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

This study is currently recruiting participants.
Verified October 2016 by Fernanda Lima, Universidade Federal do Rio de Janeiro
Sponsor:
ClinicalTrials.gov Identifier:
NCT01757899
First Posted: December 31, 2012
Last Update Posted: October 26, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Instituto de Puericultura e Pediatria Martagão Gesteira - IPPMG/UFRJ
Instituto D'Or de Pesquisa
Rio de Janeiro State Research Supporting Foundation (FAPERJ)
Information provided by (Responsible Party):
Fernanda Lima, Universidade Federal do Rio de Janeiro
  Purpose
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 Intervention Phase
Acute Lung Injury Acute Respiratory Distress Syndrome Drug: Methylprednisolone Arm Drug: Sterile Saline Arm Phase 2

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Fernanda Lima, Universidade Federal do Rio de Janeiro:

Primary Outcome Measures:
  • Effects on pulmonary organ function [ Time Frame: 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 [ Time Frame: 24 months ]
    pediatric multiple organ dysfunction score (P-MODS) by study day 7

  • Effects on inflammatory process [ Time Frame: 24 months ]
    Levels of CRP, TNFα, IL-6, IL-8, IL-10 by study day 7

  • Effects on hospitalization-related outcomes [ Time Frame: 24 months ]
    Length of PICU stay


Other Outcome Measures:
  • Complications [ Time Frame: 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 [ Time Frame: 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)


Estimated Enrollment: 30
Study Start Date: February 2014
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Saline

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01757899


Contacts
Contact: Fernanda Lima 55-21-87466666 felimasetta@gmail.com
Contact: Maria Clara M Barbosa 55-21-25453503 mariaclaramb@globo.com

Locations
Brazil
Universidade Federal do Rio de Janeiro Recruiting
Rio de Janeiro, Brazil, 21.941-912
Contact: Cleyde T Vanzillotta    55-21-25453503    cleydecv@yahoo.com.br   
Contact: Arnaldo P Barbosa    55-21-25453500    apbarbosa@globo.com   
Principal Investigator: Cleyde T Vanzillotta         
Sponsors and Collaborators
Universidade Federal do Rio de Janeiro
Instituto de Puericultura e Pediatria Martagão Gesteira - IPPMG/UFRJ
Instituto D'Or de Pesquisa
Rio de Janeiro State Research Supporting Foundation (FAPERJ)
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
  More Information

Responsible Party: Fernanda Lima, MD Msc, Universidade Federal do Rio de Janeiro
ClinicalTrials.gov Identifier: NCT01757899     History of Changes
Other Study ID Numbers: CONEP 16487
First Submitted: December 21, 2012
First Posted: December 31, 2012
Last Update Posted: October 26, 2016
Last Verified: October 2016

Keywords provided by Fernanda Lima, Universidade Federal do Rio de Janeiro:
ALI
Acute Lung Injury
ARDS
Acute Respiratory Distress Syndrome
Pediatric Critical Care Medicine
Inflammatory Response

Additional relevant MeSH terms:
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Thoracic Injuries
Wounds and Injuries
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal