Caffeine for Apnea of Prematurity (CAP)

• ClinicalTrials.gov Identifier: NCT00182312
• Recruitment Status: Completed
• First Posted: September 16, 2005
• Last Update Posted: March 22, 2018
• Sponsor: McMaster University
• Collaborators: Canadian Institutes of Health Research (CIHR); National Health and Medical Research Council, Australia
• Information provided by (Responsible Party): McMaster University

Tracking Information

• First Submitted Date: September 13, 2005
• First Posted Date: September 16, 2005
• Last Update Posted Date: March 22, 2018
• Study Start Date: October 1999
• Actual Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 23, 2008): combined rate of mortality and neurodevelopmental disability in survivors at a corrected age of 18 months. [ Time Frame: corrected age of 18 months ]
• Original Primary Outcome Measures (submitted: September 13, 2005): combined rate of mortality and neurodevelopmental disability in survivors at a corrected age of 18 months.

Current Secondary Outcome Measures (submitted: September 15, 2010)

• bronchopulmonary dysplasia [ Time Frame: discharge home ]
• necrotizing enterocolitis [ Time Frame: discharge home ]
• brain injury: intra- and periventricular hemorrhage, periventricular leucomalacia and/or ventriculomegaly [ Time Frame: discharge home ]
• retinopathy of prematurity [ Time Frame: discharge home ]
• growth failure [ Time Frame: corrected age of 18 months ]
• functional status at 5 years and at 11-12 years [ Time Frame: corrected age of 5 years and chronological age of 11-12 years ]

Original Secondary Outcome Measures (submitted: September 13, 2005)

• bronchopulmonary dysplasia
• necrotizing enterocolitis
• brain injury: intra- and periventricular hemorrhage, periventricular leucomalacia and/or ventriculomegaly
• retinopathy of prematurity
• growth failure
• functional status at 5 years

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Caffeine for Apnea of Prematurity (CAP)
• Official Title: Efficacy and Safety of Methylxanthines in Very Low Birthweight Infants

Brief Summary

At least 5 of every 1000 live-born babies are very premature and weigh only 500 to 1250 grams at birth. Approximately 30-40% of these high-risk infants either die or survive with lasting disabilities. The aim of this research is to reduce this heavy burden of illness. A multi-center randomized controlled trial has been designed in which 2000 very low birth weight infants will be enrolled. Our goal is to determine whether the avoidance of methylxanthine drugs will improve survival without disability to 18 months, corrected for prematurity.

Methylxanthine drugs such as caffeine are used to prevent or treat periodic breathing and breath-holding spells in premature infants. However, there is a striking lack of evidence for the long-term efficacy and safety of this therapy. Methylxanthines block a naturally occurring substance, called adenosine, which protects the brain during episodes of oxygen deficiency. Such episodes are common in infants who are treated with methylxanthines. It is possible that methylxanthines may worsen the damage caused by lack of oxygen. Therefore, this trial will clarify whether methylxanthines cause more good than harm in very low birth weight infants.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Prevention
• Condition: Apnea of Prematurity

Intervention

Drug: Caffeine citrate injection

Loading dose: 20 mg/kg administered over at least 30 minutes via IV infusion or over at least 10 minutes via slow IV injection.

Daily maintenance dose (to commence at least 24 hours after loading dose): 5 mg/kg, administered over at least 10 minutes via IV infusion, or over at least 5 minutes via slow IV injection. Maintenance dose to be adjusted for body weight every 7 days. If indicated, maintenance dose may be increased to a maximum of 10 mg/kg. May be given orally once full enteral feeds are established.

Duration of treatment: discontinue after infant has tolerated at least 5 consecutive days without positive pressure support AND when the infant is judged by the attending clinician to be no longer a candidate for methylxanthine therapy.

