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Effects and Safety of Infusion of Low-Doses of Methylprednisolone in Early ALI and ARDS in Children (PEDALI)

Primary Purpose

Acute Lung Injury, Acute Respiratory Distress Syndrome

Status
Withdrawn
Phase
Phase 2
Locations
Brazil
Study Type
Interventional
Intervention
Methylprednisolone Arm
Sterile Saline Arm
Sponsored by
Universidade Federal do Rio de Janeiro
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lung Injury focused on measuring ALI, Acute Lung Injury, ARDS, Acute Respiratory Distress Syndrome, Pediatric Critical Care Medicine, Inflammatory Response

Eligibility Criteria

29 Days - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of ALI/ARDS within the first 72 hours based on all of the following criteria:

    • Respiratory failure requiring mechanical ventilation - via endotracheal intubation or noninvasive positive pressure ventilation;
    • Acute onset of bilateral pulmonary densities on chest radiograph in the context of appropriate predisposing injury or illness with no evidence of left ventricular failure;
    • Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2:FiO2 ) ≤ 300 (criteria for ALI) or 200 (criteria for ARDS) with FiO2 ≥ 0,5 and PEEP = 5 cmH2O.
  • To sign the Informed Consent to participate.

Exclusion Criteria:

  • ALI/ARDS with more than 72 hours of diagnosis
  • Failure to obtain written informed consent to participate in the study;
  • Condition requiring > 0.5mg/Kg/day of prednisone equivalent (i.e., acute asthma or bronchopulmonary dysplasia)
  • Patients enrolled in another experimental (interventional) protocol within the past 30 days, which might adversely impact on the results of this study as determined by the investigators;
  • Primary or secondary neuromuscular dysfunction
  • Patients using aminoglycosides combined with neuromuscular blockers
  • Cardiopulmonary arrest within 7 days or anytime during present hospitalization prior to enrollment;
  • Irreversible cessation of all brain function;
  • Immunosuppression, including HIV+ status, history of bone marrow or solid organ transplantation, current malignancy, neutropenia, receiving cytotoxic therapy for any reason, and acute burn injury;
  • Severe chronic liver disease (Child-Pugh Class C score > 10 points).

Sites / Locations

  • Universidade Federal do Rio de Janeiro

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Methylprednisolone Arm

Sterile Saline Arm

Arm Description

The patients in this arm will receive methylprednisolone, which is available in vials containing 125 mg/2mL after dilution, as it follows: Day 0 Loading dose 1 mg/kg IV bolus mixed in 5 mL NS (30 min) followed by continuous infusion Days 0 to 07 - 1 mg/kg/day mixed in 24cc NS and infused at 1 cc/hr Days 08 to 10 - 0.5 mg/kg/day mixed in 24cc NS and infused at 1 cc/hr Days 11 to 12 - 0.25 mg/kg/day Days 13 to 14 - 0.125 mg/kg/day

Patients randomized to the control arm will receive sterile normal saline in an amount that would equal the total diluted dose of study drug (ie. if initial loading dose equals a total of 24 cc [methylprednisolone + diluting fluid], then the patient will receive 24 cc of sterile normal saline). Tapering doses will be equivalent to that of the study arm, so that investigators will remain blinded to therapy. The unblinded party will be composed of the research ARDS pharmacist. Five days after the patient is able to ingest medications, placebo is administered per os (PO) in one single daily equivalent dose. The placebo will be manipulated by the pharmacist as to resemble identical to the active drug.

Outcomes

Primary Outcome Measures

Effects on pulmonary organ function
a ≥ 1-point reduction in LIS by study day 7 or successful extubation by day 7 For patients remaining intubated on study day 7, improvement in lung function is defined as a 7-day LIS ≤ 2 (if initial LIS ≤ 2,9) or a 7-day LIS ≥ 2,5 (if initial LIS ≥ 3) Duration of mechanical ventilation defined as: ventilator free days at 28 days of entry study days of mechanical ventilation on day 28

Secondary Outcome Measures

Effects on extra-pulmonary organ function
pediatric multiple organ dysfunction score (P-MODS) by study day 7
Effects on inflammatory process
Levels of CRP, TNFα, IL-6, IL-8, IL-10 by study day 7
Effects on hospitalization-related outcomes
Length of PICU stay

Full Information

First Posted
December 21, 2012
Last Updated
July 8, 2020
Sponsor
Universidade Federal do Rio de Janeiro
Collaborators
Instituto de Puericultura e Pediatria Martagão Gesteira - IPPMG/UFRJ, Instituto D'Or de Pesquisa, Rio de Janeiro State Research Supporting Foundation (FAPERJ)
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1. Study Identification

