An interventional study of Intracalvariosseous injection vancomycin/tigecycline/polymyxin B and Intravenous injection vancomycin/tigecycline/polymyxin B in Blood-Brain Barrier and Bacterial Meningitis, sponsored by yilong Wang. Not yet recruiting at 6 sites in China. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2026-03-27.
Sponsored by yilong Wang · Not applicable, Interventional, and Treatment
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.
Bacterial meningitis remains a major cause of death and neurological disability despite advances in antimicrobial therapy, vaccination, and critical care. Moderate-to-severe disease, particularly healthcare-associated infection and cases caused by multidrug-resistant pathogens, continues to pose substantial therapeutic challenges because intravenous antibiotic therapy alone may not achieve sufficiently rapid or sustained drug exposure in cerebrospinal fluid and at the meningeal surface. Although intrathecal and intraventricular administration can increase local drug concentrations, these approaches are invasive and have limited diffusion.
Anatomical and physiological studies have demonstrated communication among calvarial bone marrow, dura, cerebrospinal fluid spaces, and glymphatic pathways, supporting the rationale for intracalvariosseous (ICO) injection as a regional route for drug delivery to the central nervous system. Preclinical and clinical studies, including the investigators' published work and the ongoing SOLUTION series, suggest that ICO injection can enhance local central nervous system drug exposure with an acceptable safety profile. In addition, an exploratory study conducted by the investigators, using vancomycin administered via ICO injection in an experimental animal model of bacterial meningitis, further supported the potential of this route to improve anti-infective efficacy.
This trial is a multicenter, prospective, randomized, open-label, blinded-endpoint study comparing ICO injection plus intravenous antibiotic therapy with intravenous antibiotic therapy alone.
The study aims to evaluate differences in efficacy and safety between combined treatment with ICO injection and intravenous antibiotics versus intravenous antibiotics alone in participants with moderate-to-severe bacterial meningitis who have shown a suboptimal response to treatment.
Participants with moderate-to-severe bacterial meningitis and inadequate improvement after 48-72 hours of initial intravenous treatment will be randomized in a 1:1 ratio.
In the intervention group, bilateral parietal ICO access devices will be placed, and the selected antibiotic will be continuously administered through the calvarial bone marrow route for 7 days while the same antibiotic is also given intravenously.
In the control group, treatment will consist of intravenous antibiotic therapy alone.
Guideline-based supportive care, including intracranial pressure management, seizure control, organ support, and other standard measures, will be provided in both groups.
Face-to-face visits will be conducted at randomization (baseline), 48-72 hours, Day 5, Day 8, Day 10, Day 14, Day 30 (±3 days), or on the day of discharge. A telephone follow-up visit will be conducted at Month 3 (±7 days).
A Data and Safety Monitoring Board (DSMB) will regularly monitor safety throughout the study. The trial has been approved by the Institutional Review Board (IRB) and Ethics Committee (EC) of Beijing Tiantan Hospital, Capital Medical University.
38 studies on the registry are indexed under Meningitis, Bacterial; 11 are open to participants now.
This study's planned enrollment of 86 is below the median of 226 across 22 interventional studies indexed under Meningitis, Bacterial.
Browse Meningitis, Bacterial studies →yilong Wang is the lead sponsor of 7 studies on the registry; 7 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
2. 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;
3. 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:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.
Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
INR, PT and aPTT (clotting tests)
Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.
Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
NYHA class (heart failure)
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
Continuous intracalvariosseous infusion of polymyxin B (12.5 mg/day), tigecycline (12.5 mg/day), and vancomycin (125 mg/day).
Intravenous infusion of polymyxin B (100 mg/day), tigecycline (100 mg/day), and vancomycin (2000 mg/day).
Standard treatment and management according to related guidelines during the entire treatment period
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.
Time frame: 8,10 and 14 days after randomization
Cure rate after 7 days of randomization
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. Reference Values for CSF Indicators: white blood cell count \< 100 × 10⁶/L, protein concentration \< 50 mg/dL, CSF/serum glucose ratio \> 0.5.
Time frame: 8,10 and 14 days after randomization
Improvement rate after 7 days of randomization
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. Reference Values for CSF Indicators: white blood cell count \< 100 × 10⁶/L, protein concentration \< 50 mg/dL, CSF/serum glucose ratio \> 0.5.
