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Trial registered on ANZCTR


Registration number
ACTRN12618000303246
Ethics application status
Approved
Date submitted
1/02/2018
Date registered
28/02/2018
Date last updated
9/03/2020
Date data sharing statement initially provided
13/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Paracetamol or Ibuprofen in the Primary Prevention of Asthma in Tamariki (PIPPA Tamariki).
Scientific title
Randomised controlled trial of paracetamol or ibuprofen, as required for fever and pain in the first year of life, for prevention of asthma at age six years: Paracetamol or Ibuprofen in the Primary Prevention of Asthma in Tamariki (PIPPA Tamariki).
Secondary ID [1] 293914 0
Nil known.
Universal Trial Number (UTN)
U1111-1203-1961
Trial acronym
PIPPA Tamariki.
Linked study record
ACTRN12614000556640 - pilot study.

Health condition
Health condition(s) or problem(s) studied:
Asthma 306393 0
Bronchiolitis 306394 0
Viral induced wheeze 306395 0
Eczema 306396 0
Atopy 306397 0
Condition category
Condition code
Respiratory 305480 305480 0 0
Asthma
Skin 305481 305481 0 0
Dermatological conditions
Inflammatory and Immune System 305482 305482 0 0
Allergies
Respiratory 305877 305877 0 0
Other respiratory disorders / diseases
Infection 305878 305878 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Paracetamol oral suspension (120 mg/5 mL, 250 mg/5 mL):
-Child from 1 month of age
15 mg/kg/dose every 4 hours as required for fever and/or pain at discretion of parents/caregivers and /or health professionals;
Maximum of 60 mg/kg per day.
-Under 1 month of age, paracetamol may be used (15 mg/kg every 6 hours as required; maximum of 60 mg/kg per day), but ONLY under the advice of a healthcare professional.
Intervention period 12 months.
Adherence to intervention will be recorded by parents/caregivers using paper-based and electronic trial diaries, and follow-up questionnaires (either telephone or electronic) at 1, 3, 6, 9 and 12 months of age.
Intervention code [1] 300183 0
Treatment: Drugs
Intervention code [2] 300442 0
Prevention
Comparator / control treatment
Ibuprofen oral suspension (100 mg/5 mL):
-Child 1 to 3 months of age
5 mg/kg every 6 hours as required for fever and/or pain at discretion of parents/caregivers and /or health professionals;
Maximum 20 mg/kg per day.
-Child over 3 months of age
10 mg/kg every 6 hours as required for fever and/or pain at discretion of parents/caregivers and /or health professionals;
Maximum 30 mg/kg per day.
-Under 1 month of age, ibuprofen may be used (5 mg/kg every 6 hours as required; maximum 20 mg/kg per day), but ONLY under the advice of a healthcare professional.
Intervention period 12 months.
Adherence to intervention will be recorded by parents/caregivers using paper-based and electronic trial diaries, and follow-up questionnaires (either telephone or electronic) at 1, 3, 6, 9 and 12 months of age.
Control group
Active

Outcomes
Primary outcome [1] 304619 0
Asthma; assessed as the proportion of participants whose parent/caregiver answers “yes” to the question “Has your child had wheezing or whistling in the chest in the past 12 months?” using the International Study of Asthma and Allergies in Childhood (ISAAC) Phase III Core Questionnaire for Asthma for 6 to7 year olds.
Timepoint [1] 304619 0
Age 6 years.
Secondary outcome [1] 342573 0
At least one hospitalisation for bronchiolitis, viral induced wheeze or asthma; assessed as the proportion of participants with at least one hospitalisation for bronchiolitis, viral induced wheeze or asthma using International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) codes, and querying the Ministry of Health ‘National Non-Admitted Patient Collection’ and ‘National Minimum Dataset’.
Timepoint [1] 342573 0
Age 1, 3 and 6 years.
Secondary outcome [2] 342574 0
At least one prescription for asthma medication; assessed as the proportion of participants completing at least one prescription for inhaled corticosteroids (ICS), short acting beta agonists (SABAs), long acting beta agonists (LABAs), or montelukast, by querying the Ministry of Health ‘Pharmaceutical Collection’.
Timepoint [2] 342574 0
Age 1, 3 and 6 years.
Secondary outcome [3] 342575 0
Eczema; assessed as the proportion of participants whose parent/caregiver answers “yes” to both the questions “In the last year, has your child had an itchy skin condition – by itchy, we mean scratching or rubbing the skin?” and IF YES “Has this skin condition ever affected the skin creases in the past - by skin creases we mean fronts of elbows, behind the knees, fronts of ankles, around the neck, or around the eyes?” using the United Kingdom Diagnostic Criteria for Eczema questionnaire.
Timepoint [3] 342575 0
Age 1, 3 and 6 years.
Secondary outcome [4] 342576 0
At least one hospitalisation for eczema; assessed as the proportion of participants with at least one hospitalisation for eczema using ICD-10 codes and querying the Ministry of Health ‘National Non-Admitted Patient Collection’ and ‘National Minimum Dataset’.
Timepoint [4] 342576 0
Age 1, 3 and 6 years.
Secondary outcome [5] 342577 0
At least one prescription for eczema medication; assessed as proportion of participants completing at least one prescription for topical steroids, by querying the Ministry of Health ‘Pharmaceutical Collection’.
Timepoint [5] 342577 0
Age 1, 3 and 6 years.
Secondary outcome [6] 342580 0
Wheeze; assessed as the proportion of participants whose parent/caregiver answers “yes” to the question “Has your child had wheezing or whistling in the chest in the past 12 months?” using the ISAAC Phase III Core Questionnaire for Asthma for 6 to 7 year olds.
Timepoint [6] 342580 0
Age 3 years.
Secondary outcome [7] 342581 0
Atopy; assessed as the proportion of participants whose parent/caregiver answers “yes” to the question “Has your child had wheezing or whistling in the chest in the past 12 months?” using the ISAAC Phase III Core Questionnaire for Asthma for 6 to7 year olds, AND/OR “yes” to the questions “In the last year, has your child had an itchy skin condition – by itchy, we mean scratching or rubbing the skin?” and IF YES “Has this skin condition ever affected the skin creases in the past - by skin creases we mean fronts of elbows, behind the knees, fronts of ankles, around the neck, or around the eyes?” using the United Kingdom Diagnostic Criteria for Eczema questionnaire, AND/OR “yes” to the questions “In the past 12 months, has your child had a problem with sneezing, or a runny, or blocked nose when he/she DID NOT have a cold or the flu?” and IF YES “In the past 12 months, has this nose problem been accompanied by itchy-watery eyes?” using the ISAAC Phase III Core Questionnaire for Rhinitis for 6 to 7 year olds.
Timepoint [7] 342581 0
Age 3 and 6 years.
Secondary outcome [8] 342596 0
Adverse Events; death, empyema/pleural effusion requiring intervention (diagnostic aspiration or drainage), probable or confirmed bacterial meningitis, probable or confirmed osteomyelitis, confirmed septicaemia (positive microbiology and a clinical picture consistent with sepsis), intensive care admission with probable or confirmed varicella, intensive care admission with probable or confirmed sepsis, intensive care admission with probable or confirmed bacterial pneumonia, intensive care admission with probable or confirmed cellulitis, gastrointestinal (GI) bleeding/haemorrhage requiring endoscopy or transfusion with blood products, acute liver failure, renal failure, study medication overdose (presentation to an emergency department (ED) with a diagnosis of overdose), and delayed diagnosis with rheumatic fever (only for household members <10 years of age provided with trial medication). The above adverse events will be assessed by active surveillance of Wellington, Kidz First (Middlemore) and Starship Hospital admission and discharge lists to determine if any participant, or household member <10 years of age provided with study medication, has been admitted with an adverse event. Active reporting of adverse events by clinicians in the three hospitals will also be encouraged. Passive surveillance using ICD-10 codes and querying the Ministry of Health ‘National Minimum Dataset’ for: 1. All infective admissions to hospital (including all admissions to EDs for longer than 3 hours) on the basis of ICD-10 codes (every admission will be counted); 2. All renal failure admissions to hospital on the basis of ICD-10 codes (only the first admission will be counted); 3. All liver failure admissions to hospital on the basis of ICD-10 codes (only the first admission will be counted); 4. All GI haemorrhage admissions to hospital on the basis of ICD-10 codes (every admission will be counted); 5. All intentional and unintentional overdoses (every admission will be counted); 6. All admissions to hospital with varicella (every admission will be counted); 7. Death. All adverse events will have the following data collected: Detailed use of study medication in the one month prior to presentation; Length of hospital stay; Length of intensive care stay; Outcome at one month (discharge from hospital normal function; discharge from hospital likely mild impairment of pre-admission function; discharge from hospital likely moderate/severe impairment of pre-admission function; remains admitted in hospital likely mild impairment of pre-admission function; remains admitted in hospital likely moderate/severe impairment of pre-admission function; death); Positive microbiology specimens (including site and organism); Initial length of antibiotic treatment; Initial length of antiviral treatment; Use of N-Acetylcysteine (NAC) for paracetamol overdose; Use of renal replacement therapy; Participant being considered for renal or liver transplant; Event description of admission and clinical course; Opinion of local investigator as to relationship of adverse event to study intervention.
Timepoint [8] 342596 0
Up to one month post the intervention year

