Partial Oral Antibiotic Treatment for Bacterial Brain Abscess

Brain Abscess Clinical Trial

— ORAL  

Official title:

Partial Oral Antibiotic Treatment for Bacterial Brain Abscess: An Open-label Randomised Non-inferiority Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04140903
• Other study ID #: 1
• Status: Recruiting
• Phase: Phase 4
• Start date: November 6, 2020
• Est. completion date: August 31, 2025

Study information

• Verified date: July 2023
• Source: Aalborg University Hospital
• Contact: Jacob Bodilsen, MD
• Phone: +45 97663920
• Email: jacob.bodilsen[@]rn.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: August 31, 2025
• Est. primary completion date: August 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Abscess
• Brain Abscess
• Cerebral Abscess

Intervention

Drug:
• Early transition to oral antibiotics
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
• Standard treatment of intravenous antibiotics
Patients will continue standard intravenous antibiotic therapy for brain abscess (e.g. 3rd generation cephalosporin + metronidazole) according to international guidelines and pathogen susceptibility patterns.

Locations

Country	Name	City	State
Denmark	Aalborg University Hospital	Aalborg
Denmark	Aarhus University Hospital	Aarhus
Denmark	Rigshospitalet	Copenhagen
Denmark	Odense University Hospital	Odense

Sponsors (1)

Lead Sponsor	Collaborator
Henrik Nielsen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Six months after randomisation
Secondary	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	At last day of antibiotic treatment for brain abscess, and 3- and 12-months after randomisation
Secondary	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)	At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation
Secondary	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)	At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation
Secondary	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)	At 6 months since randomisation
Secondary	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)	At 6 months since randomisation
Secondary	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)	At 6 months since randomisation
Secondary	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)	At 6 months since randomisation
Secondary	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).	At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation
Secondary	Central line associated complications	Number of participants with bleeding, infection, venous thrombosis or need for replacement of central line due to mechanical malfunction	6 months since randomisation
Secondary	Clostridial diarrhea	Number of participants who develop Clostridioides difficile associated gastro-enteritis during antibiotic treatment for brain abscess	From randomisation up until last day antibiotic treatment for brain abscess
Secondary	Duration of admission	Days spent as admitted patient in hospital up to 6 months since randomisation (does not include outpatient hospital care)	From randomisation until hospital discharge to home or rehabilitation unit or death, whichever comes first, assessed up to 6 months
Secondary	Duration of treatment	Number of days treated with antibiotics for brain abscess up to 6 months since randomisation	From randomisation until last day of antibiotic treatment for brain abscess up to 6 months since randomisation
Secondary	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	From randomisation until last day of antibiotic treatment for brain abscess, assessed up to 6 months since randomisation
Secondary	Oedema on cranial imaging	Number of participants with residual perilesional oedema on cranial imaging up to 3 months since randomisation	3 months since randomisation
Secondary	SAE	Number of participants with severe adverse events	From randomisation until last day of antibiotic treatment for brain abscess
Secondary	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)	At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation
Secondary	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)	At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation
Secondary	EQ-VAS	EuroqQol Visual Analogue Scale (range 0=poor health status to 100=excellent health status)	At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation
Secondary	Cognitive impairment	Montreal Cognitive Assessment (MoCA) scores (range 0=poor cognitive performance to 30=normal cognitive performance)	At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation