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

Sponsor

Universidade Federal do Rio de Janeiro (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01757899

Collaborator

Instituto de Puericultura e Pediatria Martagão Gesteira - IPPMG/UFRJ (Other), Instituto D'Or de Pesquisa (Other), Rio de Janeiro State Research Supporting Foundation (FAPERJ) (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lung Injury Acute Respiratory Distress Syndrome	Drug: Methylprednisolone Arm Drug: Sterile Saline Arm	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Jan 1, 2014

Anticipated Primary Completion Date :

Jan 1, 2016

Anticipated Study Completion Date :

Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Methylprednisolone Arm 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	Drug: Methylprednisolone Arm 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 Other Names: Solumedrol
Placebo Comparator: Sterile Saline Arm 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.	Drug: Sterile Saline Arm 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. Other Names: Saline

Arm

Intervention/Treatment

Active Comparator: Methylprednisolone Arm

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

Drug: Methylprednisolone Arm

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

Other Names:

Solumedrol

Placebo Comparator: Sterile Saline Arm

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.

Drug: Sterile Saline Arm

Other Names:

Saline

Outcome Measures

Primary Outcome Measures

Effects on pulmonary organ function [24 months]
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 [24 months]
pediatric multiple organ dysfunction score (P-MODS) by study day 7
Effects on inflammatory process [24 months]
Levels of CRP, TNFα, IL-6, IL-8, IL-10 by study day 7
Effects on hospitalization-related outcomes [24 months]
Length of PICU stay

Other Outcome Measures

Complications [12 months]
Rate of new infections after study entry, defined as: number of patients with new nosocomial infections number of new nosocomial infections after study entry
Complications [12 months]
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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

29 Days to 17 Years

Sexes Eligible for Study:

All

Accepts 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).