History of Changes for Study: NCT04876131

Version	Submitted Date	Changes
1	May 2, 2021	None (earliest Version on record)
2	May 12, 2021	Arms and Interventions, Outcome Measures, Study Description, Eligibility, Study Design and Study Status
3	June 9, 2021	Study Status
4	February 28, 2022	Contacts/Locations, Outcome Measures, Arms and Interventions, Study Status, Study Description, Eligibility and Study Identification
5	May 23, 2022	Recruitment Status, Study Status and Contacts/Locations
6	June 21, 2022	Study Status
7	February 4, 2023	Study Status, Eligibility and Study Description
8	March 20, 2024	Study Status

Brief Summary:

Urinary tract infections (UTI) are commonly encountered in children, with 7% diagnosed with at least one UTI by the age of 19 years. The evidence for treatment of uncomplicated UTI is clear; oral antibiotics are as good as intravenous (IV) antibiotics, usually for a total of 7 days. Complicated UTIs (cUTIs) on the other hand, are common reasons for hospital admissions for IV antibiotics and constitute a major burden for healthcare systems. There is considerable variation in care for children who present with UTI and have complicating features such as vomiting, dehydration, urological abnormalities or have a previous history of UTI. Australian and international guidelines lack clear, evidence-based recommendations to guide treatment in this group. Without gold standard evidence, these children will continue to receive unnecessary IV antibiotics, longer hospital stays and poorer health outcomes.

This multicentre, non-inferiority randomised trial will investigate if One dose - single dose of IV followed by 2 days oral antibiotics is as non-inferior to Three doses for children with UTI and co-existing complicating factors presenting to the Emergency Department (ED). In other words, this study will compare if a single dose of IV antibiotics plus two days oral antibiotics is as clinically effective as 3 doses antibiotics in resolving UTI symptoms at 72 hours after the first dose of IV antibiotics, for complicated UTIs in children presenting to the ED. All participants will receive a total of 7 days of antibiotics for the complicated urinary tract infection. If 1 dose IV and 2 days oral antibiotics is found to be as good as 3 days, the duration of IV antibiotics for complicated UTI can be reduced along with avoidance of the inherent risks of unnecessary hospital admission by administering a single IV dose in an outpatient/ED setting. On the other hand if a single IV dose results in prolonged symptoms or treatment failure, this will inform practice for the proportion of children who have a single dose of IV antibiotics in the ED and are sent home on oral antibiotics. Regardless of the outcome, this trial will inform clinical practice for complicated UTI to improve health outcomes for this group.

Detailed Description:

Study design:

An open label, multi-centre, pragmatic, non-inferiority randomised controlled trial (RCT).

It will incorporate a two-arm, non-inferiority design with parallel groups and 1:1 allocation of children with ≥3 complicated features of UTI presenting to the ED in whom clinicians deem parenteral antibiotics are required.

Primary objective:

The primary objective of this trial is to compare whether 1 dose of a daily parenteral antibiotic followed by 2 days oral antibiotics is as clinically effective (non-inferior) in resolving UTI symptoms at 72 hours after the first IV dose, as 3 doses of a daily parenteral antibiotic for complicated urinary tract infections presenting to the ED.

Definition:

1 dose: one dose of a daily dose IV to cover Gram negative bacteria +/- one dose IV to cover Enterococcus spp. This will be followed by two days oral antibiotics.

3 doses: three doses of a daily dose IV to cover Gram negative bacteria +/- 3 days IV antibiotics to cover Enterococcus spp.

Secondary objectives:

The secondary objectives of this trial are to compare the following outcomes between the 1 dose and the 3 doses arms:

