be obtained
Study Duration Completion of enrollment is anticipated within 6 months
Despite recent advances in supportive care for patients with acute respiratory distress syndrome ARDS mortality remains 40 Fever worsens and hypothermia mitigates animal models of ALI and in small non-randomized in patients with ARDS Since hypothermia reduces oxygen utilization as long as shivering is blocked TH may reduce injury in part by allowing lower levels of assisted ventilation TH likely exerts additional lung protective effects by directly modifying temperature-dependent cellular processes in endothelium epithelium and leukocytes Neuromuscular blockade NMB is the ultimate treatment to block shivering and is frequently used in patients with ARDS to facilitate ventilator management Since the recently completed NHLBI PETAL ROSE trial showed that NMB caused conferred neither benefit nor harm in patients with moderate to severe ARDS the investigators have bundled TH with NMB to reduce shivering An open-label study of 8 ARDS patients showed that studying TH NMB in patients with moderate to severe ARDS was feasible Moreover the patients treated with TH NMB had more 28-day ventilator-free days VFDs ICU-free days ICU-FDs and greater hospital survival 75 vs 25 p 0027 than historical controls with ARDS and NMB but without TH Within the limits of historical comparisons these results support further study of TH in ARDS A Department of Defense-funded Phase IIb multicenter trial of THNMB in patients with moderate to severe ARDS will begin enrolling in Fall 2020 Since COVID-19 has become the most common cause of ARDS it is important to understand whether patients with COVID-19-associated ARDS can be included in the multicenter trial
Focus of Study We will conduct a single-site feasibility and safety RCT pilot of THNMB for 48h vs usual temperature management in 20 patients with COVID-19-associated ARDS We will also analyze efficacy markers to help decide whether the treatment duration 48h to be used in the multicenter trial is appropriate for patients with COVID-19-associated ARDS The results of this pilot help us decide whether to include patients with COVID-19-associated ARDS in our planned multicenter trial of THNMB in ARDS from all causes or to pursue a separate trial focused on patients with COVID-19-associated ARDS
Primary and secondary objectives The primary objective is to assess the safety and feasibility of the 48h THNMB treatment protocol The secondary objective is to compare the THNMB and control arms for efficacy markers to be used in the multicenter trial
Study design The CHILL trial is a single center RCT
Intervention The study intervention is TH to core temperature 34-35C NMB for 48h Patients in the THNMB arm will receive deep sedation continuous infusion of cisatracurium and mechanical ventilation for at least 48h Decisions about transition to unassisted breathing extubation and transfer from ICU will be based on criteria in the CHILL study protocol
THNMB Once sedation and NMB are confirmed TH to 34-35C will be initiated using surface cooling Temperature will be measured from a central probe Once target temperature is reached TH will be maintained for 48h Patients will then be rewarmed to 355C by 03Ch and the cooling devices removed Post-TH fever suppression is not part of the CHILL protocol and will be performed at the discretion of the primary ICU team THNMB will be aborted for persistent severe bradycardia uncontrolled bleeding and intractable arrhythmias
Usual temperature management Patients will receive light sedation RASS 0 to -1 During the 54h post-randomization treatment period acetaminophen will be given for core temperature 38C and surface cooling will be initiated if core temperature remains 38C within 45 minutes of receiving acetaminophen and adjusted to maintain core temperature 38C If core temperature 36C patients in this arm will receive surface warming to core temperature 37C Following the 54h treatment period temperature will be managed at the discretion of the primary ICU team
Concomitant Treatment Since prone positioning independently improves survival in ARDS starting and stopping rules for prone positioning have been protocolized
Primary and Secondary Endpoints
Primary endpoint The low and high core temperatures in each 2-hour period will be recorded for each of the first four study days The time required to reach the target temperature and the percent of readings within the target range in the THNMB arm will be determined
Secondary endpoints
Clinical a 28-day VFDs The 28-day VFDs will be calculated at day 28 b 28-day ICU-FDs The 28-day ICU-FDs will be calculated at day 28 c day 0 1 2 3 4 and 7 non-neurologic SOFA score d Glasgow coma score at hospital discharge e 60- and 90-day survival f 60- and 90-day functional status The Montreal Cognitive Assessment Tool MOCA will be administered at ICU and hospital discharge
Physiologic a day-3 and -7 driving pressure b day-3 and day-7 oxygen saturation index OSI
Plasma Biomarker Day 0 1 2 3 4 and 7 plasma IL-1ß IL-6 IL-8 IL-18 soluble-RAGE surfactant protein-D soluble ICAM-1 MMP8 and soluble TNFRI
Safety
1 For the first 54h a continuous cardiac monitoring for bradycardia with associated hypotension requiring iv fluid or vasopressors b every 6h blood glucose measurement c every 12 h potassium magnesium and phosphate d significant bleeding event requiring 2u packed red blood cells or surgical or interventional radiologic intervention
2 First 7 days a Ventilator-associated pneumonia VAP b other secondary infections c monitor for SAEs
