Plain English Summary
Background and study aims
Apnea of prematurity is a condition where premature babies stop breathing for short periods. Methylxanthine drugs such as caffeine are used to prevent or treat apnea of prematurity but it is not known whether methylxanthines have other short- and long-term benefits or risks in infants with very low birth weight. The aim of this study is to clarify whether methylxanthines cause more good than harm in very low birth weight infants.
Who can participate?
Babies during the first 10 days of life with a very low birth weight (500 to 1250 g) who require methylxanthine treatment for apnea of prematurity.
What does the study involve?
Participating babies are randomly allocated to receive either caffeine or placebo (a dummy drug), until drug treatment for apnea of prematurity is no longer needed. Survival and disability rates are compared between the two groups 18 months later.
What are the possible benefits and risks of participating?
Not provided at time of registration
Where is the study run from?
McMaster University (Canada)
When is the study starting and how long is it expected to run for?
October 1999 to July 2016
Who is funding the study?
1. Canadian Institutes of Health Research (CIHR) (Canada)
2. MRC Canada
3. NHMRC Australia (supplementary funding to Australian centres only)
Who is the main contact?
Dr Barbara Schmidt
schmidt@mcmaster.ca
Trial website
Contact information
Type
Scientific
Primary contact
Dr Barbara Kristina Schmidt
ORCID ID
Contact details
McMaster University
DBCVSRI Level 4 C4-109
Neonatal Trials Group
Hamilton General Hospital Campus
237 Barton Street East
Hamilton
L8L 2X2
Canada
+1 (0)905 521 2100 X 40748
schmidt@mcmaster.ca
Additional identifiers
EudraCT number
ClinicalTrials.gov number
NCT00182312
Protocol/serial number
MCT-13288; MOP-102601
Study information
Scientific title
Efficacy and safety of methylxanthines in very low birthweight infants: a randomised controlled trial
Acronym
CAP
Study hypothesis
Avoidance of methylxanthines (caffeine) to prevent or treat apnea of prematurity reduces the risk of adverse outcomes in very low birth weight infants.
Ethics approval
McMaster University Research Ethics Board approved on 21/05/1999
Amendment for MOP-102601 approved on 15/07/2010
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Apnea of prematurity
Intervention
Control arm: caffeine will be administered intravenously or orally (via feeding tube) as follows: Loading dose 20 mg/kg caffeine citrate; maintenance dose 5 mg/kg once every 24 hours. The volume of the maintenance dose will be adjusted every 7 days according to the actual body weight on that day. In case of persistent apnea, the responsible physician will have the option to increase the maintenance dose in two steps to a maximum of 10 mg/kg of caffeine citrate.
Intervention group: an equivalent volume of sterile sodium chloride 0.9% without preservative.
Intervention type
Drug
Phase
Not Applicable
Drug names
Methylxanthines (caffeine)
Primary outcome measure
Combined rate of mortality and neurodevelopmental disability in survivors at a corrected age of 18 months
Secondary outcome measures
1. Neonatal complications typically associated with respiratory insufficiency and very low birth weight (VLBW):
1.1. Bronchopulmonary dysplasia (BPD) is diagnosed in all infants who still require supplemental oxygen at a postconceptual age of 36 weeks. In addition, quantitative comparisons of the duration of support will be performed (days on positive pressure ventilation via endotracheal tube, days on non-invasive continuous positive airway pressure [CPAP], days in oxygen)
1.2. Intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) and ventriculomegaly are diagnosed ultrasonographically. Serial cranial ultrasound assessments are routinely performed in VLBW infants to detect hemorrhagic and ischemic changes. The worst scans obtained between days 14 and 28, and between 34-36 weeks post conception, respectively, will be recorded
1.3. Necrotising enterocolitis (NEC) is diagnosed at surgery, at autopsy, or by either the finding of pneumatosis intestinalis, hepatobiliary gas or free intraperitoneal air on abdominal X-ray. In the absence of these findings, suspected NEC is recorded in any infant in whom enteral feeds are withheld for more than 5 days, because of symptoms and signs suggestive of NEC
1.4. Retinopathy of prematurity (ROP) is diagnosed at routine ophthalmologic examinations, beginning at 32 weeks postconceptional age. The severity of ROP will be graded according to the international classification of ROP
2. Weight gain and head circumference will be recorded weekly until discharge from the study centre
3. Functional status at 5 years and at 11-12 years
Overall trial start date
01/10/1999
Overall trial end date
31/07/2016
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Birth weight 500-1250 g
2. Postnatal age day 1-day 10, either sex
3. Infant considered a candidate for methylxanthine therapy by clinical staff
Participant type
Patient
Age group
Neonate
Gender
Both
Target number of participants
2006
Participant exclusion criteria
1. Dysmorphic features or congenital malformations that adversely affect life expectancy or neurodevelopment
2. Unlikely to comply with long-term follow-up
3. Prior treatment with a methylxanthine
Recruitment start date
01/10/1999
Recruitment end date
01/10/2004
Locations
Countries of recruitment
Australia, Canada, Germany, Israel, Netherlands, Sweden, Switzerland, United Kingdom, United States of America
Trial participating centre
McMaster University
Hamilton
L8L 2X2
Canada
Sponsor information
Organisation
McMaster University Faculty of Health Sciences (Canada)
Sponsor details
Office of the Associate Dean
Research
1200 Main Street West
Room HSC-3N8
Hamilton
L8N 3Z5
Canada
+1 (0)905 525 9140 ext. 22465
hsresadm@mcmaster.ca
Sponsor type
University/education
Website
Funders
Funder type
Research organisation
Funder name
Canadian Institutes of Health Research (CIHR) (Canada) - http://www.cihr-irsc.gc.ca (ref: MCT-13288 & MOP-102601)
Alternative name(s)
Instituts de Recherche en Santé du Canada, CIHR, IRSC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
Canada
Funder name
Medical Research Council Canada
Alternative name(s)
Medical Research Council, Canada, Medical Research Council, Medical Research Council of Canada, MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
Canada
Funder name
National Health and Medical Research Council (supplementary funding to Australian centres only)
Alternative name(s)
NHMRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
Australia
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2006 results in: http://www.ncbi.nlm.nih.gov/pubmed/16707748
2007 results in: http://www.ncbi.nlm.nih.gov/pubmed/17989382
2010 results in: http://www.ncbi.nlm.nih.gov/pubmed/19926098
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28437520
Publication citations
-
Results
Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W, , Caffeine therapy for apnea of prematurity., N. Engl. J. Med., 2006, 354, 20, 2112-2121, doi: 10.1056/NEJMoa054065.
-
Results
Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W, , Long-term effects of caffeine therapy for apnea of prematurity., N. Engl. J. Med., 2007, 357, 19, 1893-1902, doi: 10.1056/NEJMoa073679.
-
Results
Davis PG, Schmidt B, Roberts RS, Doyle LW, Asztalos E, Haslam R, Sinha S, Tin W, , Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups., J. Pediatr., 2010, 156, 3, 382-387, doi: 10.1016/j.jpeds.2009.09.069.