Readmission due to persistent fever, vomiting, rigors, or clinical deterioration (e.g., poor feeding, dehydration) within 14 days of the initial dose of IV antibiotics.
Readmission due to persistent fever, vomiting, rigors, or clinical deterioration (e.g., poor feeding, dehydration) within 1 month of the initial dose of IV antibiotics.
Transfer from HITH/ambulatory care to ward care during admission within 72 hours of the initial dose of IV antibiotics.
Time to resolution of fever/vomiting/rigors within 72 hours of the initial dose of IV antibiotics as reported by parents/guardian.
Improvement as determined by parents/guardian at 72 hours after the first IV dose.
Antiemetic use for 72 hours from the initial IV antibiotic dose.
Duration of IV antibiotics (actually received by patient) from the first dose of IV antibiotics to last dose of IV antibiotics.
Duration of oral antibiotics (actually received by patient) from the first dose of oral antibiotics (after IV antibiotics started) to last dose of IV antibiotics.
Total duration of antibiotics: sum of duration of IV antibiotics and oral antibiotics.
Recurrence of UTI within 14 days from the first dose of IV antibiotics.
Recurrence of UTI within 1 month from the first dose of IV antibiotics.
Complications of UTI from the initial IV antibiotics dose to 14 days after the initial dose.
Adverse events from the initial IV antibiotics dose to 14 days after the initial dose.
Quality of life (QoL) indicators on Day 1 of IV antibiotics (within 24 hours of initial IV antibiotics) and after Day 4 (72 hours up to Day 7).
Parental QoL on Day 14.
Cost-effectiveness - hospital administrative data on costs and patient/parents reported costs.
Follow up microbiological urine culture after commencing IV antibiotics.
Imaging reports - ultrasound or other imaging results will be collected for patients who have them performed.

Intervention:

Patients who are eligible for the study will be randomised to receive 1 dose of daily IV antibiotics followed by 2 days of oral antibiotics or 3 doses of daily IV antibiotics . All participants will receive a total of 7 days treatment with antibiotics for the complicated urinary tract infection.

Oral antibiotics will start as soon as able to tolerate, within 12 hours of the last IV dose for both arms.

Study methodology:

Enrolment and randomisation: During ED assessment, clinicians will identify patients with a suspected UTI and screen patients against eligibility criteria. The relevant clinical team at each site will receive standardized, study specific education based on centrally developed study education materials. Presence of the following symptoms/sign will be recorded at baseline (fever, vomiting, rigors, tachycardia). Participants will be randomised to one of the 2 arms after written informed consent is obtained.

Intervention Day 1:

The first dose of the antibiotics will be commenced in the ED. Care of the patient will be as per routine clinical care. Decision for admission to hospital and location of treatment (ambulatory/Hospital-in-the-Home care) will be determined by the treating clinician as per routine clinical care. Parents will be provided with a thermometer and a diary to record a daily assessment of their child (fever, rigors, vomiting).

Intervention Day 4 :

72 hours after the first dose of IV antibiotics, a research nurse will conduct an assessment over phone or telehealth to obtain the primary outcome data: Persistence of baseline symptoms (fever, vomiting, rigors) or development of these symptoms (if not previously present) since baseline will beas documented at baseline. Any ambiguity with regards to symptoms being attributable to UTI will be judged by a blinded clinician external to the research team.

Follow up Day 14:

14 days after the first dose of IV antibiotics, a research nurse will conduct an assessment over phone or telehealth for follow up data including whether GP/ED visit or readmission occurred for UTI and total duration of antibiotics taken by the patient.

Follow up 1 month:

1 month after the first dose of IV antibiotics, a research nurse will conduct an assessment over phone or telehealth for follow up data including whether GP/ED visit or readmission occurred for UTI, total duration of antibiotics taken by the patient.

Arms

Assigned Interventions

Experimental: Arm 1, 1 dose

Single dose IV to cover Gram negative bacteria followed by 2 days of oral antibiotics
Single dose IV to cover Enterococcus spp

IV antibiotics are as per local institutional guidelines and microbiology eg: IV gentamicin with or without IV benzylpenicillin. Gentamicin is used when Gram Negative coverage is appropriate, benzylpenicillin is also used when Enterococcus coverage is appropriate, depending on local microbiology data. Once the IV component is complete the patient will be given an oral antibiotic (cefalexin) on day 2 and 3 of the study.

Drug: Benzylpenicillin - single dose

Participants will receive a single dose of IV antibiotic (benzylpenicillin).

Benzylpenicillin dosing: 1 month - 18 years, IV or Intramuscular (IM) 30 mg/kg (maximum 1.2 g) every 6 hours.

Drug: Gentamicin - single dose

Participants will receive a single dose of IV antibiotic (gentamicin).

