Caffeine for Apnea of Prematurity (CAP)

NCT00182312 | Completed Phase 3 DMC

• 4 other identifiers: CTMG-1999-CAPISRCTN44364365MCT-13288MOP-102601
• Study Type: interventional
• Target: 2,000
• Locations: 9 countries
• Sites: 34

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.

Conditions

Apnea of Prematurity

Keywords

preterm infants; very low birthweight; apnea of prematurity; methylxanthines; developmental disabilities

Outcome Measures

Primary Outcomes (1)

• combined rate of mortality and neurodevelopmental disability in survivors at a corrected age of 18 months.

  corrected age of 18 months

Secondary Outcomes (6)

• bronchopulmonary dysplasia

  discharge home

• necrotizing enterocolitis

  discharge home

• brain injury: intra- and periventricular hemorrhage, periventricular leucomalacia and/or ventriculomegaly

  discharge home

• retinopathy of prematurity

  discharge home

• growth failure

  corrected age of 18 months

Interventions

Caffeine citrate injection DRUG

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.

Also known as: CafCit

Eligibility Criteria

• Age: Up to 10 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• McMaster University: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• National Health and Medical Research Council, Australia: collaborator

Study Sites (34)

Brooklyn Hospital Center

Brooklyn, New York, 11201, United States

Location

Canberra Hospital

Canberra, Australian Capital Territory, 2605, Australia

Location

Women's & Children's Hospital

Adelaide, South Australia, 5006, Australia

Location

Mercy Hospital for Women

Melbourne, Victoria, 3002, Australia

Location

Royal Women's Hospital

Melbourne, Victoria, 3053, Australia

Location

Foothills Hospital

Calgary, Alberta, T2N 4N1, Canada

Location

Children's & Women's Health Centre of BC

Vancouver, British Columbia, V6H 3V4, Canada

Location

Victoria General Hospital

Victoria, British Columbia, V8Z 6R5, Canada

Location

St. Boniface General Hospital

Winnipeg, Manitoba, R2H 2A6, Canada

Location

Moncton Hospital

Moncton, New Brunswick, E1C 6Z8, Canada

Location

McMaster University

Hamilton, Ontario, L8S 4J9, Canada

Location

Kingston General Hospital

Kingston, Ontario, K7L 2V7, Canada

Location

Ottawa Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Mount Sinai Hospital

Toronto, Ontario, M5G 1X5, Canada

Location

Sunnybrook & Women's College Health Science Centre

Toronto, Ontario, M5S 1B2, Canada

Location

Windsor Regional Hospital

Windsor, Ontario, N8W 1L9, Canada

Location

Royal Victoria Hospital

Montreal, Quebec, H3A 1A1, Canada

Location

University of Sherbrooke

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Royal University Hospital

Saskatoon, Saskatchewan, S7N 0W8, Canada

Location

Centre Hospitalier Universitaire de Quebec

Québec, G1L 3L5, Canada

Location

Ludwig Maximilian University

Munich, 81377, Germany

Location

University of Tuebingen

Tübingen, D-72076, Germany

Location

Soroka University Medical Center

Beersheba, 84101, Israel

Location

Meir General Hospital

Kfar Saba, 44281, Israel

Location

Kaplan Medical Center

Rehovot, Israel

Location

Academisch Medisch Centrum

Amsterdam, 1100 DD, Netherlands

Location

University Hospital Maastricht

Maastricht, Netherlands

Location

Astrid Lindgren's Children's Hospital

Stockholm, SE-17176, Sweden

Location

University Children's Hospital Basel

Basel, CH-4005, Switzerland

Location

University Hospitals of Geneve

Geneva, 1211, Switzerland

Location

University of Zurich

Zurich, CH-8091, Switzerland

Location

Royal Maternity Hospital

Belfast, Northern Ireland, BT12 6BB, United Kingdom

Location

South Cleveland Hospital

Middlesbrough, TS4 3BW, United Kingdom

Location

Royal Victoria Infirmary

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Related Publications (11)

• 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.

  PMID: 16707748 RESULT

• 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.

  PMID: 17989382 RESULT

• 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.

  PMID: 19926098 RESULT

• 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.

  PMID: 22253394 RESULT

• 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.

  PMID: 21173002 RESULT

• 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.

  PMID: 24496539 RESULT

• 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.

  PMID: 24840756 RESULT

• 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.

  PMID: 28707987 DERIVED

• 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.

  PMID: 28437520 DERIVED

• 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.

  PMID: 25784749 DERIVED

• 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.

  PMID: 25641237 DERIVED

MeSH Terms

Conditions

Apnea; Developmental Disabilities

Interventions

caffeine citrate

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurodevelopmental Disorders; Mental Disorders

Study Officials

• Barbara K Schmidt, MD

  McMaster University

  STUDY CHAIR

• 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

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2005
• First Posted: September 16, 2005
• Study Start: October 1, 1999
• Primary Completion: March 1, 2007
• Study Completion: July 1, 2016
• Last Updated: March 22, 2018

Record last verified: 2016-09

Locations

NL (2); CH (3); DE (2); GB (3); US (1); SE (1); CA (15); AU (4); IL (3)