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Partial Oral Antibiotic Treatment for Bacterial Brain Abscess (ORAL)

Primary Purpose

Brain Abscess, Cerebral Abscess

Status
Recruiting
Phase
Phase 4
Locations
Denmark
Study Type
Interventional
Intervention
Early transition to oral antibiotics
Standard treatment of intravenous antibiotics
Sponsored by
Henrik Nielsen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Brain Abscess focused on measuring Oral antibiotics

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. A clinical presentation (e.g. headache, neurological deficit or fever) and cranial imaging (CT or MRI) consistent with brain abscess AND
  2. The physician responsible for the patient decides to treat the patient for bacterial brain abscess AND
  3. Ability to take and absorb oral medications (including by nasogastric tube) AND
  4. To have received relevant antibiotic therapy for bacterial brain abscess for 14 consecutive days before randomisation AND
  5. Expected to be treated with antibiotic therapy for at least another 14 days after time of randomisation AND
  6. No progression in symptom intensity or occurrence of new-onset neurological symptoms (excluding seizures) within five days before time of randomisation.

Exclusion Criteria (patients fulfilling either criteria):

  1. Expected substantially reduced compliance with treatment (e.g. IV drug abuse)
  2. Pregnancy (proven by positive urine or plasma human chorionic gonadotropin test in fertile women <50 years of age)
  3. Concomitant (empirical) brain abscess treatment for tuberculosis, nocardiosis, Pseudomonas spp., fungi, toxoplasmosis or other CNS parasites
  4. Device related brain abscesses (e.g. deep brain stimulators, ventriculo-peritoneal shunts)
  5. Severe immuno-compromise defined as ongoing need for biological- or chemotherapy, prednisolone >20 mg/day for 14 days or longer, uncontrolled HIV/AIDS, haematological malignancies, and organ transplant recipients
  6. Concomitant or unrelated infections necessitating IV antibiotics beyond seven days of duration after time of randomisation
  7. Previous enrolment into this trial

Sites / Locations

  • Aalborg University HospitalRecruiting
  • Aarhus University HospitalRecruiting
  • RigshospitaletRecruiting
  • Odense University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Oral antibiotics

Standard treatment

Arm Description

Patients will be randomised to oral antibiotics after two weeks of appropriate antibiotic therapy for bacterial brain abscess since definitive aspiration/excision of brain abscess or, in case of no planned diagnostic neurosurgical procedure, since initiation of guideline recommended antibiotics for bacterial brain abscess

Patients will be randomised to continuation of standard intravenous antibiotics after two weeks of appropriate antibiotic therapy for bacterial brain abscess since definitive aspiration/excision of brain abscess or, in case of no planned diagnostic neurosurgical procedure, since initiation of guideline recommended antibiotics for bacterial brain abscess

Outcomes

Primary Outcome Measures

Treatment failure
A composite of number of participants with all-cause mortality, risk of intraventricular rupture of brain abscess (IVROBA), unplanned neurosurgery, relapse, or recurrence

