Efficacy and safety of methylxanthines in very low birthweight infants

ISRCTN	ISRCTN44364365
DOI	https://doi.org/10.1186/ISRCTN44364365
ClinicalTrials.gov (NCT)	NCT00182312
Protocol serial number	MCT-13288; MOP-102601
Sponsor	McMaster University Faculty of Health Sciences (Canada)
Funders	Canadian Institutes of Health Research (CIHR) (Canada) - http://www.cihr-irsc.gc.ca (ref: MCT-13288 & MOP-102601), Medical Research Council Canada, National Health and Medical Research Council (supplementary funding to Australian centres only)

Submission date: 05/09/2005
Registration date: 05/09/2005
Last edited: 25/04/2017

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Neonatal Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

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

Contact information

Dr Barbara Kristina Schmidt
Scientific

McMaster University
DBCVSRI Level 4 C4-109
Neonatal Trials Group
Hamilton General Hospital Campus
237 Barton Street East
Hamilton
L8L 2X2
Canada

Phone	+1 (0)905 521 2100 X 40748
Email	schmidt@mcmaster.ca

Study information

Primary study design	Interventional
Study design	Randomised controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Efficacy and safety of methylxanthines in very low birthweight infants: a randomised controlled trial
Study acronym	CAP
Study objectives	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(s)	McMaster University Research Ethics Board approved on 21/05/1999 Amendment for MOP-102601 approved on 15/07/2010
Health condition(s) or problem(s) studied	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 / device / biological / vaccine name(s)	Methylxanthines (caffeine)
Primary outcome measure(s)	Combined rate of mortality and neurodevelopmental disability in survivors at a corrected age of 18 months
Key secondary outcome measure(s)	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
Completion date	31/07/2016

Eligibility

Participant type(s)	Patient
Age group	Neonate
Sex	All
Target sample size at registration	2006
Key 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
Key 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
Date of first enrolment	01/10/1999
Date of final enrolment	01/10/2004

Locations

Countries of recruitment

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

Study participating centre

McMaster University

Hamilton
L8L 2X2
Canada

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	18/05/2006		Yes	No
Results article	results	08/11/2007		Yes	No
Results article	results	01/03/2010		Yes	No
Results article	results	01/06/2017		Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

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.