Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000381684
Ethics application status
Approved
Date submitted
28/03/2014
Date registered
9/04/2014
Date last updated
22/02/2024
Date data sharing statement initially provided
29/01/2020
Date results information initially provided
22/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised, placebo-controlled trial of oral nitazoxanide for the empiric treatment of acute gastroenteritis among Australian Indigenous children
Scientific title
In Australian indigenous children, what is the effect of oral nitazoxanide versus placebo on acute gastroenteritis?
Secondary ID [1] 284358 0
CVID / 2013-02
Universal Trial Number (UTN)
Trial acronym
NICE-GUT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Gastroenteritis 291517 0
Condition category
Condition code
Infection 291887 291887 0 0
Other infectious diseases
Public Health 291888 291888 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
15mg/kg oral nitazoxanide suspension to a maximum dose of 200mg twice daily for 3 days.
Participants will be treated as inpatients and treatment will be administered by study staff or ward staff. Drug accountability will be performed by Menzies School of Health Research Staff.
Intervention code [1] 289087 0
Treatment: Drugs
Comparator / control treatment
Placebo suspension identical to active treatment without the active ingredient.
Control group
Placebo

Outcomes
Primary outcome [1] 291809 0
The average time period of significant illness (defined as the period for which hospitalisation is required for medical reasons) for participants in each study treatment group.
Timepoint [1] 291809 0
60 days post randomisation
Secondary outcome [1] 307590 0
The average time period between enrolment and actual discharge from hospital
Timepoint [1] 307590 0
At discharge from index hospital admission
Secondary outcome [2] 307591 0
The average total number of (i) diarrhoeal episodes and (ii) vomiting episodes during the period of significant illness.
Timepoint [2] 307591 0
60 days post enrolment
Secondary outcome [3] 307592 0
The number and proportion of participants experiencing each solicited symptom (vomiting, diarrhoea, generally unwell) on each of study days 0-7
Timepoint [3] 307592 0
7 days post enrolment
Secondary outcome [4] 307593 0
The number and proportion of participants in whom dehydration is present and the severity of dehydration, where present, on each study day using a protocol-specific dehydration score from 0 (not dehydrated) to 3 (severely dehydrated)
Timepoint [4] 307593 0
7 days post enrolment
Secondary outcome [5] 307594 0
The average time interval between either starting IV, IO or NG rehydration or enrolment (whichever is the later), and ceasing rehydration (where the time of cessation is the time of completion of the last IV, IO or NG rehydration that is followed by discharge, or by a period of at least 24 hours before any further fluid rehydration is given)
Timepoint [5] 307594 0
7 days post enrolment
Secondary outcome [6] 307671 0
The maximum daily severity score for each adverse event , where experienced. Will be assessed using a protocol-specific grading system from 0 (normal) to 3 (severe). The expected gastroenteritis adverse events are nausea, vomiting, diarrhoea, dehydration. There aren't any specific drug-related expected adverse events, however adverse events may include fever, loss of appetite, lethargy, anorexia.
Timepoint [6] 307671 0
7 days post enrolment.

Eligibility
Key inclusion criteria
1. Infant /child between =>3 months and <5 years of age
2. Infant/ child identified as Indigenous by the legally responsible care-giver
3. Infant /child has been/will be admitted to hospital for acute infectious gastroenteritis (in the opinion of the admitted doctor and/or study doctor/nurse )
4. The legally responsible care-giver is willing for their infant/ child to participate in the study and who would be expected to comply with the requirements of the protocol, including being able and willing to be contacted by telephone after discharge where necessary
5. The legally responsible care-giver is 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
6. The legally responsible care-giver is willing to allow to allow the study team to obtain a vaccination history from Australian Childhood Immunisation Register (ACIR) and/or local provider
7. The legally responsible care-giver is willing to allow the study team to obtain an interim medical history from the participant’s electronic medical records and/or from the participant’s general practitioner for the period from enrolment to study day 60
8. Informed consent for the infant’s/child’s participation in the study has been given by the legally responsible care-giver
Minimum age
3 Months
Maximum age
5 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Admitted for =>48 hours at the point of enrolment
2. Duration of symptoms of greater than 14 days without apparent worsening of symptoms consistent with an acute pathology
3. Presence of grossly bloody diarrhoea
4. Clinical suspicion of non-infectious cause (e.g. diagnosed with a pre-existing medical condition predisposing to non-infectious diarrhoea, for example inflammatory bowel disease) except for environmental enteropathy)
5. Contraindication to the study drug or placebo (e.g. allergy)
6. Diagnosis of infection with an enteric pathogen where anti-microbial treatment with an alternative antimicrobial is the standard of care (e.g. Shigella sp.)
7. Inability to tolerate either the oral or nasogastric route (e.g. ileus)
8. Clinical suspicion of intestinal obstruction including bilious vomiting
9. Confirmed or suspected immunosuppressive or immunodeficient conditions, including human immunodeficiency virus (HIV) infection.
10. Receipt of more than 2 weeks of immuno-suppressants or immune modifying drugs, (e.g. prednisolone >0.5 mg/kg/day)
11. 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
12. Previously enrolled in the trial

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)
sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The sample size for the study is between 126 and 300 children randomised on a 1:1 basis to the two study treatment groups. Based on previously published data it is estimated that NTZ treatment will result in a decrease in the median duration of medically significant illness by 1 day. A decrease of one day is considered to be the minimum useful decrease of relevance to the study setting. It is estimated that data pertaining to the primary endpoint will be available for all participants in each group due to the short interval between enrolment and obtaining primary endpoint data.

The trial will be conducted as a fixed allocation Bayesian adaptive randomised controlled trial. The purpose of this section of the protocol is to introduce and summarize the statistical methods that will be used to analyse data within this trial. This section is intended to be practical and accessible to individuals with an understanding of common clinical trial designs and classical frequentist analytical methods but without training in Bayesian statistics. A formal description of the interim Bayesian data analysis methods fundamental to this design, which assumes substantial familiarity with Bayesian calculation of posterior distributions conditioned on observed data, will be located in the Statistical Analysis Plan. There is overlap between the protocol and statistical analysis plan so that each may serve an appropriate audience as a standalone description of the statistical methods.
Within the Bayesian framework, the intervention arms are evaluated and sequential Bayesian statistical analyses are used over time to incorporate new trial outcome information to determine if a treatment is superior, inferior, or equivalent, with respect to the primary end-point. Every child will be randomly assigned in a ratio 1:1 to placebo or nitazoxanide. Children will be classified by membership in different strata, where membership will be defined by age and geographical region. Whenever an interim analysis reports superiority, inferiority, or equivalence with respect to the primary end-point this is termed a Statistical Trigger. At any given interim analysis, a Statistical Trigger may be reached for all children or for one or more strata.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
12/05/2014
Actual
28/11/2014
Date of last participant enrolment
Anticipated
31/12/2021
Actual
20/04/2021
Date of last data collection
Anticipated
Actual
21/06/2021
Sample size
Target
300
Accrual to date
Final
216
Recruitment in Australia
Recruitment state(s)
NT
Recruitment hospital [1] 2274 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [2] 2275 0
Alice Springs Hospital - Alice Springs
Recruitment postcode(s) [1] 7949 0
0872 - Alice Springs
Recruitment postcode(s) [2] 7950 0
0800 - Darwin

Funding & Sponsors
Funding source category [1] 288997 0
Government body
Name [1] 288997 0
National Health and Medical Research Council
Country [1] 288997 0
Australia
Funding source category [2] 300701 0
Charities/Societies/Foundations
Name [2] 300701 0
CentreCorp Foundation
Country [2] 300701 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Telethon Kids Institute
Address
100 Roberts Road
Subiaco WA 6008
Country
Australia
Secondary sponsor category [1] 295040 0
None
Name [1] 295040 0
Address [1] 295040 0
Country [1] 295040 0
Other collaborator category [1] 277904 0
University
Name [1] 277904 0
Menzies School of Health Research
Address [1] 277904 0
John Mathews Building (JMB)
Building 58, Royal Darwin Hospital Campus
Darwin NT 0800
Country [1] 277904 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290806 0
Central Australian Human Research Ethics Committee
Ethics committee address [1] 290806 0
Centre for Remote Health
cnr Simpson and Skinner Sts
ALICE SPRINGS
NT 0870
Ethics committee country [1] 290806 0
Australia
Date submitted for ethics approval [1] 290806 0
28/02/2014
Approval date [1] 290806 0
26/03/2014
Ethics approval number [1] 290806 0
HREC-14-221
Ethics committee name [2] 290807 0
Human Research Ethics Committee of Northern Territory Department of Health and Menzies School of Health Research
Ethics committee address [2] 290807 0
PO Box 41096,
Casuarina NT 0811
Ethics committee country [2] 290807 0
Australia
Date submitted for ethics approval [2] 290807 0
10/03/2014
Approval date [2] 290807 0
22/07/2014
Ethics approval number [2] 290807 0
2014-2172

Summary
Brief summary
This is a multi-centre (RDH and ASH), phase IV, double-blind, randomised, placebo-controlled trial of oral NTZ for the treatment of acute gastroenteritis requiring admission to hospital. Up to 300 children aged between three months and less than five years of age will be enrolled. Study participation would be from the point of enrolment until 60 days after enrolment. Enrolment will occur within 48 hours of admission to hospital. Enrolled participants will be randomised 1:1 to Nitazoxanide (NTZ) or placebo. Other treatment and management will be as per the standard of care described in the admitting hospital’s guidelines and will be ultimately the decision and responsibility of the named medical consultant. Stool samples will be collected at the point of admission. Solicitation of symptoms will be by review of routinely collected medical data recorded in the participant’s medical record, and will be supplemented by completion of study specific diary cards until discharge. All participants will be followed up at day 7 after enrolment (by telephone if already discharged) to ascertain symptoms occurring in the intervening period. At days 30 and 60 after enrolment a clinical record review will be conducted for all participants to ascertain health care attendances following discharge.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 47338 0
Dr Tom Snelling
Address 47338 0
Telethon Kids Institute PO Box 855 West Perth WA 6872
Country 47338 0
Australia
Phone 47338 0
+61 8 6319 1817
Fax 47338 0
Email 47338 0
[email protected]
Contact person for public queries
Name 47339 0
Carly McCallum
Address 47339 0
Telethon Kids Institute PO Box 855 West Perth WA 6872
Country 47339 0
Australia
Phone 47339 0
+61 8 6319 1422
Fax 47339 0
Email 47339 0
[email protected]
Contact person for scientific queries
Name 47340 0
Dr Tom Snelling
Address 47340 0
Telethon Kids Institute PO Box 855 West Perth WA 6872
Country 47340 0
Australia
Phone 47340 0
+61 8 6319 1817
Fax 47340 0
Email 47340 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
6649Study protocolWaddington CS, McLeod C, Morris P, et al The NICE-GUT trial protocol: a randomised, placebo controlled trial of oral nitazoxanide for the empiric treatment of acute gastroenteritis among Australian Aboriginal children BMJ Open 2018;8:e019632. doi:10.1136/bmjopen-2017-019632 https://bmjopen.bmj.com/content/8/2/e019632 



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseThe NICE-GUT trial protocol: A randomised, placebo controlled trial of oral nitazoxanide for the empiric treatment of acute gastroenteritis among Australian Aboriginal children.2018https://dx.doi.org/10.1136/bmjopen-2017-019632
N.B. These documents automatically identified may not have been verified by the study sponsor.