Secondary Outcome Measures

Treatment failure
A composite of number of participants with all-cause mortality, risk of intraventricular rupture of brain abscess (IVROBA), unplanned neurosurgery, relapse, or recurrence
Unfavourable outcome
Number of participants with Extended Glasgow Outcome Scale score <7, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
All-cause mortality
Number of participants with fatal outcome, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Unplanned neurosurgery
Number of participants with unplanned (re-)aspiration or excision, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
IVROBA
Number of participants with intraventricular rupture of brain abscess, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Relapse
Number of participants with increase in brain abscess volume by 20% since randomisation, clinical deterioration attributable to brain abscess or lack of cure of at least 4 weeks or longer of assigned study treatment, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Recurrence
New brain abscess formation after end of treatment, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Unfavourable outcome - sliding dichotomy
Sliding dichotomy of extended Glasgow Outcome Scale scores according to Charlson comorbidity index score (range: 0=no comorbidity and more likely to have a favourable outcome to 40=high degree of comorbidity with a poor prognosis of a favourable outcome) at time of randomisation (0 vs. 1-2 vs. >2).
Central line associated complications
Number of participants with bleeding, infection, venous thrombosis or need for replacement of central line due to mechanical malfunction
Clostridial diarrhea
Number of participants who develop Clostridioides difficile associated gastro-enteritis during antibiotic treatment for brain abscess
Duration of admission
Days spent as admitted patient in hospital up to 6 months since randomisation (does not include outpatient hospital care)
Duration of treatment
Number of days treated with antibiotics for brain abscess up to 6 months since randomisation
Adherence to treatment
Adherence to allocated treatment. For oral treatment this will be measured using Morisky 8-item Medication Adherence scale scores (range 0=high adherence to 8=low adherence) up to 6 months since randomisation
Oedema on cranial imaging
Number of participants with residual perilesional oedema on cranial imaging up to 3 months since randomisation
SAE
Number of participants with severe adverse events
SF36
Short Form 36 is a 36 item survey of patient-reported health-related quality of life (range 0=maximum disability to 100=no disability)
EQ-5D-5L
EuroqQol - 5 dimensions - 5 level scores are derived from a standardized instrument for measuring generic health status including mobility, self-care, usual acitivities, pain/discomfort, and anxiety/depression (range 5=good health status to 25=poor health status)
EQ-VAS
EuroqQol Visual Analogue Scale (range 0=poor health status to 100=excellent health status)
Cognitive impairment
Montreal Cognitive Assessment (MoCA) scores (range 0=poor cognitive performance to 30=normal cognitive performance)

Full Information

First Posted
July 4, 2019
Last Updated
July 19, 2023
Sponsor
Henrik Nielsen
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1. Study Identification

Unique Protocol Identification Number
NCT04140903
Brief Title
Partial Oral Antibiotic Treatment for Bacterial Brain Abscess
Acronym
ORAL
Official Title
Partial Oral Antibiotic Treatment for Bacterial Brain Abscess: An Open-label Randomised Non-inferiority Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 6, 2020 (Actual)
Primary Completion Date
August 31, 2024 (Anticipated)
Study Completion Date
August 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Henrik Nielsen

4. Oversight

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.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The investigators aim to determine if oral antibiotics are clinically acceptable as treatment of brain abscess. Following 2 weeks of standard intravenous antibiotic therapy, half of patients will continue with this treatment for another 4 weeks or longer while the other half will be assigned to oral antibiotics for the remaining duration of treatment.
Detailed Description
Treatment of brain abscess remains a considerable challenge due to the precarious location of the infection and the impenetrability of the blood-brain-barrier for most drugs. Thus, cure usually requires a combination of neurosurgical evacuation of abscess material and 6-8 weeks of high-dose intravenous (IV) antibiotic therapy to ensure eradication of bacteria within the abscess cavity. Disadvantages include risks of nosocomial infections and line-associated complications (e.g. bleeding, venous thrombosis, or need for replacement due to malfunction) in addition to the considerable costs of such long-term admission. However, improved insights into the pharmacokinetic properties and favourable bioavailability of some oral antibiotics may allow such treatment at an early stage. To date, there are no randomised controlled trials to guide treatment of bacterial brain abscess. The investigators wish to determine whether a treatment strategy of transition to oral antibiotics after two weeks of treatment is non-inferior to continued IV antibiotics in clinically stable brain abscess patients assessed by the proportion with a favourable outcome at six months since randomisation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain Abscess, Cerebral Abscess
Keywords
Oral antibiotics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Investigator-initiated, international, multi-centre, randomised, parallel groups, non-inferiority trial
Masking
Outcomes Assessor
Masking Description
An independent blinded endpoint committee will assess the primary outcome.
Allocation
Randomized
Enrollment
400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Oral antibiotics
Arm Type
Experimental
Arm Description
Patients will be randomised to oral antibiotics after two weeks of appropriate antibiotic therapy for bacterial brain abscess since definitive aspiration/excision of brain abscess or, in case of no planned diagnostic neurosurgical procedure, since initiation of guideline recommended antibiotics for bacterial brain abscess
Arm Title
Standard treatment
Arm Type
Active Comparator
Arm Description
Patients will be randomised to continuation of standard intravenous antibiotics after two weeks of appropriate antibiotic therapy for bacterial brain abscess since definitive aspiration/excision of brain abscess or, in case of no planned diagnostic neurosurgical procedure, since initiation of guideline recommended antibiotics for bacterial brain abscess
Intervention Type
Drug
Intervention Name(s)
Early transition to oral antibiotics
Intervention Description
Patients will be treated with an oral antibiotic regimen (e.g. amoxicillin + metronidazole) based upon pharmacokinetic and pharmacodynamic properties of the drugs, pathogen susceptibility, and any existing drug allergies or interactions
Intervention Type
Drug
Intervention Name(s)
Standard treatment of intravenous antibiotics
Intervention Description
Patients will continue standard intravenous antibiotic therapy for brain abscess (e.g. 3rd generation cephalosporin + metronidazole) according to international guidelines and pathogen susceptibility patterns.
Primary Outcome Measure Information:
Title
Treatment failure
Description
A composite of number of participants with all-cause mortality, risk of intraventricular rupture of brain abscess (IVROBA), unplanned neurosurgery, relapse, or recurrence
Time Frame
Six months after randomisation
Secondary Outcome Measure Information:
Title
Treatment failure
Description
A composite of number of participants with all-cause mortality, risk of intraventricular rupture of brain abscess (IVROBA), unplanned neurosurgery, relapse, or recurrence
Time Frame
At last day of antibiotic treatment for brain abscess, and 3- and 12-months after randomisation
Title
Unfavourable outcome
Description
Number of participants with Extended Glasgow Outcome Scale score <7, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Time Frame
At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation
Title
All-cause mortality
Description
Number of participants with fatal outcome, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Time Frame
At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation
Title
Unplanned neurosurgery
Description
Number of participants with unplanned (re-)aspiration or excision, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Time Frame
At 6 months since randomisation
Title
IVROBA
Description
Number of participants with intraventricular rupture of brain abscess, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Time Frame
At 6 months since randomisation
Title
Relapse
Description
Number of participants with increase in brain abscess volume by 20% since randomisation, clinical deterioration attributable to brain abscess or lack of cure of at least 4 weeks or longer of assigned study treatment, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Time Frame
At 6 months since randomisation
Title
Recurrence
Description
New brain abscess formation after end of treatment, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
Time Frame
At 6 months since randomisation
Title
Unfavourable outcome - sliding dichotomy
Description
Sliding dichotomy of extended Glasgow Outcome Scale scores according to Charlson comorbidity index score (range: 0=no comorbidity and more likely to have a favourable outcome to 40=high degree of comorbidity with a poor prognosis of a favourable outcome) at time of randomisation (0 vs. 1-2 vs. >2).
Time Frame
At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation
Title
Central line associated complications
Description
Number of participants with bleeding, infection, venous thrombosis or need for replacement of central line due to mechanical malfunction
Time Frame
6 months since randomisation
Title
Clostridial diarrhea
Description
Number of participants who develop Clostridioides difficile associated gastro-enteritis during antibiotic treatment for brain abscess
Time Frame