Other Name: CafCit

• Study Arms: Not Provided

Publications *

• Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006 May 18;354(20):2112-21. doi: 10.1056/NEJMoa054065.
• Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007 Nov 8;357(19):1893-902. doi: 10.1056/NEJMoa073679.
• Davis PG, Schmidt B, Roberts RS, Doyle LW, Asztalos E, Haslam R, Sinha S, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. J Pediatr. 2010 Mar;156(3):382-7. doi: 10.1016/j.jpeds.2009.09.069. Epub 2009 Nov 18.
• Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin W, Moddemann D, Solimano A, Ohlsson A, Barrington KJ, Roberts RS; Caffeine for Apnea of Prematurity (CAP) Trial Investigators. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012 Jan 18;307(3):275-82. doi: 10.1001/jama.2011.2024.
• Dukhovny D, Lorch SA, Schmidt B, Doyle LW, Kok JH, Roberts RS, Kamholz KL, Wang N, Mao W, Zupancic JA; Caffeine for Apnea of Prematurity Trial Group. Economic evaluation of caffeine for apnea of prematurity. Pediatrics. 2011 Jan;127(1):e146-55. doi: 10.1542/peds.2010-1014. Epub 2010 Dec 20.
• Schmidt B, Davis PG, Asztalos EV, Solimano A, Roberts RS. Association between severe retinopathy of prematurity and nonvisual disabilities at age 5 years. JAMA. 2014 Feb 5;311(5):523-5. doi: 10.1001/jama.2013.282153. No abstract available.
• Doyle LW, Schmidt B, Anderson PJ, Davis PG, Moddemann D, Grunau RE, O'Brien K, Sankaran K, Herlenius E, Roberts R; Caffeine for Apnea of Prematurity Trial investigators. Reduction in developmental coordination disorder with neonatal caffeine therapy. J Pediatr. 2014 Aug;165(2):356-359.e2. doi: 10.1016/j.jpeds.2014.04.016. Epub 2014 May 17.
• Doyle LW, Ranganathan S, Cheong JLY. Neonatal Caffeine Treatment and Respiratory Function at 11 Years in Children under 1,251 g at Birth. Am J Respir Crit Care Med. 2017 Nov 15;196(10):1318-1324. doi: 10.1164/rccm.201704-0767OC.
• Schmidt B, Roberts RS, Anderson PJ, Asztalos EV, Costantini L, Davis PG, Dewey D, D'Ilario J, Doyle LW, Grunau RE, Moddemann D, Nelson H, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity (CAP) Trial Group. Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial. JAMA Pediatr. 2017 Jun 1;171(6):564-572. doi: 10.1001/jamapediatrics.2017.0238.
• Synnes A, Anderson PJ, Grunau RE, Dewey D, Moddemann D, Tin W, Davis PG, Doyle LW, Foster G, Khairy M, Nwaesei C, Schmidt B; CAP Trial Investigator group. Predicting severe motor impairment in preterm children at age 5 years. Arch Dis Child. 2015 Aug;100(8):748-53. doi: 10.1136/archdischild-2014-307695. Epub 2015 Mar 17.
• Manley BJ, Roberts RS, Doyle LW, Schmidt B, Anderson PJ, Barrington KJ, Bohm B, Golan A, van Wassenaer-Leemhuis AG, Davis PG; Caffeine for Apnea of Prematurity (CAP) Trial Investigators; Caffeine for Apnea of Prematurity CAP Trial Investigators. Social variables predict gains in cognitive scores across the preschool years in children with birth weights 500 to 1250 grams. J Pediatr. 2015 Apr;166(4):870-6.e1-2. doi: 10.1016/j.jpeds.2014.12.016. Epub 2015 Jan 29.

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: September 13, 2005): 2000
• Original Enrollment: Same as current
• Actual Study Completion Date: July 2016
• Actual Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• birthweight 500 to 1250 grams
• postnatal age day 1 to day 10
• infant considered a candidate for methylxanthine therapy by clinical staff

Exclusion Criteria:

• dysmorphic features or congenital malformations that adversely affect life expectancy or neurodevelopment
• unlikely to comply with long-term follow-up
• prior treatment with a methylxanthine

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 10 Days (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Germany, Israel, Netherlands, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT00182312
• Other Study ID Numbers: CTMG-1999-CAP; ISRCTN44364365 ( Registry Identifier: Current Controlled Trials ); MCT-13288 ( Other Grant/Funding Number: CIHR ); MOP-102601 ( Other Grant/Funding Number: CIHR )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: McMaster University
• Original Responsible Party: Not Provided
• Current Study Sponsor: McMaster University
• Original Study Sponsor: Same as current

Collaborators

• Canadian Institutes of Health Research (CIHR)
• National Health and Medical Research Council, Australia

Investigators

• Study Chair: Barbara K Schmidt, MD; McMaster University
• Study Director: Robin S Roberts, MTech; McMaster University
• Study Director: Peter Davis, MD; Royal Women's Hospital, Melbourne, Australia
• Study Director: Lex Doyle, MD; Royal Women's Hospital, Melbourne, Australia
• Study Director: Arne Ohlsson, MD; Mount Sinai Hospital, Canada
• Study Director: Alfonso Solimano, MD; Children & Women's Health Centre of BC, Vancouver, Canada
• Study Director: Win Tin, MD; James Cook University Hospital, Middlesbrough, UK
• Study Director: Keith J Barrington, MD; Royal Victoria Hospital/McGill University, Montreal, Canada
• Study Director: Elizabeth Asztalos, MD; Sunnybrook Health Sciences Centre, Toronto, Canada
• Study Director: Deborah Dewey, MD; University of Calgary, Alberta, Canada
• Study Director: Ruth Grunau, MD; University of British Columbia, Vancouver, Canada
• Study Director: Diane Moddemann, MD; University of Manitoba, Winnipeg, Canada
• Study Director: Peter Anderson, PhD; University of Melbourne, Australia

• PRS Account: McMaster University
• Verification Date: September 2016