Condition category
Neonatal Diseases
Date applied
Date assigned
Last edited
Retrospectively registered
Overall trial status
Recruitment status
No longer recruiting
Publication status

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

Trial website

Contact information



Primary contact

Dr Barbara Kristina Schmidt


Contact details

McMaster University
DBCVSRI Level 4 C4-109
Neonatal Trials Group
Hamilton General Hospital Campus
237 Barton Street East
L8L 2X2
+1 (0)905 521 2100 X 40748

Additional identifiers

EudraCT number number


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



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


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet


Apnea of prematurity


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



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


Overall trial end date


Reason abandoned (if study stopped)


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


Age group




Target number of participants


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


Recruitment end date



Countries of recruitment

Australia, Canada, Germany, Israel, Netherlands, Sweden, Switzerland, United Kingdom, United States of America

Trial participating centre

McMaster University
L8L 2X2

Sponsor information


McMaster University Faculty of Health Sciences (Canada)

Sponsor details

Office of the Associate Dean
1200 Main Street West
Room HSC-3N8
L8N 3Z5
+1 (0)905 525 9140 ext. 22465

Sponsor type




Funder type

Research organisation

Funder name

Canadian Institutes of Health Research (CIHR) (Canada) - (ref: MCT-13288 & MOP-102601)

Alternative name(s)

Instituts de recherche en santé du Canada, CIHR

Funding Body Type


Funding Body Subtype


Funder name

Medical Research Council Canada

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

National Health and Medical Research Council (supplementary funding to Australian centres only)

Alternative name(s)


Funding Body Type


Funding Body Subtype


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:
2007 results in:
2010 results in:
2017 results in:

Publication citations

  1. 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.

  2. 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.

  3. 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.

Additional files

Editorial Notes

25/04/2017: Publication reference added. 18/03/2016: Plain English summary added. 15/09/2010: This record was updated to include details of amendment MOP-102601. This trial has completed the recruitment and 18-month follow-up phases and is now in extended follow-up (5 years and 11-12 years). The overall trial end date was extended from 31/03/2009 to 31/07/2016 to accommodate the extended follow up.