Intracalvariosseous Plus Intravenous Antibiotics for Moderate-to-Severe Bacterial Meningitis

NCT07495150 | Not Yet Recruiting DMC

• 1 other identifier: CX25YZ07
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 6

Brief Summary

Multiple preclinical and clinical studies, including the investigators' published work and the ongoing SOLUTION series, have consistently demonstrated that intracalvariosseous (ICO) injection can markedly increase drug exposure within the central nervous system with acceptable safety. This trial is designed to further evaluate the efficacy and safety of antibiotic delivery via the ICO route in the treatment of bacterial meningitis, particularly in patients with moderate-to-severe disease who have shown an inadequate response to standard therapy.

Conditions

Blood-Brain Barrier; Bacterial Meningitis

Keywords

Blood-Brain Barrier; Bacterial meningitis; Prognosis; Intracalvariosseous; Antibiotic

Outcome Measures

Primary Outcomes (1)

• Overall effective rate after 7 days of randomization

  Overall effective rate = \[(Cure + Improvement) / Total Number of Case\] \* 100% Cure: Cerebrospinal fluid (CSF) white blood cell count, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture are all normal in three consecutive tests. Improvement: At least one of the following three CSF white blood cell counts, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture is normal. Ineffective: All three of the following CSF white blood cell counts, CSF protein concentration, CSF/serum glucose ratio, and CSF bacterial culture are abnormal. Normal Reference Values for CSF Indicators: white blood cell count \< 100 × 10⁶/L, protein concentration \< 50 mg/dL, CSF/serum glucose ratio \> 0.5.

  8,10 and 14 days after randomization

Secondary Outcomes (10)

• Cure rate after 7 days of randomization

  8,10 and 14 days after randomization

• Improvement rate after 7 days of randomization

  8,10 and 14 days after randomization

• Cerebrospinal fluid white blood cell count at 48-72 hours and Days 5, 8, 10, and 14 after randomization

  48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization

• Cerebrospinal fluid protein concentration at 48-72 hours and Days 5, 8, 10, and 14 after randomization

  48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization

• Cerebrospinal fluid-to-serum glucose concentration ratio at 48-72 hours and Days 5, 8, 10, and 14 after randomization

  48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization

Other Outcomes (21)

• The ratio of the concentrations of the antibiotics used after randomization in cerebrospinal fluid and plasma

  0.25, 0.5, 1, 2, 4, 8, 12, 24 hours after randomization

• Glasgow Outcome Scale (GOS) scores at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization

  1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization

• Cure rate without neurological sequelae at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization

  1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization

Study Arms (2)

Intracalvariosseous injection + Intravenous injection

EXPERIMENTAL

In patients who fail to respond to the initial intravenous antibiotic regimen, intravenous treatment will be switched to the indicated antibiotic (polymyxin B, tigecycline, or vancomycin). At the same time, bilateral parietal outer-table drill holes will be created, delivery devices will be secured, and the corresponding antibiotic will be continuously infused via the intracalvariosseous route. The combined ICO and intravenous treatment will be administered concurrently for 7 × 24 hours, after which the ICO devices will be removed. The duration of intravenous therapy will then be adjusted according to treatment response, including clinical symptoms, signs, and laboratory findings. If a change in antibiotic selection is required during the period of combined treatment, the antibiotic administered via the intracalvariosseous route must remain consistent with that administered intravenously.

Procedure: Intracalvariosseous injection vancomycin/tigecycline/polymyxin B; Drug: Intravenous injection vancomycin/tigecycline/polymyxin B; Other: Conventional treatment

Intravenous injection

ACTIVE COMPARATOR

In patients who fail to respond to the initial intravenous antibiotic regimen, intravenous treatment will be switched to the indicated antibiotic (polymyxin B, tigecycline, or vancomycin). The duration of intravenous therapy will be adjusted according to treatment response, including clinical symptoms, signs, and laboratory findings.

Drug: Intravenous injection vancomycin/tigecycline/polymyxin B; Other: Conventional treatment

Interventions

Intracalvariosseous injection vancomycin/tigecycline/polymyxin B PROCEDURE

Continuous intracalvariosseous infusion of polymyxin B (12.5 mg/day), tigecycline (12.5 mg/day), and vancomycin (125 mg/day).

Intracalvariosseous injection + Intravenous injection

Intravenous injection vancomycin/tigecycline/polymyxin B DRUG

Intravenous infusion of polymyxin B (100 mg/day), tigecycline (100 mg/day), and vancomycin (2000 mg/day).

Intracalvariosseous injection + Intravenous injection; Intravenous injection

Conventional treatment OTHER

Standard treatment and management according to related guidelines during the entire treatment period

Intracalvariosseous injection + Intravenous injection; Intravenous injection

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Age 18-75 years, gender not limited;
• \. Meeting the diagnostic criteria for moderate to severe bacterial meningitis:
• Meeting the diagnostic criteria for bacterial meningitis, i.e., meeting at least item i:
• i. Abnormal body temperature (\>38℃ or \<36℃), turbid or purulent Cerebrospinal fluid (CSF) , CSF leukocytosis (\>500×10⁶/L), CSF glucose/serum glucose concentration \<0.4, CSF protein concentration \>50mg/dL, meeting the clinical diagnosis; ii. In addition to item i, positive microbial tests or cultures of specimen smears, drainage tube heads, implants, and CSF (excluding contamination and colonization), meeting the etiological diagnosis;
• GCS score ≤12 points or a decrease of 2 points from the previous score;
• At least one of the following conditions is present: altered consciousness, seizures, brain parenchymal involvement, severe manifestations such as mechanical ventilation or circulatory support.
• \. After 48-72 hours of antibiotic treatment, if the investigator determines that the patient's condition shows no significant improvement or continues to worsen, or if at least one of the following conditions is present:
• Symptoms and signs related to intracranial infection show no trend of relief or worsen;
• CSF white blood cell count shows no trend of decrease, or increases after decreasing;
• CSF protein concentration shows no trend of decrease, or increases after decreasing;
• CSF/serum glucose concentration shows no trend of increase, or decreases after increasing;
• CSF bacterial culture remains positive or becomes positive again after initially being negative.
• \. Based on the patient's condition, treatment with polymyxin B, tigecycline, or vancomycin may be necessary.
• \. Obtain informed consent.

You may not qualify if:

• \. History of allergy to polymyxin B, tigecycline, or vancomycin;
• \. Received intrathecal or intraventricular antibiotic treatment before randomization;
• \. Patients with severe pulmonary infection/acute respiratory distress syndrome (PaO₂/FiO₂ \< 150 mmHg, FiO₂ ≥ 0.6, PEEP ≥ 5 cmH₂O) or whose primary cause of mechanical ventilation is not determined to be intracranial infection;
• \. Patients with a primary extracranial infection focus (e.g., lungs, abdomen, urinary tract, etc.) who, after adequate fluid resuscitation, require vasoactive drugs to maintain MAP ≥ 65 mmHg (e.g., norepinephrine ≥ 0.25 μg/kg/min) and lactate \> 2 mmol/L, or whose primary cause of critical illness is not determined to be intracranial infection;
• \. Patients with contraindications to transcranial administration, such as severe skull fracture, poor visualization of the skull diploic, or planned decompressive craniectomy, which may affect transcranial administration.
• \. Clinical signs of brain herniation, such as unilateral or bilateral pupillary dilation and fixation; or loss of other brainstem reflexes determined by the investigator to be caused by meningitis or brain herniation; or other uncontrollable signs of unstable vital signs;
• \. Bleeding tendency deemed unfavorable for the procedure by the investigator: abnormal coagulation function (e.g., platelet count \<50×10⁹/L; prothrombin time \[PT\]\>3s), patients with a previous diagnosis of hemophilia or other coagulation disorders;
• \. Patients with severe hepatic or renal insufficiency (where severe hepatic insufficiency is defined as alanine aminotransferase (ALT) value ≥3 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) value ≥3 times the ULN; severe renal insufficiency is defined as serum creatinine (CRE) ≥1.5 times the ULN or glomerular filtration rate (eGFR) \<40 mL/min/1.73m²;
• \. Within the past 3 months, the patient has experienced an acute ST-segment elevation myocardial infarction and/or decompensated heart failure (meeting New York Heart Association \[NYHA\] functional class III or IV).
• \. Patients with severe or extremely severe anemia (hemoglobin \< 60 g/L) at the time of randomization;
• \. Patients with active hepatitis B infection (positive hepatitis B surface antigen and/or positive serum HBV DNA or serum HBV DNA \> 2 × 10⁸ IU/ml);
• \. Patients with positive hepatitis C virus antibody or a history of positive testing;
• \. Patients with positive HIV test or a history of positive testing;
• \. Pregnant, lactating, or potentially pregnant patients, or patients planning to become pregnant;
• \. Patients currently participating in other interventional trials or who have used other investigational drugs within one month or five drug half-lives;

Sponsors & Collaborators

• yilong Wang: lead

Study Sites (6)

Beijing Tiantan Hospital

Beijing, Beijing Municipality, 100071, China

Location

Kaifeng Central Hospital

Kaifeng, Henan, China

Location

The First Affiliated Hospital of Xinxiang Medical University

Xinxiang, Henan, China

Location

Henan Provincial People's Hospital

Zhengzhou, Henan, 450000, China

Location

Linyi City People Hospital

Linyi, Shandong, China

Location

Tianjin Huanhu Hospital

Tianjin, Tianjin Municipality, 300000, China

Location

MeSH Terms

Conditions

Meningitis, Bacterial

Condition Hierarchy (Ancestors)

Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Study Officials

• Yilong Wang, PhD+MD

  Beijing Tiantan Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yilong Wang, PhD+MD

CONTACT

13569869755; yilong528@aliyun.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Vice President of Beijing Tiantan Hospital

Study Record Dates

• First Submitted: March 9, 2026
• First Posted: March 27, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): July 1, 2027
• Last Updated: March 27, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (6)