Partial Oral Antibiotic Treatment for Bacterial Brain Abscess (ORAL)

• ClinicalTrials.gov Identifier: NCT04140903
• Recruitment Status: Recruiting
• First Posted: October 28, 2019
• Last Update Posted: February 17, 2022
• Sponsor: Henrik Nielsen
• Information provided by (Responsible Party): Henrik Nielsen, Aalborg University Hospital

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.

Condition or disease	Intervention/treatment	Phase
Brain Abscess; Cerebral Abscess	Drug: Early transition to oral antibiotics; Drug: Standard treatment of intravenous antibiotics	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Investigator-initiated, international, multi-centre, randomised, parallel groups, non-inferiority trial
• Masking: Single (Outcomes Assessor)
• Masking Description: An independent blinded endpoint committee will assess the primary outcome.
• Primary Purpose: Treatment
• Official Title: Partial Oral Antibiotic Treatment for Bacterial Brain Abscess: An Open-label Randomised Non-inferiority Trial
• Actual Study Start Date: November 6, 2020
• Estimated Primary Completion Date: August 31, 2023
• Estimated Study Completion Date: August 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Oral antibiotics; 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	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
Active Comparator: Standard treatment; 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	Drug: 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.

Outcome Measures

Primary Outcome Measures :

1. Treatment failure [ Time Frame: Six months after randomisation ]
   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 :

1. Treatment failure [ Time Frame: At last day of antibiotic treatment for brain abscess, and 3- and 12-months after randomisation ]
   A composite of number of participants with all-cause mortality, risk of intraventricular rupture of brain abscess (IVROBA), unplanned neurosurgery, relapse, or recurrence
2. Unfavourable outcome [ Time Frame: At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation ]
   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)
3. All-cause mortality [ Time Frame: At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation ]
   Number of participants with fatal outcome, overall and stratified by study centre, oral cavity bacteria (yes/no) and largest brain abscess diameter (+/- 3 cm)
4. Unplanned neurosurgery [ Time Frame: At 6 months since randomisation ]
   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)
5. IVROBA [ Time Frame: At 6 months since randomisation ]
   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)
6. Relapse [ Time Frame: At 6 months since randomisation ]
   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)
7. Recurrence [ Time Frame: At 6 months since randomisation ]
   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)
8. Unfavourable outcome - sliding dichotomy [ Time Frame: At last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months after randomisation ]
   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).
9. Central line associated complications [ Time Frame: 6 months since randomisation ]
   Number of participants with bleeding, infection, venous thrombosis or need for replacement of central line due to mechanical malfunction
10. Clostridial diarrhea [ Time Frame: From randomisation up until last day antibiotic treatment for brain abscess ]
    Number of participants who develop Clostridioides difficile associated gastro-enteritis during antibiotic treatment for brain abscess
11. Duration of admission [ Time Frame: From randomisation until hospital discharge to home or rehabilitation unit or death, whichever comes first, assessed up to 6 months ]
    Days spent as admitted patient in hospital up to 6 months since randomisation (does not include outpatient hospital care)
12. Duration of treatment [ Time Frame: From randomisation until last day of antibiotic treatment for brain abscess up to 6 months since randomisation ]
    Number of days treated with antibiotics for brain abscess up to 6 months since randomisation
13. Adherence to treatment [ Time Frame: From randomisation until last day of antibiotic treatment for brain abscess, assessed up to 6 months since randomisation ]
    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
14. Oedema on cranial imaging [ Time Frame: 3 months since randomisation ]
    Number of participants with residual perilesional oedema on cranial imaging up to 3 months since randomisation
15. SAE [ Time Frame: From randomisation until last day of antibiotic treatment for brain abscess ]
    Number of participants with severe adverse events
16. SF36 [ Time Frame: At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation ]
    Short Form 36 is a 36 item survey of patient-reported health-related quality of life (range 0=maximum disability to 100=no disability)
17. EQ-5D-5L [ Time Frame: At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation ]
    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)
18. EQ-VAS [ Time Frame: At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation ]
    EuroqQol Visual Analogue Scale (range 0=poor health status to 100=excellent health status)
19. Cognitive impairment [ Time Frame: At time of randomisation, last day of antibiotic treatment for brain abscess, and 3-, 6-, and 12-months since randomisation ]
    Montreal Cognitive Assessment (MoCA) scores (range 0=poor cognitive performance to 30=normal cognitive performance)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Jacob Bodilsen, MD; +45 97663920; jacob.bodilsen@rn.dk

Contact: Henrik Nielsen, Professor; +45 97663920; henrik.nielsen@rn.dk

Locations

Denmark

Aalborg University Hospital; Recruiting

Aalborg, Denmark

Contact: Jacob Bodilsen, MD PhD

Aarhus University Hospital; Recruiting

Aarhus, Denmark

Contact: Merete Storgaard, MD

Rigshospitalet; Recruiting

Copenhagen, Denmark

Contact: Lars H Omland, MD

Odense University Hospital; Recruiting

Odense, Denmark

Contact: Lykke Larsen, MD

Sponsors and Collaborators

Henrik Nielsen

Investigators

• Principal Investigator: Jacob Bodilsen, MD; Aalborg University Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Henrik Nielsen, Professor, Aalborg University Hospital
• ClinicalTrials.gov Identifier: NCT04140903
• Other Study ID Numbers: 1
• First Posted: October 28, 2019
• Last Update Posted: February 17, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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/).
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: 6 months until 3 years after publication
• 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.
• URL: https://data.mendeley.com

• 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

Keywords provided by Henrik Nielsen, Aalborg University Hospital:

Oral antibiotics

Additional relevant MeSH terms:

Abscess; Brain Abscess; Suppuration; Infections; Inflammation; Pathologic Processes; Central Nervous System Infections; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Anti-Bacterial Agents; Antibiotics, Antitubercular; Anti-Infective Agents; Antitubercular Agents