From randomisation up until last day antibiotic treatment for brain abscess
Title
Duration of admission
Description
Days spent as admitted patient in hospital up to 6 months since randomisation (does not include outpatient hospital care)
Time Frame
From randomisation until hospital discharge to home or rehabilitation unit or death, whichever comes first, assessed up to 6 months
Title
Duration of treatment
Description
Number of days treated with antibiotics for brain abscess up to 6 months since randomisation
Time Frame
From randomisation until last day of antibiotic treatment for brain abscess up to 6 months since randomisation
Title
Adherence to treatment
Description
Adherence to allocated treatment. For oral treatment this will be measured using Morisky 8-item Medication Adherence scale scores (range 0=high adherence to 8=low adherence) up to 6 months since randomisation
Time Frame
From randomisation until last day of antibiotic treatment for brain abscess, assessed up to 6 months since randomisation
Title
Oedema on cranial imaging
Description
Number of participants with residual perilesional oedema on cranial imaging up to 3 months since randomisation
Time Frame
3 months since randomisation
Title
SAE
Description
Number of participants with severe adverse events
Time Frame
From randomisation until last day of antibiotic treatment for brain abscess
Title
SF36
Description
Short Form 36 is a 36 item survey of patient-reported health-related quality of life (range 0=maximum disability to 100=no disability)
Time Frame
At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation
Title
EQ-5D-5L
Description
EuroqQol - 5 dimensions - 5 level scores are derived from a standardized instrument for measuring generic health status including mobility, self-care, usual acitivities, pain/discomfort, and anxiety/depression (range 5=good health status to 25=poor health status)
Time Frame
At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation
Title
EQ-VAS
Description
EuroqQol Visual Analogue Scale (range 0=poor health status to 100=excellent health status)
Time Frame
At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation
Title
Cognitive impairment
Description
Montreal Cognitive Assessment (MoCA) scores (range 0=poor cognitive performance to 30=normal cognitive performance)
Time Frame
At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: A clinical presentation (e.g. headache, neurological deficit or fever) and cranial imaging (CT or MRI) consistent with brain abscess AND The physician responsible for the patient decides to treat the patient for bacterial brain abscess AND Ability to take and absorb oral medications (including by nasogastric tube) AND To have received relevant antibiotic therapy for bacterial brain abscess for 14 consecutive days before randomisation AND Expected to be treated with antibiotic therapy for at least another 14 days after time of randomisation AND No progression in symptom intensity or occurrence of new-onset neurological symptoms (excluding seizures) within five days before time of randomisation. Exclusion Criteria (patients fulfilling either criteria): Expected substantially reduced compliance with treatment (e.g. IV drug abuse) Pregnancy (proven by positive urine or plasma human chorionic gonadotropin test in fertile women <50 years of age) Concomitant (empirical) brain abscess treatment for tuberculosis, nocardiosis, Pseudomonas spp., fungi, toxoplasmosis or other CNS parasites Device related brain abscesses (e.g. deep brain stimulators, ventriculo-peritoneal shunts) Severe immuno-compromise defined as ongoing need for biological- or chemotherapy, prednisolone >20 mg/day for 14 days or longer, uncontrolled HIV/AIDS, haematological malignancies, and organ transplant recipients Concomitant or unrelated infections necessitating IV antibiotics beyond seven days of duration after time of randomisation Previous enrolment into this trial
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jacob Bodilsen, MD
Phone
+45 97663920
Email
jacob.bodilsen@rn.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Henrik Nielsen, Professor
Phone
+45 97663920
Email
henrik.nielsen@rn.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jacob Bodilsen, MD
Organizational Affiliation
Aalborg University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Aalborg University Hospital
City
Aalborg
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jacob Bodilsen, MD PhD
Facility Name
Aarhus University Hospital
City
Aarhus
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Merete Storgaard, MD
Facility Name
Rigshospitalet
City
Copenhagen
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lars H Omland, MD
Facility Name
Odense University Hospital
City
Odense
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lykke Larsen, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Beginning six months and ending three years after publication, an anonymized dataset can be shared with qualified researchers who provide a methodologically sound proposal for a post-hoc study assessed by the members of the steering committee. The anonymized dataset will include baseline demographics of patients, laboratory results, treatments and primary outcome at six months since randomisation. In addition, the study protocol, statistical analysis plan, informed consent form, clinical study report and analytic code can also be shared. Proposals should be directed to the trial manager. To gain access, data requestors will need to sign a data access agreement. Data will be deposited at Mendeley Data (https://data.mendeley.com/).
IPD Sharing Time Frame
6 months until 3 years after publication
IPD Sharing Access Criteria
Qualified researchers who provide a methodologically sound proposal for a post-hoc study assessed by the members of the steering committee may gain access to data after proper governmental approvals have been obtained.
IPD Sharing URL
https://data.mendeley.com
Citations:
PubMed Identifier
34772441
Citation
Bodilsen J, Brouwer MC, van de Beek D, Tattevin P, Tong S, Naucler P, Nielsen H. Partial oral antibiotic treatment for bacterial brain abscess: an open-label randomized non-inferiority trial (ORAL). Trials. 2021 Nov 12;22(1):796. doi: 10.1186/s13063-021-05783-8.
Results Reference
derived

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Partial Oral Antibiotic Treatment for Bacterial Brain Abscess

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