Eligibility
Key inclusion criteria
1. Birth within Auckland and Wellington regions.
2. Age <8 weeks (chronological age).
Minimum age
No limit
Maximum age
8 Weeks
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Infants will not be enrolled if ANY of the following apply:
1. Parent is unable to give informed consent for participation in the trial;
2. Highly unlikely to remain in New Zealand for the first 6 years of life;
3. Chronic disease associated with limited life expectancy (i.e., less than 6 years);
4. Gestational age at birth <32 weeks;
5. Previous exposure to paracetamol or ibuprofen since birth.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This is an open randomised controlled trial. Allocation concealment will be by a secure database which contains the randomisation sequence accessible only to the study statistician and independent data manager, utilised just for this role. Allocation will only be revealed to the research staff once the participating infant is enrolled, and their baseline demographic details and family contact details are entered into the study database.

In the instance of multiple birth, or subsequent birth occurring in the same household, those infants will be allocated to the same intervention (that is the ‘household’ will be randomised to the allocation). In the event of a ‘mixed household’ occurring, where two enrolled households combine, each allocated to a different study medication, subsequent infants enrolled from that mixed household will be allocated to the same study medication as the youngest participant.

This is an ‘open-label’ trial and after randomisation there will be no further concealment of allocation from the parents/guardians.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated sequence with randomly permuted block sizes for each site, generated by the study statistician, independent of the researchers and study investigators.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size: The primary outcome variable is asthma defined as the prevalence of wheeze in the last 12 months at age 6 years using the ISAAC Phase III study questionnaire. In New Zealand the ISAAC Phase III study reported the prevalence of wheeze in 6 to 7 year old children in the last 12 months was 22.2% and the estimate from the earlier ISAAC Phase I in the same population was 23.6%. An analysis of the full ISAAC Phase III data from 194,555 children aged 6 to 7 years, in 29 countries, estimated that use of paracetamol for fever in the first year of life was associated with an increased risk of wheeze in the last 12 months with an odds ratio of 1.46 (95% CI 1.36 to 1.56). Inverting this odds ratio based risk, and based on a prevalence of between 22.2-23.6%, this is consistent with a relative risk of approximately 0.75 for wheeze in non-users of paracetamol.

We propose recruiting 3,922 participants into the PIPPA Tamariki study based on an event rate of wheezing or asthma, in the paracetamol group of 22%. This number (3,922) will give 90% power to detect a relative risk for wheeze of 0.8 in the ibuprofen group compared to the paracetamol group, with an alpha of 5%. This number also allows for an overall withdrawal/loss to follow-up rate of 10%, and a for an efficacy dilution factor of 10% due to participants assigned to each intervention arm who are likely to be exposed to the alternative intervention within the first year of life. Previous studies of 6 year old children recruited in the perinatal period by members of the study team have achieved > 90% follow-up with a similar frequency of scheduled participant contact to that proposed.

Statistical methods: The primary and secondary efficacy analysis will be by intention-to-treat. The primary analysis of the primary outcome variable will be by logistic regression comparing the two randomised groups to allow comparison of the main effect with a sensitivity analysis incorporating the following important variables: parental history of asthma, maternal exposure to paracetamol during pregnancy, number of respiratory infections, smoke exposure, pet exposure, housing, and breast-feeding status.

