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Single Dose Intravenous Antibiotics for Complicated Urinary Tract Infections in Children (CHOICE UTI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04876131
Recruitment Status : Recruiting
First Posted : May 6, 2021
Last Update Posted : June 23, 2022
Sponsor:
Collaborator:
Royal Children's Hospital
Information provided by (Responsible Party):
Murdoch Childrens Research Institute

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.


Condition or disease Intervention/treatment Phase
Complicated Urinary Tract Infection Infection Pediatric Infectious Disease Drug: Benzylpenicillin - single dose Drug: Benzylpenicillin - three days Drug: Gentamicin - single dose Drug: Gentamicin - three days Drug: Cefalexin - post single dose of IV antibiotics for the remaining two days Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 452 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 30, 2022
Estimated Primary Completion Date : May 16, 2028
Estimated Study Completion Date : May 16, 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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

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.

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)





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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   3 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04876131


Contacts
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Contact: Laila Ibrahim +61401765546 laila.ibrahim@mcri.edu.au
Contact: Marijana Vanevski +61410519022 marijana.vanevski@mcri.edu.au

Locations
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Australia, South Australia
Women and Children's Hospital Not yet recruiting
Adelaide, South Australia, Australia
Contact: Amit Kochar, Dr       Amit.Kochar@health.sa.gov.au   
Contact: Scott Sypek, Dr       Scott.Sypek@sa.gov.au   
Australia, Victoria
Monash Health Not yet recruiting
Melbourne, Victoria, Australia, 3168
Contact: Simon Craig, Prof       Simon.Craig@monashhealth.org   
Contact: Peter Gowdie, Dr       Peter.Gowdie@monashhealth.org   
Royal Children's Hospital Recruiting
Parkville, Victoria, Australia, 3052
Contact: Laila Ibrahim    +61401765546    laila.ibrahim@mcri.edu.au   
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: Meredith Borland, Prof    08 6456 4988    Meredith.Borland@health.wa.gov.au   
Contact: Ariel Mace, Dr       ariel.mace@health.wa.gov.au   
New Zealand
Starship Children's Hospital Not yet recruiting
Auckland, Auckland Province, New Zealand, 1023
Contact: Stuart Dalziel, Prof       s.dalziel@auckland.ac.nz   
Contact: Cameron Grant, Prof       cc.grant@auckland.ac.nz   
Sponsors and Collaborators
Murdoch Childrens Research Institute
Royal Children's Hospital
Investigators
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Principal Investigator: Laila Ibrahim Murdoch Children's Research Institute
Principal Investigator: Penelope Bryant Murdoch Children's Research Institute
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Responsible Party: Murdoch Childrens Research Institute
ClinicalTrials.gov Identifier: NCT04876131    
Other Study ID Numbers: 72065
First Posted: May 6, 2021    Key Record Dates
Last Update Posted: June 23, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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 Materials: 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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Infections
Communicable Diseases
Urinary Tract Infections
Disease Attributes
Pathologic Processes
Urologic Diseases
Anti-Bacterial Agents
Gentamicins
Cephalexin
Penicillin G
Penicillin G Benzathine
Penicillin G Procaine
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action