Clinical trial NCT04876131: Single Dose Intravenous Antibiotics for Complicated Urinary Tract Infections in Children
Official title: CHOICE UTI - Clinical Efficacy of Single Dose (Daily) IV Antibiotics Followed by 2 Days Oral Antibiotics Compared to 3 Doses (Daily) IV Antibiotics for Children With Complicated Urinary Tract Infections: a Multicentre Randomised Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Complicated Urinary Tract Infection
Infection
Pediatric Infectious Disease
Lead sponsor: Murdoch Childrens Research Institute
Sponsor class: OTHER
Collaborators: name: Royal Children's Hospital
First posted: 2021-05-06
Enrollment: 452
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be recruited when they present to the emergency department with a complicated UTI. Once they have been consented to the study they will then be randomised into one of the treatment arms, these treatment arms will run parallel to one another.
Primary purpose: TREATMENT

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 ≥2 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/assistant 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. 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/assistant 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/assistant 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.

Eligibility criteria: Inclusion Criteria:

3 months (corrected age) to 18 years

* 2 or more of the following present: Fever (reported fever at home or measured fever of ≥38 degrees Celsius associated with the illness that triggered current ED presentation (eg fever may have been 18 hours prior to presentation but none since then because patient has been on maximal antipyretics - paracetamol or ibuprofen), Vomiting, Rigors, History of recurrent UTI, Urological abnormalities, Tachycardia
* Urine sample available (Urine culture must have been collected prior to or within an hour of 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 \* In ED, only urine dipstick or urinalysis will be available. Once urine culture is available, to be included in the efficacy analysis, culture results must meet the following criteria: Positive urine culture result with no more than 2 species of microorganisms AND Spontaneously voided urine with ≥105 microorganisms per mL of urine or Suprapubic aspirate or urinary catheter with ≥104 microorganisms per mL of urine. In the absence of a positive urine culture, ultrasonographic findings supporting pyelonephritis (per reporting radiologist) will be accepted as evidence of a urinary tract infection.

Exclusion Criteria:

* Sepsis (requiring inotropic support or more than 20ml/kg of fluid bolus in Emergency Department)
* Known allergy to all 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
* Known impaired renal function, chronic renal failure or (renal transplant patients or a 10% increase in measured expected creatinine for age/height at ED presentation )
* Unrepaired posterior urethral valves
* Indwelling stent and fever
* Previously enrolled participants in the CHOICE UTI trial.
* No available oral antibiotic option for this UTI: urine culture result already available and multi-resistant organism with susceptibility only to IV antibiotics or known intolerance to oral antibiotics (previous UTI with multi-resistant organism not an exclusion)
* Previous IV antibiotics for same UTI episode eg interhospital transfer whereby significant time has passed since first dose IV
* Patients with clinically suspected renal abscess e.g., extreme renal tenderness, out of keeping with pyelonephritis (clinically determined).
* Clinician does not intend on prescribing a course of IV antibiotics but plans on only giving a single dose from the outset
* Recurrence of urinary tract infection within 2 weeks
* Unable to obtain consent
* Patient is pregnant

Primary outcomes:
measure: Risk difference between 1 dose and 3 doses IV in the proportion of participants with clinical failure at 72 hours
timeFrame: 72 hours
Secondary outcomes:
measure: 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.
timeFrame: 14 days
measure: 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
timeFrame: 1 month
measure: 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.
timeFrame: 72 hours
measure: Risk difference between 1 dose and 3 doses IV in the proportion of participants with parental reported improvement
timeFrame: 72 hours
measure: Mean difference between 1 dose and 3 doses IV in duration of IV antibiotics usage
timeFrame: 7 days
measure: Mean difference between 1 dose and 3 doses IV in duration of oral antibiotic usage.
timeFrame: 14 days
measure: 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
timeFrame: 14 days
measure: 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
timeFrame: 1 month
measure: Risk difference in the proportion of participants with complications within 14 days of initial dose of IV antibiotics
timeFrame: 14 days
measure: Mean difference in the proportion of participants who experience at least one adverse event within 14 days of the initial dose of IV antibiotics
timeFrame: 14 days
measure: 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
timeFrame: 14 days
measure: 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.
timeFrame: 24 hours
measure: 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
timeFrame: Day 5 to 7
measure: Mean difference between 1 dose and 3 doses IV in the cost-effectiveness of treatment groups.
timeFrame: Day 14
measure: Risk difference between the 1 dose and 3 doses IV groups in the proportion of patients with bacterial growth in urine culture (day 0)
timeFrame: Day 0
measure: Risk difference between the 1 dose and 3 doses IV in the proportion of patients with bacterial growth in urine culture (Day 14)
timeFrame: Day 14
measure: Risk difference between the 1 dose and 3 doses IV group in the proportion of patients administered antiemetics
timeFrame: Up to day 3
measure: Risk difference between the 1 dose and 3 doses IV group in the proportion of patients administered antipyretic or analgesia.
timeFrame: Up to day 3
measure: Risk difference between the 1 dose and 3 doses IV group in the proportion of patients with abnormal imaging.
timeFrame: Up to1 month
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Women and Children's Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Monash Health
state: Victoria
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Perth
country: Australia
facility: Perth Children's Hospital
state: Washington
city: Auckland
country: New Zealand
facility: Starship Children's Hospital
state: Auckland Province
Study officials:
affiliation: Murdoch Childrens Research Institute
name: Laila Ibrahim
role: PRINCIPAL_INVESTIGATOR
affiliation: Murdoch Childrens Research Institute
name: Penelope Bryant
role: PRINCIPAL_INVESTIGATOR
References: