- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01721655
Determining the Effect of Spironolactone on Electrolyte Supplementation in Preterm Infants With Chronic Lung Disease
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Bronchopulmonary dysplasia (BPD), also known as chronic lung disease (CLD), is a major complication of premature birth and is associated with significant morbidity and mortality. Bronchopulmonary dysplasia most commonly affects preterm infants who have required prolonged aggressive mechanical ventilation and/or oxygen supplementation. Risk factors associated with BPD include degree of prematurity, infection, mechanical ventilation, oxygen concentration, and nutritional status. Despite significant advances in the care of preterm infants and improved survival, the incidence of BPD has been fairly static over the past decade.
Diuretics and fluid restriction are considered a mainstay of therapy in the management of BPD to combat interstitial alveolar edema. Short courses of furosemide followed by long-term therapy using a thiazide diuretic with concurrent spironolactone have shown improvement in pulmonary function and better outcomes. Double-blinded, randomized, placebo-controlled trials have shown improvement in pulmonary compliance, airway resistance, infants alive at discharge, and a decrease in fraction of inspired oxygen and need for furosemide boluses.
Spironolactone is a competitive aldosterone receptor antagonist that acts on the distal convoluted tubule and collecting duct to facilitate sodium excretion while conserving potassium and hydrogen ions. Since only a minimal amount of sodium filtered by the glomerulus reaches the distal tubule, spironolactone is considered a weak diuretic. Spironolactone is primarily used with chlorothiazide for its potassium-sparing effect to reduce the need for electrolyte supplementation. There has only been one prospective, randomized, double-blind, placebo-controlled study comparing chlorothiazide with or without the addition of spironolactone in premature infants with chronic lung disease. This study demonstrated no difference between the groups in the need for electrolyte supplementation, electrolyte balance, or pulmonary function. In addition, preterm infants' distal tubules may respond inadequately to aldosterone; thereby, limiting the role of spironolactone in this patient population.
In the neonatal population, spironolactone is primarily used in addition with chlorothiazide for its potassium-sparing effects to reduce the need for electrolyte supplementation. However, evidence and current practice suggests the majority of patients still receive electrolyte supplementation. One study evaluated spironolactone's effect on the need for electrolyte supplementation, but there is no published data with a primary outcome evaluating spironolactone's effect on the quantity of electrolyte supplementation. We hypothesize there will be no difference in the amount of electrolyte supplementation between the two groups.
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Contact
- Name: Courtney B Sweet, PharmD
- Phone Number: 304-598-4148
- Email: sweetc@wvuhealthcare.com
Study Contact Backup
- Name: Leanna K Darland, PharmD
- Phone Number: 304-598-4148
- Email: darlandl@wvuhealthcare.com
Study Locations
-
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West Virginia
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Morgantown, West Virginia, United States, 26505
- Recruiting
- West Virginia University Healthcare
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- The attending makes the decision to start enteral chlorothiazide for long-term diuretic therapy.
- Gestational age < 32 weeks at time of delivery
- If patient is currently receiving furosemide and electrolyte supplements, these must be discontinued prior to enrollment.
Exclusion Criteria:
- Renal anomaly
- Receiving maintenance IV fluids for more than the previous 48 hours
- Any contraindication to receiving enteral medication
- Serum Na < 132 mEq/L
- Serum K < 3.0 mEq/L
- Serum Cl < 92 mEq/L
- Presence of ostomy of any sort
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Spironolactone
Oral spironolactone suspension dosed at 3 mg/kg/day will be administered once-daily to the patients assigned to the treatment arm.
|
Patients will continue to receive standard of care as if they were not enrolled in the study.
All patients will receive oral chlorothiazide 40 mg/kg/day divided twice-daily, electrolyte supplementation as needed based on a standard algorithm, and if needed, rescue enteral furosemide 2 mg/kg/day.
The intervention will be enteral spironolactone 3 mg/kg once daily
Other Names:
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Placebo Comparator: Placebo suspension
An oral placebo suspension dosed at 3 mg/kg/day administered once-daily will be given to patients in the placebo arm.
|
Patients will continue to receive standard of care as if they were not enrolled in the study.
All patients will receive oral chlorothiazide 40 mg/kg/day divided twice-daily, electrolyte supplementation as needed based on a standard algorithm, and if needed, rescue enteral furosemide 2 mg/kg/day.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Dose of potassium chloride in milliequivalents/kg/day
Time Frame: Day 28
|
The primary objective of this study is to assess the effect of spironolactone on the quantity of electrolyte supplementation in preterm infants receiving a standard regimen for chronic lung disease.
The primary endpoint compared between groups will be the dose of potassium chloride in milliequivalents/kg/day from baseline to day 28.
|
Day 28
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Requirement of electrolyte supplementation
Time Frame: Day 28
|
Treatment and control groups will be compared to assess if there is a difference between the need for electrolyte supplementation.
|
Day 28
|
Analyze the use of furosemide rescue doses
Time Frame: Day 28
|
The groups will be compared to assess the difference in the need for rescue furosemide doses (enteral furosemide at 2 mg/kg once daily).
|
Day 28
|
Number of furosemide doses utilized
Time Frame: Day 28
|
The total number of rescue furosemide doses utilized will be compared between groups.
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Day 28
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Escalation in respiratory support
Time Frame: Day 28
|
Groups will be compared to determine if there is a difference in the need for an escalation in respiratory support throughout the study period.
Escalation in respiratory support is defined as an increase in mean airway pressure for patients on the ventilator, 20% or greater increase in the fraction of inspired oxygen, or an escalation in the mode of support.
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Day 28
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Collaborators and Investigators
Investigators
- Principal Investigator: Courtney B Sweet, PharmD, WVU Healthcare
Publications and helpful links
General Publications
- Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001 Jun;163(7):1723-9. doi: 10.1164/ajrccm.163.7.2011060. No abstract available.
- Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967 Feb 16;276(7):357-68. doi: 10.1056/NEJM196702162760701. No abstract available.
- Jeng SF, Hsu CH, Tsao PN, Chou HC, Lee WT, Kao HA, Hung HY, Chang JH, Chiu NC, Hsieh WS. Bronchopulmonary dysplasia predicts adverse developmental and clinical outcomes in very-low-birthweight infants. Dev Med Child Neurol. 2008 Jan;50(1):51-7. doi: 10.1111/j.1469-8749.2007.02011.x.
- Gien J, Kinsella JP. Pathogenesis and treatment of bronchopulmonary dysplasia. Curr Opin Pediatr. 2011 Jun;23(3):305-13. doi: 10.1097/MOP.0b013e328346577f.
- Smith VC, Zupancic JA, McCormick MC, Croen LA, Greene J, Escobar GJ, Richardson DK. Trends in severe bronchopulmonary dysplasia rates between 1994 and 2002. J Pediatr. 2005 Apr;146(4):469-73. doi: 10.1016/j.jpeds.2004.12.023.
- Jobe AH, Ikegami M. Mechanisms initiating lung injury in the preterm. Early Hum Dev. 1998 Nov;53(1):81-94. doi: 10.1016/s0378-3782(98)00045-0.
- Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res. 1999 Dec;46(6):641-3. doi: 10.1203/00006450-199912000-00007. No abstract available.
- Shah PS. Current perspectives on the prevention and management of chronic lung disease in preterm infants. Paediatr Drugs. 2003;5(7):463-80. doi: 10.2165/00128072-200305070-00004.
- Tropea K, Christou H. Current pharmacologic approaches for prevention and treatment of bronchopulmonary dysplasia. Int J Pediatr. 2012;2012:598606. doi: 10.1155/2012/598606. Epub 2012 Jan 3.
- Biniwale MA, Ehrenkranz RA. The role of nutrition in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol. 2006 Aug;30(4):200-8. doi: 10.1053/j.semperi.2006.05.007.
- Albersheim SG, Solimano AJ, Sharma AK, Smyth JA, Rotschild A, Wood BJ, Sheps SB. Randomized, double-blind, controlled trial of long-term diuretic therapy for bronchopulmonary dysplasia. J Pediatr. 1989 Oct;115(4):615-20. doi: 10.1016/s0022-3476(89)80297-5.
- Kao LC, Durand DJ, McCrea RC, Birch M, Powers RJ, Nickerson BG. Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia. J Pediatr. 1994 May;124(5 Pt 1):772-81. doi: 10.1016/s0022-3476(05)81373-3.
- Kao LC, Warburton D, Cheng MH, Cedeno C, Platzker AC, Keens TG. Effect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasia: results of a double-blind crossover sequential trial. Pediatrics. 1984 Jul;74(1):37-44.
- Engelhardt B, Blalock WA, DonLevy S, Rush M, Hazinski TA. Effect of spironolactone-hydrochlorothiazide on lung function in infants with chronic bronchopulmonary dysplasia. J Pediatr. 1989 Apr;114(4 Pt 1):619-24. doi: 10.1016/s0022-3476(89)80708-5.
- Brion LP, Primhak RA, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for preterm infants with (or developing) chronic lung disease. Cochrane Database Syst Rev. 2002;(1):CD001817. doi: 10.1002/14651858.CD001817.
- Segar JL. Neonatal diuretic therapy: furosemide, thiazides, and spironolactone. Clin Perinatol. 2012 Mar;39(1):209-20. doi: 10.1016/j.clp.2011.12.007. Epub 2011 Dec 29.
- Hoffman DJ, Gerdes JS, Abbasi S. Pulmonary function and electrolyte balance following spironolactone treatment in preterm infants with chronic lung disease: a double-blind, placebo-controlled, randomized trial. J Perinatol. 2000 Jan-Feb;20(1):41-5. doi: 10.1038/sj.jp.7200307.
- Sulyok E, Varga F, Gyory E, Jobst K, Csaba IF. Postnatal development of renal sodium handling in premature infants. J Pediatr. 1979 Nov;95(5 Pt 1):787-92. doi: 10.1016/s0022-3476(79)80737-4.
- Spitzer A. The role of the kidney in sodium homeostasis during maturation. Kidney Int. 1982 Apr;21(4):539-45. doi: 10.1038/ki.1982.60.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Respiratory Tract Diseases
- Infant, Newborn, Diseases
- Lung Injury
- Infant, Premature, Diseases
- Ventilator-Induced Lung Injury
- Lung Diseases
- Bronchopulmonary Dysplasia
- Physiological Effects of Drugs
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Natriuretic Agents
- Diuretics
- Hormone Antagonists
- Mineralocorticoid Receptor Antagonists
- Diuretics, Potassium Sparing
- Spironolactone
Other Study ID Numbers
- H-24305
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