Schedule of Clinical and Laboratory Evaluations
1 Definitions
1 Day 0 day of randomization
2 Comprehensive metabolic panel CMP includes basic electrolytes BUN creatinine ALT AST alkaline phosphatase bilirubin calcium magnesium phosphate C-reactive protein CRP
3 CBC complete blood count
4 Driving Pressure Plateau Pressure - PEEP with patient NOT making inspiratory effort on NMB or post-NMB and observed RR at set ventilator rate
5 OSI Mean airway pressure x 100 x FIO2SpO2
2 Clinical and Research laboratory testing Two purple top EDTA 14 ml blood tubes will be collected for biomarker analysis at randomization and on study days 1 2 3 4 and 7 at 800-1000 on study days 1 2 3 4 and 7 Clinical laboratory testing required for secondary clinical outcomes at enrollment and on study days 1 2 3 4 and will be performed as part of usual clinical care whenever possible at 600-1000 AM and 600-1000 PM
3 Day -2 to 0 Screening and enrollment To facilitate randomization within the inclusion window we will consent and enroll based on partial fulfillment of randomization criteria and randomize once all criteria are met Patients with COVID-19 receiving mechanical ventilation for 7 days and have bilateral pulmonary opacities not fully explained by pleural effusions atelectasis or hydrostatic pulmonary edema for 48h will be offered enrollment and will be randomized when PF ratio is 200 In patients without arterial blood gas values the PF ratio will be inferred from SpO2 readings as described by Brown et al Chest 150307 2016
1 Pregnancy testing in women of child-bearing years
2 Obtain informed consent from patient or Legally Authorized Representative LAR depending on capacity
3 Complete Screening enrollment and randomization CRFs
4 If PF200 at enrollment proceed with randomization otherwise follow until PF 200 or patient exits the 48 hr ARDS or 7 day mechanical ventilation windows
3 Day 0 Randomization day Pt identified in screen
1 Obtain baseline plasma for research testing If 8h since last CBC and CMP or 24 since last CRP send new samples to lab
2 Randomize
3 If patient does not have a central temperature probe place esophageal probe
4 For THNMB arm confirm adequate sedation RASS -4 and NMB Train of four 2 twitch and initiate TH protocol
5 Complete Randomization Worksheet and Randomization and Baseline Data CRFs
6 Note time cooling initiated and time patient first reached target temperature on Baseline CRF
4Day 1-4
a Fill out Daily CRFs b Collect plasma for research testing c Measure Driving Pressure and OSI d Make sure CBC and CMP sent every 12h and CRP every 24h e Rewarming starts after 48h cooling on day 3 f Complete Unassisted Breathing Checklist form if applicable g Assess for adverse events
5 Days 5-6
a Follow for ventilator status ICU status survival SAEs b Follow CRP daily c Complete Unassisted Breathing Checklist form if applicable d Assess for adverse events
6 Day 7
a Fill out Day 7 CRF b Collect plasma for research testing c Measure Driving Pressure and OSI d Make sure CBC CMP and CRP sent e Complete Unassisted Breathing Checklist form if applicable f Assess for adverse events
7 Day 8-27
a Follow for ventilator status ICU status survival SAEs b Complete Unassisted Breathing Checklist form if applicable
8 Day 28
1 Complete Day 28 CRF
2 Calculate 28 day VFDs and ICU-FDs
9 When patient is discharged from the ICU complete ICU discharge CRF
10 When patient is discharged from the hospital complete Hospital discharge CRF
11 Day 60 and 90 Follow up about patient status Complete phone follow-up CRF
Study population Adult patients with COVID-19 diagnosed by PCR testing within previous 2 weeks and moderate to severe ARDS based on Berlin criteria PF 200 while on PEEP 8 cm H2O 48h in duration
Data Analysis This is a pilot trial to determine whether patients with COVID-19-associated patients with ARDS should be included in a multicenter trial of THNMB in patients with ARDS from all causes The data from this pilot will not be merged with data from the planned multicenter trial The primary analysis of this pilot study will be to determine the effectiveness of the THNMB protocol in maintaining targeted temperature and to determine whether there are any safety issues with the THNMB protocol in this patient population
Data Management Data for this pilot RCT will be recorded on paper CRFs Completion of all fields will be checked in real-time The forms have been designed to be compatible with the electronic versions developed for the multicenter trial
Randomization Plan The investigators will use a randomization protocol stratified for proning status using pre-generated random assignment lists Assignments will be made using an in-house Excel-based assignment tool which blinds the observer to the assignment list
Subject Participation Duration The duration of intervention TH NMB vs usual temperature management is 48h followed by rewarming for 3-6h in the TH group NMB will be discontinued and sedation reduced when subjects are rewarmed to core temperature 355C In the control group fever and hypothermia during continuous renal replacement therapy CRRT will be treated by protocol for 54h post-randomization Physiologic and clinical parameters will be collected through study day 7 In hospital follow-up up to 90 days will include determination of 28-day VFDs and ICU-FDs and day of hospital discharge When the patient regains competence consent for continued participation will be obtained
Study Duration Completion of enrollment is anticipated within 6 months
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None