Clinical trial NCT00182312: Caffeine for Apnea of Prematurity (CAP)
Official title: Efficacy and Safety of Methylxanthines in Very Low Birthweight Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Apnea of Prematurity
Keywords: preterm infants
very low birthweight
apnea of prematurity
methylxanthines
developmental disabilities
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: National Health and Medical Research Council, Australia
First posted: 2005-09-16
Enrollment: 2000
Sex: ALL
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: combined rate of mortality and neurodevelopmental disability in survivors at a corrected age of 18 months.
timeFrame: corrected age of 18 months
Secondary outcomes:
measure: bronchopulmonary dysplasia
timeFrame: discharge home
measure: necrotizing enterocolitis
timeFrame: discharge home
measure: brain injury: intra- and periventricular hemorrhage, periventricular leucomalacia and/or ventriculomegaly
timeFrame: discharge home
measure: retinopathy of prematurity
timeFrame: discharge home
measure: growth failure
timeFrame: corrected age of 18 months
measure: functional status at 5 years and at 11-12 years
timeFrame: corrected age of 5 years and chronological age of 11-12 years
Other outcomes:
Locations:
city: Brooklyn
country: United States
facility: Brooklyn Hospital Center
state: New York
city: Canberra
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Adelaide
country: Australia
facility: Women's & Children's Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Mercy Hospital for Women
state: Victoria
city: Melbourne
country: Australia
facility: Royal Women's Hospital
state: Victoria
city: Calgary
country: Canada
facility: Foothills Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's & Women's Health Centre of BC
state: British Columbia
city: Victoria
country: Canada
facility: Victoria General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Moncton
country: Canada
facility: Moncton Hospital
state: New Brunswick
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook & Women's College Health Science Centre
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Hospital
state: Ontario
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Sherbrooke
country: Canada
facility: University of Sherbrooke
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
city: Quebec
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
city: Munich
country: Germany
facility: Ludwig Maximilian University
city: Tuebingen
country: Germany
facility: University of Tuebingen
city: Beer Sheva
country: Israel
facility: Soroka University Medical Center
city: Kfar-Saba
country: Israel
facility: Meir General Hospital
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Maastricht
country: Netherlands
facility: University Hospital Maastricht
city: Stockholm
country: Sweden
facility: Astrid Lindgren's Children's Hospital
city: Basel
country: Switzerland
facility: University Children's Hospital Basel
city: Geneva
country: Switzerland
facility: University Hospitals of Geneve
city: Zurich
country: Switzerland
facility: University of Zurich
city: Belfast
country: United Kingdom
facility: Royal Maternity Hospital
state: Northern Ireland
city: Middlesbrough
country: United Kingdom
facility: South Cleveland Hospital
city: Newcastle-upon-Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
Study officials:
affiliation: McMaster University
name: Barbara K Schmidt, MD
role: STUDY_CHAIR
affiliation: McMaster University
name: Robin S Roberts, MTech
role: STUDY_DIRECTOR
affiliation: Royal Women's Hospital, Melbourne, Australia
name: Peter Davis, MD
role: STUDY_DIRECTOR
affiliation: Royal Women's Hospital, Melbourne, Australia
name: Lex Doyle, MD
role: STUDY_DIRECTOR
affiliation: Mount Sinai Hospital, Canada
name: Arne Ohlsson, MD
role: STUDY_DIRECTOR
affiliation: Children & Women's Health Centre of BC, Vancouver, Canada
name: Alfonso Solimano, MD
role: STUDY_DIRECTOR
affiliation: James Cook University Hospital, Middlesbrough, UK
name: Win Tin, MD
role: STUDY_DIRECTOR
affiliation: Royal Victoria Hospital/McGill University, Montreal, Canada
name: Keith J Barrington, MD
role: STUDY_DIRECTOR
affiliation: Sunnybrook Health Sciences Centre, Toronto, Canada
name: Elizabeth Asztalos, MD
role: STUDY_DIRECTOR
affiliation: University of Calgary, Alberta, Canada
name: Deborah Dewey, MD
role: STUDY_DIRECTOR
affiliation: University of British Columbia, Vancouver, Canada
name: Ruth Grunau, MD
role: STUDY_DIRECTOR
affiliation: University of Manitoba, Winnipeg, Canada
name: Diane Moddemann, MD
role: STUDY_DIRECTOR
affiliation: University of Melbourne, Australia
name: Peter Anderson, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.