All members of one family will receive the same study intervention. Twins, and higher order multiple birth infants, will be eligible for enrolment into the study. Although we anticipate that this will be a small proportion of participants as part of the sensitivity analysis we will also use a generalized linear mixed model to account for possible correlation between participants from the same family (household as random effect).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2018
Actual
19/04/2018
Date of last participant enrolment
Anticipated
28/02/2022
Actual
Date of last data collection
Anticipated
1/04/2028
Actual
Sample size
Target
3922
Accrual to date
1157
Final
Recruitment outside Australia
Country [1] 9539 0
New Zealand
State/province [1] 9539 0

Funding & Sponsors
Funding source category [1] 298538 0
Government body
Name [1] 298538 0
Health Research Council of New Zealand
Country [1] 298538 0
New Zealand
Primary sponsor type
Government body
Name
Auckland District Health Board
Address
Physical:
2 Park Road Grafton
Auckland

Postal:
Private Bag 92024
Wellesley Street
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 297685 0
None
Name [1] 297685 0
Address [1] 297685 0
Country [1] 297685 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299512 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 299512 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 299512 0
New Zealand
Date submitted for ethics approval [1] 299512 0
07/11/2017
Approval date [1] 299512 0
26/01/2018
Ethics approval number [1] 299512 0
17/NTA/233

Summary
Brief summary
Asthma rates in New Zealand are amongst the highest in the world.

Previous research has suggested that paracetamol given in the first year of life may be responsible for up to 22% of later asthma.

To test this hypothesis, we propose randomising 3,922 babies to receive EITHER paracetamol or ibuprofen, as required for the treatment of fever and pain, in their first 12 months of life.

We will follow participants up until the age of six years, when we will assess whether the rates of asthma between the two randomised groups are different.

To assist with adherence to the study treatment, we propose prescribing the same randomised medication to all children in the household under 10 years of age over the same 12 month period.

Follow up of the participants will occur in two ways; 1) Direct contact with participant's parents, by phone, or through online questionnaires at 1, 3, 6, and 9 months, and then 1, 3 years and 6 years. 2) Data retrieval from a) National datasets such as the 'National Non-­Admitted Patient Collection', the 'National Minimum Dataset', the 'Pharmaceutical Collection' and the 'National Immunisation Register'; b) Medical records; c) Institute of Environmental Science and Research (ESR) laboratory databases; d) Ministry of Health, B4 School Check data.

Monitoring will also be undertaken for the children under 10 in the household who have been prescribed study medications through the national datasets (for the year of their siblings randomisation).
Trial website
www.PIPPATamariki.ac.nz
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80670 0
Prof Stuart R Dalziel
Address 80670 0
Children's Emergency Department
Starship Children's Hospital
Auckland District Health Board
Private Bag 92024
Auckland 1142
Country 80670 0
New Zealand
Phone 80670 0
+64 9 307 4949
Fax 80670 0
Email 80670 0
[email protected]
Contact person for public queries
Name 80671 0
Judith Riley
Address 80671 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
Country 80671 0
New Zealand
Phone 80671 0
+64 4 805 0147
Fax 80671 0
Email 80671 0
[email protected]
Contact person for scientific queries
Name 80672 0
Stuart R Dalziel
Address 80672 0
Children's Emergency Department
Starship Children's Hospital
Auckland District Health Board
Private Bag 92024
Auckland 1142
Country 80672 0
New Zealand
Phone 80672 0
+64 9 307 4949
Fax 80672 0
Email 80672 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The PIPPA Tamariki trial uses identifiable individual patient data that are subject to restriction, including ethics, consent, and privacy issues. Anonymised data will be available on request from the corresponding author, where possible within these constraints for use.
When will data be available (start and end dates)?
From time of publication of main manuscript for 5 years.
Available to whom?
Researchers.
Available for what types of analyses?
Available for meta-analysis.
How or where can data be obtained?
Anonymised data will be available on request from the corresponding author, Professor Stuart Dalziel.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseRandomised controlled trial of paracetamol or ibuprofen, as required for fever and pain in the first year of life, for prevention of asthma at age 6 years: Paracetamol or ibuprofen in the primary prevention of asthma in Tamariki (PIPPA Tamariki) protocol.2020https://dx.doi.org/10.1136/bmjopen-2020-038296
N.B. These documents automatically identified may not have been verified by the study sponsor.