Unique Protocol Identification Number
NCT01757899
Brief Title
Effects and Safety of Infusion of Low-Doses of Methylprednisolone in Early ALI and ARDS in Children
Acronym
PEDALI
Official Title
Phase II, Randomized, Placebo-Controlled, Double-Blind Clinical Trial to Evaluate the Effects and Safety of Infusion of Low-Doses of Methylprednisolone in Early ALI and ARDS in Children
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Withdrawn
Why Stopped
Technical problems
Study Start Date
January 2014 (Anticipated)
Primary Completion Date
January 2016 (Anticipated)
Study Completion Date
January 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Universidade Federal do Rio de Janeiro
Collaborators
Instituto de Puericultura e Pediatria Martagão Gesteira - IPPMG/UFRJ, Instituto D'Or de Pesquisa, Rio de Janeiro State Research Supporting Foundation (FAPERJ)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to investigate the effects of prolonged low-dose methylprednisolone infusion on pulmonary function (LIS and ventilation-free days), extra pulmonary organ function (PMODS score), inflammatory markers - RCP (Reactive C Protein), IL6 (Interleukine 6), TNFα (Tumor Necrosis Factor), IL8 (Interleukine 8), IL10 (Interleukine 10) and length of Pediatric Intensive Care Unit (PICU) stay in early ALI/ARDS in children.
Detailed Description
Scientific background. Dysregulated systemic inflammation - characterized by protracted elevation of inflammatory cytokines in the circulation - is a key pathogenetic mechanism for morbidity and mortality in ALI/ARDS, and is associated with tissue insensitivity and/or resistance to inappropriately elevated endogenous glucocorticoids. In one study, prolonged methylprednisolone treatment of ARDS patients resulted in rapid and sustained reduction in circulating and pulmonary levels of pro-inflammatory cytokines, chemokines, and procollagen. Preliminary work. Two recent metanalysis evaluating the use of low doses of corticosteroids in acute lung injury/ARDS in adults reported a significant physiological improvement, a sizable reduction in duration of mechanical ventilation and ICU length of stay and reduction in mortality. Hypothesis. We hypothesized that prolonged administration of low doses of methylprednisolone in pediatric ALI/ARDS is safe and downregulates systemic inflammation and leads to earlier resolution of pulmonary and extra pulmonary organ dysfunction and a reduction in duration of mechanical ventilation and ICU stay. Objective. To investigate the effects of prolonged low-dose methylprednisolone infusion on pulmonary function (LIS and ventilation-free days), extra pulmonary organ function (PMODS score), inflammatory markers - RCP (Reactive C Protein), IL6 (Interleukine 6), TNFα (Tumor Necrosis Factor), IL8 (Interleukine 8), IL10 (Interleukine 10) and length of Pediatric Intensive Care Unit (PICU) stay in early ALI/ARDS in children. Study design. Prospective randomized, placebo-controlled, double-blind clinical trial.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lung Injury, Acute Respiratory Distress Syndrome
Keywords
ALI, Acute Lung Injury, ARDS, Acute Respiratory Distress Syndrome, Pediatric Critical Care Medicine, Inflammatory Response

