Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001597189
Ethics application status
Approved
Date submitted
4/09/2019
Date registered
20/11/2019
Date last updated
12/04/2023
Date data sharing statement initially provided
20/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Joint UK and Australia multicentre, randomised, double blind, placebo controlled pragmatic trial comparing 52 weeks of azithromycin to placebo in children with neurological impairment at risk of lower respiratory tract infection (the PARROT trial).
Scientific title
The effect of prophylactic antibiotics on chest infections in children with neurological impairment (Parrot) trial.
Secondary ID [1] 299072 0
Sponsor (UK): UoL001460
Secondary ID [2] 299073 0
NIHR HTA (UK): 16/17/01
National Health and Medical Research Council (Australia): 1157228, APP1149332
Secondary ID [3] 299074 0
ISRCTN71955516
Universal Trial Number (UTN)
Trial acronym
PARROT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neurological impairment 314260 0
Lower respiratory tract infection 314261 0
Condition category
Condition code
Neurological 312615 312615 0 0
Other neurological disorders
Respiratory 312636 312636 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Azithromycin

The dosing regimen is based on body weight (10mg/kg rounded) and will be administered as an oral suspension 3 times weekly (Mon/Wed/Fri) for 52 weeks.

Adherence will be monitored at 13, 26, 39 and 52 weeks using an IMP treatment diary and withdrawals from study treatment will also be monitored.
Intervention code [1] 315465 0
Treatment: Drugs
Comparator / control treatment
Arm 2: Placebo

Placebo matching azithromycin will be supplied as powder for oral suspension.

For both UK and Australia, inert, matched excipients are used.
Control group
Placebo

Outcomes
Primary outcome [1] 321268 0
Proportion of children hospitalised* with Lower Respiratory Tract Infection (LRTI) over the 52-week intervention period.

Parents will be asked at the timepoints specified below if they have attended hospital due to a LRTI. The research team will review any admissions to the recruiting centre against the LRTI criteria specified in the protocol and document on the applicable CRF. Parents will be asked and patients hospital records will be checked as part of the follow-up visit.

*Hospitalisation includes those who are admitted to hospital for only a short period with LRTI e.g. 12 hours and go home with a course of antibiotics. However, if participants are hospitalised again within 2 weeks of the initial admission, this will be classified as the same event.
Timepoint [1] 321268 0
At 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks:

Hospitalisations due to LRTI.

Primary outcome assessment will be at 52 weeks.

Secondary outcome [1] 374491 0
Change in health related QoL of parent / carer (composite outcome).
Timepoint [1] 374491 0
At baseline, 13, 26, 39, 52 weeks
• Parent QoL assessment (Warwick-Edinburgh)
• Patient QoL assessment (DISABKIDS)
Secondary outcome [2] 374492 0
Safety events
Timepoint [2] 374492 0
At 4, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks:
• Assessment of adverse reactions

Known adverse reactions include mild diarrhoea, stomach pains, nausea or vomiting, headache and dizziness. There is also a small chance that azithromycin may cause a rash, or hearing problems.

Participants will attend face-to-face visits and scheduled phone/email contact will be made. Any data related to adverse reactions will be collected at these timepoints and recorded on the CRFs. PIs and delegated investigators are responsible for reporting all adverse reactions via the adverse event CRF within 7 days of becoming aware of the event and are responsible for reporting serious adverse reactions via the serious adverse reaction CRF within 24 hours of becoming aware of the event.
Secondary outcome [3] 374493 0
Changes in respiratory medication usage (composite outcome).

Parent will be asked about changes to respiratory medication and patient medical notes can also be used (not using data linkage).
Timepoint [3] 374493 0
At baseline, 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks:
• Review of concomitant medication which could impact the respiratory system

At baseline and 52 weeks:
• Vaccinations
Secondary outcome [4] 374494 0
Changes in weight based on World Health Organisation z-scores using WHO Anthro (3.2.2) calculator (https://www.who.int/growthref/tools/en/). Weight will be measured in accordance with local standard practice.
Timepoint [4] 374494 0
At baseline, 13, 26, 39, 52 and 78 weeks:
• Weight
Secondary outcome [5] 374495 0
Change in quality / amount of parent's sleep.

(Composite outcome).
Timepoint [5] 374495 0
At baseline and 52 weeks:
• Primary caregiver sleep actigraphy and corresponding primary caregiver sleep log (UK only)
Secondary outcome [6] 374496 0
Change in respiratory symptoms assessed (composite outcome).

Respiratory symptoms will be assessed using methods specified below. Symptoms assessed by the questionnaires include:- Cough, wheeze, shortness of breath, ‘rattly’ chest, snoring, noisy breathing not from chest, noisy breathing from throat, fast breathing, feeding, activity levels, sleep disturbance, fatigue. Also the effect on family activities, adjustment to family life, disturbed sleep, worry / anxiety will be assessed.
Timepoint [6] 374496 0
At / baseline, 13, 26, 39, 52 and 78*weeks:
• LRSQ-Neuro score
• Respiratory symptom questionnaire

At 13, 26, 39, 52 and 78* weeks:
• Changes to respiratory treatments / support
• Surgical and other interventions

*assessment will only take place at 78 weeks if recruitment is still ongoing

Parent will be asked about changes to respiratory treatments/support, surgical and other interventions. Medical notes would also be reviewed (no data linkage).
Secondary outcome [7] 374497 0
Number, duration and severity of LRTI; time to first LRTI (composite outcome)
Timepoint [7] 374497 0
At 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks:
• Attendance at Hospital, GP and number of days unwell with LRTI
• Changes to respiratory treatments / support
• Assessment of adverse reactions

Parent will be asked about attendance at hospital, GP and number of days unwell with LRTI, changes to respiratory treatments/support and whether they have/are experiencing any adverse reactions. Patient records will also be checked for hospital admissions.
Secondary outcome [8] 374498 0
Unscheduled medical presentations (GP visits and A&E attendances) for LRTI
Note: The LRTI definition at GPs will vary to the primary endpoint definition of LRTI
Timepoint [8] 374498 0
At baseline weeks:
• Medical history review

At 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks:
• Attendance at Hospital and GP for LRTI
• Assessment of adverse reactions

Parent will be asked about medical history, attendance at hospital, GP and number of days unwell with LRTI and whether they have/are experiencing any adverse reactions. Patient records will also be checked for hospital admissions.
Secondary outcome [9] 374499 0
Use of other health and social care services, school attendance and indirect costs (composite outcome)
Timepoint [9] 374499 0
At baseline, 13, 26, 39, 52 and 78* weeks:
• Resource use questionnaire (Study-specific).

For participants that attend English centres at 52 and 78* weeks:
• Hospital Episode Statistics (HES)



*assessment at 78 weeks will only take place if recruitment to the trial is still ongoing
Secondary outcome [10] 374500 0
Number of courses of ‘rescue’ antibiotics prescribed for LRTI
Timepoint [10] 374500 0
At baseline, 4, 8, 13, 17, 21, 26, 30, 34, 39, 43, 47 52 and 78* weeks:
• Review of concomitant medications which could impact the respiratory system

Parent will be asked about respiratory medication usage. Medical records will also be reviewed.

*assessment at 78 weeks will only take place if recruitment to the trial is still ongoing
Secondary outcome [11] 374501 0
Quality-adjusted life years (QALY) assessment (composite outcome).
Timepoint [11] 374501 0
At baseline, 13, 26, 39, 52 and 78* weeks:
• CHU9D and EQ-5D-Y

CHU9D and EQ-5D-Y are used to evaluate the outcome measure ‘’Quality-adjusted life years (QALY) assessment.’’

*assessment at 78 weeks will only take place if recruitment to the trial is still ongoing
Secondary outcome [12] 374502 0
Nasal swab microbiology and resistance profiling; viral and bacterial causes of acute LRTI requiring hospitalisation (composite outcome)
Timepoint [12] 374502 0
At baseline, 26, 52 and 78* weeks:
• Nasal swab

*assessment at 78 weeks will only take place if recruitment to the trial is still ongoing
Secondary outcome [13] 374503 0
Nasal swab/nasopharyngeal aspirate to investigate viral causes of acute LRTI
Timepoint [13] 374503 0
When / if children are hospitalised with acute LRTI
Secondary outcome [14] 374504 0
Cough swab/sputum collection to investigate bacterial causes of acute LRTI
Timepoint [14] 374504 0
When / if children are hospitalised with acute LRTI
Secondary outcome [15] 375400 0
Change in health related QoL of child and parent/carer (composite outcome)
Timepoint [15] 375400 0
At baseline, 13, 26, 39, 52 weeks
• Parent QoL assessment (Warwick-Edinburgh)
• Patient QoL assessment (DISABKIDS)

Parent QoL assessment (Warwick-Edinburgh Mental Wellbeing Scale) and Patient QoL assessment (DISABKIDS) are used to evaluate the outcome measure ‘’Change in health related QoL of child and parent / carer’’(composite outcome).
Secondary outcome [16] 375401 0
Tolerability
Timepoint [16] 375401 0
At 4, 13, 17, 21, 26, 30, 34, 39, 43, 47 and 52 weeks:
• Assessment of adverse reactions
Parents will be asked if there have been any adverse events and an assessment of adverse reactions will be made by site.

At 13, 26, 39 and 52 weeks:
• Withdrawals from study treatment
Secondary outcome [17] 375402 0
Adherence to study medication.
Timepoint [17] 375402 0
At 13, 26, 39 and 52 weeks:
• IMP treatment diary
• Withdrawals from study treatment
Secondary outcome [18] 375403 0
Change in quality / amount of child / young person’s sleep (composite outcome).
Timepoint [18] 375403 0
At baseline and 52 weeks:
• Child’s Sleep Habits Questionnaire
• 1 week patient sleep diary

Eligibility
Key inclusion criteria
1. Children and young people who are aged between 3-17 years (inclusive) at randomisation
2. Written informed consent from participant (or appropriate person if incapacitated / minor)
3. Participant (or appropriate person if incapacitated / underage) and caregiver have a good understanding of the English language
4. Diagnosed with non-progressive, non-neuromuscular NI
5. Persistent respiratory symptoms*
6. One or more of the following:
a) Received at least 2 courses of oral antibiotics for LRTI in 52 weeks prior to eligibility
b) Have been hospitalised with a LRTI within 52 weeks prior to eligibility and completed 13 week ‘washout’ period (where applicable)**
c) Prescribed prophylactic antibiotics for LRTIs and undergone a 13 week ‘washout’ period**.

* Defined by: LRSQ-Neuro score of equal to or higher than 95%CI for age:
Age (in years) LRSQ-Neuro total score
greater than or equal to 3 and less than 6 greater than or equal to 11
greater than or equal to 6 and less than 11 greater than or equal to 5
greater than or equal to 11 and less than or equal to 17 greater than or equal to4

**Must have undergone a 13 week ‘washout’ period where administered IV antibiotics during hospitalisation or have been previously prescribed and administered prophylactic antibiotics.
Minimum age
3 Years
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any neuromuscular disorders including SMA, Duchenne muscular dystrophy etc., or neurological disorders in which progressive deterioration in neurological condition are known to occur (e.g. Rett syndrome, some neurometabolic syndromes)
2. Pre-existing non-neurological conditions that impact on respiratory function such as cystic fibrosis (CF), immunodeficiency etc.
Note: Children with NI known to have bronchiectasis will not be excluded.
3. Known contra-indication to using (e.g. prolonged QT syndrome) or hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic or to any of the excipients contained in the study drug
4. Use of macrolide antibiotics within 90 days prior to eligibility
5. Known significant hepatic disease (hepatic impairment per Child-Pugh classification C)
6. Treatment with ergot derivatives (dihydroergocristine, dihydroergotamine, dihydroergotoxine, nicergoline or a combination of dihydroergocryptine with caffeine)
7. Child/young person already taking prophylactic antibiotics for non-respiratory causes (e.g. UTIs).
8. Previously randomised in PARROT
9. Recruited to another IMP trial and continuing to administer the IMP.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Parrot is a double-blind trial so the research / treating clinical team will be blinded to treatment allocation. There will be a designated unblinding team (usually pharmacy) at each centre who will be unblinded to treatment allocations. Randomisation will occur via a randomisation system and there will be back-up randomisation envelopes. Only the unblinded team will receive information regarding the unblinded treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation lists will be generated using block randomisation with random variable block length, stratified by site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
To detect a 30% reduction in hospitalisation rate in children with NI and respiratory symptoms at risk of LRTI, with 90% power (alpha 0.05), we would require 225 patients per group, increasing to 250 allowing for 10% loss to follow-up/attrition, i.e. 500 children in total.

A Statistical Analysis Plan (SAP) will be developed for use in the interim and final analyses of the trial.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
22/06/2020
Actual
28/07/2020
Date of last participant enrolment
Anticipated
24/04/2023
Actual
Date of last data collection
Anticipated
31/08/2023
Actual
Sample size
Target
500
Accrual to date
85
Final
Recruitment in Australia
Recruitment state(s)
NT,QLD,VIC
Recruitment hospital [1] 14712 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 14713 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 14720 0
Royal Darwin Hospital - Tiwi
Recruitment postcode(s) [1] 27752 0
4101 - South Brisbane
Recruitment postcode(s) [2] 27753 0
3052 - Parkville
Recruitment postcode(s) [3] 27760 0
0810 - Tiwi
Recruitment outside Australia
Country [1] 21831 0
United Kingdom
State/province [1] 21831 0

Funding & Sponsors
Funding source category [1] 303607 0
Government body
Name [1] 303607 0
National Institute of Health Research Technology Assessment Programme (UK)
Country [1] 303607 0
United Kingdom
Funding source category [2] 303714 0
Government body
Name [2] 303714 0
National Health and Medical Research Council (Australia)
Country [2] 303714 0
Australia
Primary sponsor type
University
Name
University of Liverpool
Address
2nd Floor Block D, Waterhouse Building,
3 Brownlow Street,
Liverpool,
L69 3GL
Country
United Kingdom
Secondary sponsor category [1] 303698 0
University
Name [1] 303698 0
Menzies School of Health Research
Address [1] 303698 0
John Mathews Building (Building 58)
Royal Darwin Hospital Campus
Rocklands Drive
Casuarina NT 0810
Country [1] 303698 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304136 0
Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 304136 0
Ethics committee country [1] 304136 0
Australia
Date submitted for ethics approval [1] 304136 0
Approval date [1] 304136 0
06/08/2019
Ethics approval number [1] 304136 0
HREC/19/QCHQ/56353

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95930 0
Prof Paul Stephen McNamara
Address 95930 0
Consultant in Paediatric Respiratory Medicine, Alder Hey Children’s NHS Foundation Trust
Professor of Child Health, University of Liverpool
Institute in The Park
Alder Hey Children’s Hospital
Eaton Road
Liverpool
L12 2AP
Country 95930 0
United Kingdom
Phone 95930 0
+44151 282 4531
Fax 95930 0
Email 95930 0
mcnamp@liverpool.ac.uk
Contact person for public queries
Name 95931 0
Paul Stephen McNamara
Address 95931 0
Consultant in Paediatric Respiratory Medicine, Alder Hey Children’s NHS Foundation Trust
Professor of Child Health, University of Liverpool
Institute in The Park
Alder Hey Children’s Hospital
Eaton Road
Liverpool
L12 2AP
Country 95931 0
United Kingdom
Phone 95931 0
+44151 794 9838
Fax 95931 0
Email 95931 0
parrot@liverpool.ac.uk
Contact person for scientific queries
Name 95932 0
Paul Stephen McNamara
Address 95932 0
Consultant in Paediatric Respiratory Medicine, Alder Hey Children’s NHS Foundation Trust
Professor of Child Health, University of Liverpool
Institute in The Park
Alder Hey Children’s Hospital
Eaton Road
Liverpool
L12 2AP
Country 95932 0
United Kingdom
Phone 95932 0
+44151 794 9838
Fax 95932 0
Email 95932 0
parrot@liverpool.ac.uk

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Discussions at the University of Liverpool Clinical Trials Unit are currently ongoing regarding data sharing and how we are planning to share patient level data for all of our trials. This field will be updated once a decision has been made.


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
No additional documents have been identified.