Gentamicin dosing: Children ≤10 years old: 7.5 mg/kg (maximum dose 320 mg) Children >10 years old: 6-7 mg/kg (maximum dose 560 mg)

Drug: Cefalexin - post single dose of IV antibiotics for the remaining two days

Oral antibiotic will be as per local guidelines. i.e. Cefalexin 25mg/kg (maximum dosage 500mg) 4 times a day or 33mg/kg (maximum dosage 500mg) 3 times a day

Active Comparator: Arm 2, 3 doses

3 doses IV to cover Gram negative bacteria
3 days IV antibiotics to cover Enterococcus spp

Drug: Benzylpenicillin - three days

Participants will receive three days of this IV antibiotic (benzylpenicillin).

Benzylpenicillin dosing: 1 month - 18 years, IV or Intramuscular (IM) 30 mg/kg (maximum 1.2 g) every 6 hours. For severe infections, use up to 60 mg/kg (maximum 2.4 g) every 4-6 hours.

Drug: Gentamicin - three days

Participants will receive three days of this IV antibiotic (gentamicin).

Gentamicin dosing: Children ≤10 years old: 7.5 mg/kg (maximum dose 320 mg) Children >10 years old: 6-7 mg/kg (maximum dose 560 mg)

Outcome Measures


Primary Outcome Measures:
1.	Risk difference between 1 dose and 3 doses IV in the proportion of participants with clinical failure at 72 hours [ Time Frame: 72 hours ] Clinical failure is defined as persistence of baseline symptoms (fever, vomiting or rigors) or development of new symptoms (fever, vomiting or rigors) attributable to UTI at 72 hours. Assessment of clinical failure to be conducted at least 6 hours after antipyretic. Presence of fever, vomiting, or rigors reported by parents within 6 hours of assessment will be recorded as present at assessment.
Secondary Outcome Measures:
1.	Risk difference between 1 dose and 3 doses IV in the proportion of participants readmitted or attending the ED within 14 days of the initial dose of IV antibiotic. [ Time Frame: 14 days ] Proportion of readmissions within 14 days of the initial dose of IV antibiotics due to persistent fever, vomiting, rigors, or clinical deterioration (eg poor feeding, dehydration) that can be attributable to the UTI
2.	Risk difference between 1 dose and 3 doses IV in the proportion of participants readmitted or attending the ED within 1 month of the initial dose of IV antibiotics [ Time Frame: 1 month ] Proportion of readmission within 1 month of the initial dose of IV antibiotics due to persistent fever, vomiting, rigors, or clinical deterioration (eg poor feeding, dehydration) that can be attributable to the UTI.
3.	Risk difference between 1 dose and 3 doses IV in proportion of participants transferred from HITH or ambulatory care to ward care within 72 hours of initial dose of IV antibiotics. [ Time Frame: 72 hours ] Proportions of participants transferred from HITH or ambulatory care to ward care within 72 hours of initial dose of IV antibiotics.
4.	Risk difference between 1 dose and 3 doses IV in the proportion of participants with parental reported improvement [ Time Frame: 72 hours ] Proportion of patients who are reported as 'generally improved/better' at 72 hours of the initial IV antibiotic dose. This will be reported via the daily diary completed by the parent on day 1, 2 and 3.
5.	Mean difference between 1 dose and 3 doses IV in duration of IV antibiotics usage [ Time Frame: 7 days ] Mean difference between 1 dose and 3 doses IV group in duration (number of days up to 1 decimal point) of IV antibiotics, i.e. mean time difference from first dose of IV antibiotics to last dose of IV antibiotics
6.	Mean difference between 1 dose and 3 doses IV in duration of oral antibiotic usage. [ Time Frame: 14 days ] Mean difference between 1 dose and 3 doses IV in the duration (number of days up to 1 decimal point) of oral antibiotics administered to patients, i.e mean time difference between last dose of IV antibiotics and the last dose of oral antibiotics.
7.	Risk difference between 1 dose and 3 doses IV in the proportion of participants with recurrence of UTI symptoms within 14 days of initial dose of IV antibiotics [ Time Frame: 14 days ] Risk difference between 1 dose and 3 doses IV in the proportion of participants with recurrence of UTI symptoms within 14 days of the first dose of IV antibiotics. Recurrence of symptoms depends on what symptoms the patient initially presented with but may be classified as recurrence of fever, vomiting, rigors or tachycardia.
8.	Risk difference between 1 dose and 3 doses IV in the proportion of participants with recurrence of UTI symptoms within 1 month of initial dose of IV antibiotics [ Time Frame: 1 month ] Risk difference between 1 dose and 3 doses IV in the proportion of participants with recurrence of UTI symptoms within 1 month of initial dose of IV antibiotics. Recurrence of symptoms depends on what symptoms the patient initially presented with but may be classified as recurrence of fever, vomiting, rigors or tachycardia.
9.	Risk difference in the proportion of participants with complications within 14 days of initial dose of IV antibiotics [ Time Frame: 14 days ] Risk difference in the proportion of participants with complications within 14 days of initial dose of IV antibiotics. Complications are defined as abscess, sepsis, meningitis from the initial IV antibiotics dose to 14 days after the initial dose that are attributable to the UTI as judged by a clinician.
10.	Mean difference in the proportion of participants who experience at least one adverse event within 14 days of the initial dose of IV antibiotics [ Time Frame: 14 days ] Mean difference in the proportion of participants who experience at least one adverse event within 14 days of the initial dose of IV antibiotics. An adverse event is described as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
11.	Risk difference between the 1 dose and 3 doses IV groups in the proportion of participants who experience an allergic reaction attributable to the antibiotics administered within 14 days of the initial dose of IV antibiotics [ Time Frame: 14 days ] Risk difference in the proportion of participants who experience an allergic reaction attributable to the antibiotics administered within 14 days of the initial dose of IV antibiotics. An allergic reaction is classified as an overreactive immune system to a harmless substance known as an allergen in this case a medicinal (investigational) product.
12.	Mean difference between 1 dose and 3 doses IV on the weighted total score of the Child Health Utility instrument administered within 24 hours after initial dose of IV antibiotics. [ Time Frame: 24 hours ] The Child Health Utility instrument is a 9 item parent-rated, preference-weighted measure used to calculate quality adjusted life years for children. This survey consist of 9 questions asking how the child is feeling and questions about their activity levels. The minimum score is zero and the maximum score for this survey is 1 which indicates optimal health. This should be completed within 24 hours of initial IV antibiotics
13.	Mean difference between 1 dose and 3 doses IV on the weighted total score of the Child Health Utility instrument administered between day 5-7 of initial dose of IV antibiotics [ Time Frame: Day 5 to 7 ] The Child Health Utility instrument is a 9 item parent-rated, preference-weighted measure used to calculate quality adjusted life years for children. This survey consist of 9 questions asking how the child is feeling and questions about their activity levels. The minimum score is zero and the maximum score for this survey is 1 which indicates optimal health. This should be completed between day 5 to 7 after initial IV antibiotics
14.	Mean difference between 1 dose and 3 doses IV in the cost-effectiveness of treatment groups. [ Time Frame: Day 14 ] Mean difference between 1 dose and 3 doses IV in the cost-effectiveness of treatment. As judged by survey provided to the families asking about their out of pocket expenses or loss of productive work hours.
15.	Risk difference between the 1 dose and 3 doses IV groups in the proportion of patients with bacterial growth in urine culture (day 0) [ Time Frame: Day 0 ] Risk difference between the 1 dose and 3 doses IV groups in the proportion of patients with bacterial growth: for example E.Coli, Enterococcus.
16.	Risk difference between the 1 dose and 3 doses IV in the proportion of patients with bacterial growth in urine culture (Day 14) [ Time Frame: Day 14 ] Risk difference between the 1 dose and 3 doses IV groups in the proportion of patients with bacterial growth: for example E.Coli, Enterococcus.
17.	Risk difference between the 1 dose and 3 doses IV group in the proportion of patients administered antiemetics [ Time Frame: Up to day 3 ] Risk difference between the 1 dose and 3 doses IV in the proportion of patients administered antiemetics (commonly used antiemetics in children are metoclopramide, domperidone, ondansetron and prochlorperazine). As determined by parent reported diary, completed daily for the first 3 days after enrolment.
18.	Risk difference between the 1 dose and 3 doses IV group in the proportion of patients administered antipyretic or analgesia. [ Time Frame: Up to day 3 ] Risk difference between the 1 dose and 3 doses IV group in the proportion of patients administered antipyretic or analgesia (commonly used antipyretics and analgesia in children are paracetamol, ibuprofen, naproxen). As determined by parent reported diary, completed daily for the first 3 days after enrolment.
19.	Risk difference between the 1 dose and 3 doses IV group in the proportion of patients with abnormal imaging. [ Time Frame: Up to1 month ] Risk difference between the 1 dose and 3 doses IV group in the proportion of patients with Ultrasound reported abnormalities of the renal tract.