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Methylprednisolone Arm
Arm Type
Active Comparator
Arm Description
The patients in this arm will receive methylprednisolone, which is available in vials containing 125 mg/2mL after dilution, as it follows: Day 0 Loading dose 1 mg/kg IV bolus mixed in 5 mL NS (30 min) followed by continuous infusion Days 0 to 07 - 1 mg/kg/day mixed in 24cc NS and infused at 1 cc/hr Days 08 to 10 - 0.5 mg/kg/day mixed in 24cc NS and infused at 1 cc/hr Days 11 to 12 - 0.25 mg/kg/day Days 13 to 14 - 0.125 mg/kg/day
Arm Title
Sterile Saline Arm
Arm Type
Placebo Comparator
Arm Description
Patients randomized to the control arm will receive sterile normal saline in an amount that would equal the total diluted dose of study drug (ie. if initial loading dose equals a total of 24 cc [methylprednisolone + diluting fluid], then the patient will receive 24 cc of sterile normal saline). Tapering doses will be equivalent to that of the study arm, so that investigators will remain blinded to therapy. The unblinded party will be composed of the research ARDS pharmacist. Five days after the patient is able to ingest medications, placebo is administered per os (PO) in one single daily equivalent dose. The placebo will be manipulated by the pharmacist as to resemble identical to the active drug.
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone Arm
Other Intervention Name(s)
Solumedrol
Intervention Description
Day 0 - Loading dose 1 mg/kg IV bolus mixed in 5 mL NS (30 min) followed by continuous infusion Days 0 to 07 - 1 mg/kg/day mixed in 24cc NS and infused at 1 cc/hr Days 08 to 10 - 0.5 mg/kg/day mixed in 24cc NS and infused at 1 cc/hr Days 11 to 12 - 0.25 mg/kg/day Days 13 to 14 - 0.125 mg/kg/day
Intervention Type
Drug
Intervention Name(s)
Sterile Saline Arm
Other Intervention Name(s)
Saline
Intervention Description
Patients randomized to the control arm will receive sterile normal saline in an amount that would equal the total diluted dose of study drug (ie. if initial loading dose equals a total of 24 cc [methylprednisolone + diluting fluid], then the patient will receive 24 cc of sterile normal saline). Tapering doses will be equivalent to that of the study arm, so that investigators will remain blinded to therapy. The unblinded party will be composed of the research ARDS pharmacist. Five days after the patient is able to ingest medications, placebo is administered per os (PO) in one single daily equivalent dose. The placebo will be manipulated by the pharmacist as to resemble identical to the active drug.
Primary Outcome Measure Information:
Title
Effects on pulmonary organ function
Description
a ≥ 1-point reduction in LIS by study day 7 or successful extubation by day 7 For patients remaining intubated on study day 7, improvement in lung function is defined as a 7-day LIS ≤ 2 (if initial LIS ≤ 2,9) or a 7-day LIS ≥ 2,5 (if initial LIS ≥ 3) Duration of mechanical ventilation defined as: ventilator free days at 28 days of entry study days of mechanical ventilation on day 28
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Effects on extra-pulmonary organ function
Description
pediatric multiple organ dysfunction score (P-MODS) by study day 7
Time Frame
24 months
Title
Effects on inflammatory process
Description
Levels of CRP, TNFα, IL-6, IL-8, IL-10 by study day 7
Time Frame
24 months
Title
Effects on hospitalization-related outcomes
Description
Length of PICU stay
Time Frame
24 months
Other Pre-specified Outcome Measures:
Title
Complications
Description
Rate of new infections after study entry, defined as: number of patients with new nosocomial infections number of new nosocomial infections after study entry
Time Frame
12 months
Title
Complications
Description
Rate of potential complications associated with treatment, defined as: number of patients developing hyperglycemia requiring insulin pancreatitis (defined by elevated serum lipase level) gastrointestinal bleeding hypernatremia behavioral disorders (clinical judgment and parents report)
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
29 Days
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of ALI/ARDS within the first 72 hours based on all of the following criteria: Respiratory failure requiring mechanical ventilation - via endotracheal intubation or noninvasive positive pressure ventilation; Acute onset of bilateral pulmonary densities on chest radiograph in the context of appropriate predisposing injury or illness with no evidence of left ventricular failure; Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2:FiO2 ) ≤ 300 (criteria for ALI) or 200 (criteria for ARDS) with FiO2 ≥ 0,5 and PEEP = 5 cmH2O. To sign the Informed Consent to participate. Exclusion Criteria: ALI/ARDS with more than 72 hours of diagnosis Failure to obtain written informed consent to participate in the study; Condition requiring > 0.5mg/Kg/day of prednisone equivalent (i.e., acute asthma or bronchopulmonary dysplasia) Patients enrolled in another experimental (interventional) protocol within the past 30 days, which might adversely impact on the results of this study as determined by the investigators; Primary or secondary neuromuscular dysfunction Patients using aminoglycosides combined with neuromuscular blockers Cardiopulmonary arrest within 7 days or anytime during present hospitalization prior to enrollment; Irreversible cessation of all brain function; Immunosuppression, including HIV+ status, history of bone marrow or solid organ transplantation, current malignancy, neutropenia, receiving cytotoxic therapy for any reason, and acute burn injury; Severe chronic liver disease (Child-Pugh Class C score > 10 points).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maria Clara M Barbosa
Organizational Affiliation
Instituto D'Or de Pesquisa
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Arnaldo P Barbosa
Organizational Affiliation
Rio de Janeiro Federal University
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Antonio José LA Cunha
Organizational Affiliation
Rio de Janeiro Federal University
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Fernanda Lima
Organizational Affiliation
Instituto D'Or de Pesquisa
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universidade Federal do Rio de Janeiro
City
Rio de Janeiro
ZIP/Postal Code
21.941-912
Country
Brazil

12. IPD Sharing Statement

Citations:
PubMed Identifier
28422025
Citation
Sweeney RM, McAuley DF. Prolonged glucocorticoid treatment in acute respiratory distress syndrome - Authors' reply. Lancet. 2017 Apr 15;389(10078):1516-1517. doi: 10.1016/S0140-6736(17)30953-4. No abstract available.
Results Reference
derived

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Effects and Safety of Infusion of Low-Doses of Methylprednisolone in Early ALI and ARDS in Children

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