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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Acute Respiratory Distress Syndrome; Acute Lung Injury
• Intervention / Treatment: Drug: Methylprednisolone Arm; Drug: Sterile Saline Arm

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 Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 21.941-912
    • Universidade Federal do Rio de Janeiro

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	24 months

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complications	Rate of new infections after study entry, defined as: number of patients with new nosocomial infections; number of new nosocomial infections after study entry	12 months
Complications	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)	12 months

Collaborators and Investigators

• Sponsor: Universidade Federal do Rio de Janeiro
• Collaborators: Rio de Janeiro State Research Supporting Foundation (FAPERJ); Instituto de Puericultura e Pediatria Martagão Gesteira - IPPMG/UFRJ; Instituto D'Or de Pesquisa
• Investigators: Study Chair: Maria Clara M Barbosa, Instituto D'Or de Pesquisa; Study Director: Arnaldo P Barbosa, Rio de Janeiro Federal University; Study Director: Antonio José LA Cunha, Rio de Janeiro Federal University; Principal Investigator: Fernanda Lima, Instituto D'Or de Pesquisa

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2014
• Primary Completion (Anticipated): January 1, 2016
• Study Completion (Anticipated): January 1, 2016

Study Registration Dates

• First Submitted: December 21, 2012
• First Submitted That Met QC Criteria: December 21, 2012
• First Posted (Estimate): December 31, 2012

Study Record Updates

• Last Update Posted (Actual): July 10, 2020
• Last Update Submitted That Met QC Criteria: July 8, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: ARDS; Acute Respiratory Distress Syndrome; Inflammatory Response; Acute Lung Injury; ALI; Pediatric Critical Care Medicine
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Wounds and Injuries; Infant, Newborn, Diseases; Infant, Premature, Diseases; Thoracic Injuries; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Lung Injury; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: CONEP 16487