Minimum Age:

3 Months

Maximum Age:

18 Years

Sex:

All

Gender Based:

Accepts Healthy Volunteers:

Criteria:

Inclusion Criteria:

3 months (corrected age) to 18 years

3 or more of the following present: Fever, Vomiting, Rigors, History of recurrent UTI, Urological abnormalities, Tachycardia
Urine sample available (Urine culture must have been collected prior to antibiotic treatment, either at the GP or ED - in order to assess urine culture as per below).
Abnormal urinary dipstick leucocyte esterase >1+ or nitrite positive OR ≥5 White Blood Cells (WBCs) per high-power field in centrifuged urine OR≥ 10 White Blood Cells (WBCs) per mm3 in uncentrifuged urine and bacteriuria with any bacteria per high-power field
ED clinician determines the child requires treatment with IV antibiotics

Exclusion Criteria:

Sepsis (requiring inotropic support or more than 20ml/kg of fluid bolus)
Known allergy to the once daily study drug options (gentamicin or ceftriaxone or amikacin)
If the patient has another co-existing condition which requires (based on established evidence-based guidelines) more than 1 dose of IV antibiotics eg meningitis
Impaired renal function (abnormal creatinine at ED presentation or known renal impairment or renal transplant patients)
Unrepaired posterior urethral valves
Indwelling stent and fever pyonephrosis (pus in the renal pelvis) is a potential diagnosis and cannot be ruled out (ultrasound ruling out pyonephrosis prior to randomisation)
Patients with clinically suspected renal abscess e.g., extreme renal tenderness, out of keeping with pyelonephritis (clinically determined).

Central Contact Person:

Laila Ibrahim
Telephone: +61401765546
Email: laila.ibrahim@mcri.edu.au

Central Contact Backup:

Marijana Vanevski
Telephone: +61410519022
Email: marijana.vanevski@mcri.edu.au

Study Officials:

Laila Ibrahim
Principal Investigator
Murdoch Children's Research Institute

Penelope Bryant
Principal Investigator
Murdoch Children's Research Institute

Locations:

Australia, South Australia

Women and Children's Hospital
[Not yet recruiting]
Adelaide, South Australia, Australia
Contact:Contact: Amit Kochar, Dr Amit.Kochar@health.sa.gov.au
Contact:Contact: Scott Sypek, Dr Scott.Sypek@sa.gov.au

Australia, Victoria

Monash Health
[Not yet recruiting]
Melbourne, Victoria, Australia, 3168
Contact:Contact: Simon Craig, Prof Simon.Craig@monashhealth.org
Contact:Contact: Peter Gowdie, Dr Peter.Gowdie@monashhealth.org

Royal Children's Hospital
[Recruiting]
Parkville, Victoria, Australia, 3052
Contact:Contact: Laila Ibrahim +61401765546 laila.ibrahim@mcri.edu.au
Contact:Contact: Marijana Vanevski +61410519022 marijana.vanevski@mcri.edu.au

Australia, Western Australia

Perth Children's Hospital
[Not yet recruiting]
Perth, Western Australia, Australia, 6009
Contact:Contact: Meredith Borland, Prof 08 6456 4988 Meredith.Borland@health.wa.gov.au
Contact:Contact: Ariel Mace, Dr ariel.mace@health.wa.gov.au

New Zealand, Auckland Province

Starship Children's Hospital
[Not yet recruiting]
Auckland, Auckland Province, New Zealand, 1023
Contact:Contact: Stuart Dalziel, Prof s.dalziel@auckland.ac.nz
Contact:Contact: Cameron Grant, Prof cc.grant@auckland.ac.nz

Plan to Share IPD:

Yes
The de-identified data set collected for this study will be available six months after publication of the results. The study protocol, analysis plan and consent forms will also be available. This will all be available by contacting Murdoch Children's Research Institute.

Supporting Information:

Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

Time Frame:

6 months after publication of primary outcome

Access Criteria:

Prior to this data being made available a data access agreement much be signed between the relevant parties and approval by the trial steering committee. Data will only be shared with recognised research institutions

URL: