Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000590561
Ethics application status
Not required
Date submitted
19/05/2015
Date registered
5/06/2015
Date last updated
12/10/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase II double-blind randomised, placebo-controlled clinical trial of oral nitazoxanide for the treatment of bronchiolitis in infants presenting to hospital emergency departments.
Scientific title
Finding a better treatment for bronchiolitis:
A phase II double-blind randomised, placebo-controlled clinical trial of oral nitazoxanide for the treatment of bronchiolitis in infants presenting to hospital emergency departments.
Secondary ID [1] 286622 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchiolitis 294942 0
Condition category
Condition code
Respiratory 295199 295199 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Nitazoxanide (NTZ) is a synthetic drug of the nitrothiazolide class. The main metabolite of NTZ is tizoxanide. The active ingredient is 2-acetyloxy-N (5-nitro-2-thiazolyl) benzamide) at a concentration of 100mg/5ml.

The dose to be given is 7.5mg/kg by mouth (or nasogastric/nasoenteric tube) three times per day for five days.

The oral suspension is supplied as a pink coloured powder formulation that is reconstituted with 48 ml water prior to use to a final volume of 60 ml. To reconstitute, the bottle containing the powder should be tapped until the powder flows freely. Approximately one-half of the total amount of water required for reconstitution is then added and vigorously shaken to suspend the powder. The remaining volume of water is then added and again shaken. Where possible NTZ should be administered with food. Should the participant vomit within 15 minutes of study drug administration, the dose should be repeated once.

To monitor adherence, drug accountability will be completed by the clinical trials pharmacist in conjunction with the principal investigator. At dispensing participants will be counseled on the returns procedures for the study drug and compliance will be checked on return of study drug by a member of the research team as delegated by the principal investigator in conjunction with the clinical trials pharmacist.
Intervention code [1] 291758 0
Treatment: Drugs
Comparator / control treatment
Placebo-The placebo is identical to the active drug except that it does not contain the active compound nitazoxanide. It is reconstituted, administered and dosed as per the active study drug.
Control group
Placebo

Outcomes
Primary outcome [1] 294954 0
To determine the effect of treatment with nitazoxanide compared to placebo on the severity of respiratory distress.
Timepoint [1] 294954 0
The Respiratory Assessment Change Scores (RACS) as measured by the change in Respiratory Distress Assessment Instrument (RDAI) at day 1 and study day 4 (two time points) adjusted for the change in respiratory rate
Secondary outcome [1] 314455 0
To determine the effect of treatment with nitazoxanide compared to placebo on:
The amount of virus in nasal secretions
Timepoint [1] 314455 0
The change in the amount of virus detected in nasal secretions (obtained by nasal swab) from the first calendar day of randomisation (study day 1) and study day 3 as measured by quantitative PCR.
Secondary outcome [2] 314456 0
To determine the effect of treatment with nitazoxanide compared to placebo on:
The duration and severity of parent reported solicited symptoms associated with bronchiolitis.
Timepoint [2] 314456 0
The presence and maximum severity of solicited symptoms associated with bronchiolitis (loss of appetite, decreased activity level, increased work or breathing and irritability) (study day 1) to the end of study day 7.
Secondary outcome [3] 314457 0
To determine the effect of treatment with nitazoxanide compared to placebo on:
Actual duration of hospital admission for any reason
Timepoint [3] 314457 0
The period of time for which hospitalisation is required for any medical reason, defined as the time from randomisation to the time of actual discharge from hospital, excluding time in hospital for social reasons.
Secondary outcome [4] 314458 0
To determine the effect of treatment with nitazoxanide compared to placebo on:
The need for and duration of interventional supportive medical care
Timepoint [4] 314458 0
Between randomisation and Study Day 7, the use of:
1. oxygen therapy
2. supportive ventilation
3. intensive care unit
4. supportive hydration therapy (NG or IV)
Duration of use is calculated from the calendar day
of randomisation to the date of cessation

Eligibility
Key inclusion criteria
1. Aged greater than or equal to 1 month to less than or equal to 12 months
2. Diagnosed with bronchiolitis by the assessing doctor
3. Parent/ legally responsible carer has provided informed consent for their infant/ child to participate in the study
4. Parent/ legally responsible carer able and willing to comply with the requirements of the protocol
5. Parent/ legally responsible carer able and willing to attend a study follow up visit on study day 3 if their infant/child has previously been discharged from hospital
6. Parent/ legally responsible carer willing to allow other parties involved in the treatment of his or her child (including the general practitioner, paediatrician, hospital medical and nursing staff, community clinic staff) to be notified of participation in the trial
7. Infants and children whose parent is willing to allow the study team to obtain an interim medical history from the participant’s electronic medical records (including immunisation records)and/or from the participant’s general practitioner or other medical professional for the period
from enrolment to study day 180
Minimum age
1 Months
Maximum age
12 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Presence of symptoms of bronchiolitis (breathing difficulty, difficulty feeding, cough, poor
feeding) for greater than or equal to 48 hours at the point of enrollment
2. Born at a gestational age of less than 32 weeks
3. Has a history of any condition associated with risk of severe bronchiolitis including:
*Significant cardiovascular disease, including congenital heart disease
*Significant respiratory disease, including chronic lung disease
*Trisomy 21 (Down’s syndrome)
*Significant neurological disease (including history of seizure disorder)
*Significant impairment/ alteration of the immune system (including congenital
immunodeficiency)
*Any other disorder considered relevant by a medically qualified investigator
4. Requiring admission to intensive care unit at enrollment
5. Clinical suspicion of illness other than bronchiolitis
6. Contraindication to the study drug or placebo (e.g. allergy)Medical condition or treatment with
medication which in the opinion of the admitting team would make the child unsuitable for the
trial
7. Receipt of investigational drug/vaccine, other than the drugs used in the study, within 30 days
prior to receiving the first dose of NTZ or their planned use during the study period, until 1
month after the administration of the final dose of NTZ
8. Previously enrolled in the trial
9. Parent less than 18 years of age

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)
Enrolled participants will be assigned the lowest available numbered bottle from the relevant block of randomisation numbers provided to the site by Romark Laboratories, L.C Florida, USA
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation allocation will be generated by an independent statistician. The randomisation list will be computer generated using an appropriate block size to account for the number of study sites involved. The allocation ratio with be 1:1 active NTZ: placebo.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Factorial
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
All endpoints will be analysed on an intent-to-treat and per protocol basis. The Intent to Treat population (ITT) is defined as all randomised participants whose parents have provided informed consent. Participants will be included in the treatment group to which they were randomised irrespective of the treatment received. The Per-protocol population is defined as all randomised participants with informed consent who:
I. receive and tolerated a minimum of six doses of the treatment they received in the period between randomisation and Study Day 4 clinical assessment.
II. did not receive rescue treatment with NTZ

Primary Endpoint:
The RACS will be calculated as the sum of change from baseline to Study Day 4 in the RDAI score and the standardised score for respiratory rate (RR) percentage change over the same time. The standardised score for change in RR is weighted such that there is a reduction of 1 unit for a decrease in rate of >5% but equal to <15%, 2 units for a decrease of 15-25%, etc., thus negative values signify improvement.
RACS=(RDAI baseline-RDAI Day 4) + round (1-RR Day 4/RR baseline) x -10

Secondary Endpoints:
Mean change in log transformed viral nasal secretion between baseline and Study Day 4 will be compared between the placebo and NTZ treatment groups using a two sample t-test. Geometric mean difference with appropriate 95% confidence intervals will be presented.

Duration of hospital admission will be coded as the time until hospital discharge and compared between the treatment groups using a log rank test. Kaplan Meier estimates, with 95% confidence intervals, will be calculated and graphed to illustrate the length of time that the participants remain in hospital for each treatment group.

The frequency of use of oxygen therapy, supportive ventilation, intensive care unit and supportive hydration therapy will be compared between the placebo and NTZ treatment groups using Fisher's Exact test. The duration of use of each procedure will be tabulated by treatment group.

Further analyses may be deemed necessary for all efficacy endpoints using either multivariate regression of Cox Proportional Hazard Models to adjust for importance covariance; these may include age at enrolment, pre-term birth, smoking and overcrowding in the household. Appropriate adjustment for multiple testing will be applied to all secondary efficacy endpoints. An A priori stratified analyse will also be performed by causative pathogen, grouped possession of the NTZ target glycoprotein.

The frequency of all safety and tolerability endpoints will be compared between the placebo and NTZ treatment groups using Fisher's Exact test. No correction will be employed for multiple testing.

A sample size of 49 completers per treatment arm are required to detect a change of at least two points on the RACS scale. This is based on a standard deviation of approximately three (from previous studies, Lowell et al. 1897, Schuh et al. 2002), a significance level of 5% and power of at least 90%. A completer is defined as an eligible patient who has a clinician assessed RACS score on study day 3 (thus requiring RDAI and respiratory rate assessments at baseline and Study Day 3). It is anticipated that 20% of patients will be lost to follow up or will not be available for the clinician assessment within +/- 6 hours of Study Day 3, therefore, 62 patients will be recruited per treatment arm. A decrease of two points on the RACS scale is considered to be a useful decrease of clinical relevance to the study setting. The total sample size for the study is 124 infants and children equally randomised (1:1) to placebo or NTZ treatment, which is reasonable over the planned two year period of the study based on the rate of admission to the study’s site for bronchiolitis, and recruitment rates from previous studies.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
trial not proceeding as unable to secure drug supply
Date of first participant enrolment
Anticipated
2/01/2017
Actual
Date of last participant enrolment
Anticipated
30/06/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
124
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 3743 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 9626 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 291204 0
Other Collaborative groups
Name [1] 291204 0
The Western Australia Department of Health and the Channel 7 Telethon Trust
Country [1] 291204 0
Australia
Primary sponsor type
Other
Name
Telethon Kids Institute
Address
100 Roberts Road
SUBIACO WA 6008
Country
Australia
Secondary sponsor category [1] 289884 0
University
Name [1] 289884 0
The University of Western Australia
Address [1] 289884 0
35 Stirling Highway
CRAWLEY WA 6009
Country [1] 289884 0
Australia

Ethics approval
Ethics application status
Not required
Ethics committee name [1] 292771 0
Princess Margaret Hospital for Children Ethics Committee
Ethics committee address [1] 292771 0
Level 1, Children's Clinical Research Facility
Princess Margaret Hospital
Roberts Road, Subiaco WA 6008
GPO Box D184
Perth WA 6840
Ethics committee country [1] 292771 0
Australia
Date submitted for ethics approval [1] 292771 0
01/08/2016
Approval date [1] 292771 0
Ethics approval number [1] 292771 0

Summary
Brief summary
Aims:
Bronchiolitis is an extremely common cause of respiratory illness in infants caused by viral infection. The primary aim of this study is to determine whether treatment with nitazoxanide (NTZ) reduces the duration and severity of respiratory symptoms caused by bronchiolitis.

Justification:
Bronchiolitis affects over a third of infants in their first two years of life, and in Australia approximately 5,000 infants are hospitalised every year with the condition (Garcia et al. 2010). This is estimated to cost the healthcare system between 32 and 62 million dollars per year (Deshpande & Northern 2003). Infants who are born prematurely, or who have lung disease or heart disease are at the highest risk of developing bronchiolitis and also have the most severe disease. Bronchiolitis increases the risk of subsequently developing recurrent wheezing and asthma in childhood (Shay et al. 1999). An effective treatment would be of enormous benefit, not only by reducing infant suffering, but also by reducing the impact on parents and the healthcare system and the long-term consequences of infection.

Participant Groups:
This study will involve 124 infants between the ages of 1 and 12 months with a clinical diagnosis of bronchiolitis (62 in each study arm).

Project Design:
This study is a phase II double-blind randomised, placebo-controlled clinical trial of oral nitazoxanide for the treatment of bronchiolitis.

Methods:
Parents of infants presenting to Princess Margaret Hospital and diagnosed with bronchiolitis will be invited to participate. Following a full explanation of the study, informed consent will be taken from interested parents. A brief clinical history of the illness will be taken, and the infant assessed for respiratory distress using a validated scoring system (the Respiratory Distress Assessment Instrument). A painless swab will be taken from the front of the infant’s nose to try and detect the virus that has triggered the illness. Infants will then be allocated at random (similar to tossing a coin) to receive either treatment with NTZ or placebo for five days. Infants will be reviewed after three days of treatment, and
their respiratory distress score repeated. The change in the score, combined with a change in respiratory rate will be used to calculate the Respiratory Assessment Change Score (RACS). In order to assess if NTZ is a useful treatment for bronchiolitis the RACS will be compared between the placebo
and the NTZ groups. Symptoms over the first week of illness and oxygen requirement will also be compared using a parental completed diary card. To see if NTZ reduces the amount of virus present, a nasal swabs at day 3 and day 5 will be collected and the viral load compared with that at baseline. For infants that need to be admitted to hospital, the amount of medical support need ed will be recorded (for
example, the need for oxygen therapy) as well as the duration of hospitalisation. The number of times that the infant has to come back to hospital for either bronchiolitis or wheeze will be recorded over the six months after treatment using electronic hospital records.

Expected Outcomes:
This study will determine whether NTZ is an effective empirical treatment for bronchiolitis. It will also help us to understand what effect NTZ has on the amount of virus present and how viral load changes over the course of the disease. If this study shows that NTZ is a useful treatment, then a larger study will be conducted enrolling infants that present to primary care facilities.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 56898 0
Dr Claire WADDINGTON
Address 56898 0
Wesfarmers Centre of Vaccine and Infectious Diseases
Telethon Kids Institute
PO Box 855
WEST PERTH WA 6872
Country 56898 0
Australia
Phone 56898 0
+61 8 9489 7848
Fax 56898 0
Email 56898 0
[email protected]
Contact person for public queries
Name 56899 0
Ms Carly Foulis
Address 56899 0
Wesfarmers Centre of Vaccine and Infectious Diseases
Telethon Kids Institute
PO Box 855
WEST PERTH WA 6872
Country 56899 0
Australia
Phone 56899 0
+61 8 9489 7608
Fax 56899 0
Email 56899 0
[email protected]
Contact person for scientific queries
Name 56900 0
Dr Claire WADDINGTON
Address 56900 0
Wesfarmers Centre of Vaccine and Infectious Diseases
Telethon Kids Institute
PO Box 855
WEST PERTH WA 6872
Country 56900 0
Australia
Phone 56900 0
+61 8 9489 7848
Fax 56900 0
Email 56900 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



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