Time frame: 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
Cerebrospinal fluid white blood cell count
Time frame: 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
Cerebrospinal fluid protein concentration
Time frame: 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
Cerebrospinal fluid-to-serum glucose concentration ratio
Time frame: 48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization
Cerebrospinal fluid bacteriological culture results at 48-72 hours and Days 5, 8, 10, and 14 after randomization
Cerebrospinal fluid bacteriological culture results
Time frame: 48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization
Glasgow Coma Scale (GCS) scores at 48-72 hours and Days 5, 8, 10, and 14 after randomization
Glasgow Coma Scale (GCS) is a neurological scale that assesses level of consciousness using 3 components: eye opening, verbal response, and motor response. The total score ranges from 3 to 15, with higher scores indicating a better neurological outcome / level of consciousness and lower scores indicating a worse outcome / deeper impairment of consciousness.
Time frame: 48-72 hours after randomization, Days 5, 8, 10, and 14 after randomization
Proportion of participants who require conversion to intrathecal or intraventricular antibiotic therapy during the 48-72 hour period after randomization
This proportion is defined as the number of participants who are evaluated during the 48-72-hour period after randomization and are judged to have an unsatisfactory treatment response requiring conversion to intrathecal or intraventricular antibiotic therapy, divided by the total number of participants in the corresponding treatment group. An unsatisfactory treatment response is defined as the absence of an improving trend, compared with baseline, in cerebrospinal fluid white blood cell count, protein concentration, and cerebrospinal fluid-to-serum glucose concentration ratio.
Time frame: During the 48-72 hour period after randomization
All-cause mortality from baseline to 14-day
All-cause mortality
Time frame: Baseline to Day 14
Mortality due to meningitis from baseline to 14-day
Mortality due to meningitis. The diagnostic criteria are the absence of a downward trend in the cerebrospinal fluid leukocyte count, protein concentration, and the ratio of cerebrospinal fluid glucose concentration to serum glucose concentration prior to death.
Time frame: Baseline to Day 14
The ratio of the concentrations of the antibiotics used after randomization in cerebrospinal fluid and plasma
The ratio of cerebrospinal fluid drug concentration to plasma drug concentration
Time frame: 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
Glasgow Outcome Scale (GOS) is a 5-point functional outcome scale used to assess recovery after brain injury or severe neurological disease. The total score ranges from 1 to 5, where 1 = death, 2 = vegetative state, 3 = severe disability, 4 = moderate disability, and 5 = good recovery; therefore, higher scores indicate a better outcome and lower scores indicate a worse outcome.
Time frame: 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
Cure rate without neurological sequelae：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, and were not accompanied by neurological symptoms attributable to meningitis at baseline. Normal Reference Values for CSF Indicators: white blood cell count \< 100 × 10⁶/L, protein concentration \< 50 mg/dL, CSF/serum glucose ratio \> 0.5.
Time frame: 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
All-cause mortality rate at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
All-cause mortality is equal to the ratio of the number of all-cause deaths to the total number of cases within the same treatment group.
Time frame: 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Meningitis-related mortality rate at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Meningitis-related mortality is equal to the ratio of the number of deaths due to meningitis to the total number of cases within the same treatment group. Meningitis-related mortality. The diagnostic criteria are the absence of a downward trend in the cerebrospinal fluid leukocyte count, protein concentration, and the ratio of cerebrospinal fluid glucose concentration to serum glucose concentration prior to death.
Time frame: 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Reinfection with the same microorganism occurred at 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Reinfection with the same microorganism
Time frame: 1 month ± 3 days (or on the day of discharge) and at 3 months ± 7 days after randomization
Breach of the inner table of the skull during calvarial drilling
Breach of the inner table of the skull
Time frame: Baseline
Dislodgement, leakage, or occlusion of the intracalvariosseous injection device
Dislodgement, leakage, or occlusion of the intracalvariosseous injection device
Time frame: Baseline to Day 8
Infection events related to intracalvariosseous injection, such as skin infection or calvarial bone marrow osteomyelitis
For example, skin infection or calvarial bone marrow osteomyelitis
Time frame: Baseline to Day 8
First occurrence of seizures after randomization, including seizures considered to be associated with antibiotic use
Seizures considered to be associated with antibiotic use
Time frame: Baseline to Day 8
Nucleated cell count in calvarial bone marrow fluid before and after intracalvariosseous injection
Nucleated cell count in calvarial bone marrow fluid
Time frame: Baseline and Day 8
Hepatic or renal dysfunction/failure after randomization
Definition: Hepatic dysfunction/failure is defined as alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal. Renal dysfunction/failure is defined as serum creatinine greater than 1.5 times the upper limit of normal or an estimated glomerular filtration rate of \<40 mL/min/1.73 m²
Time frame: Baseline to Day 8
Incidence of sensorineural hearing loss after randomization
Based on distortion-product otoacoustic emission + multiple auditory steady-state evoked responses / auditory brainstem response. Definition: Compared with baseline, hearing loss is defined as an increase of ≥20 dB at any single frequency, an increase of ≥10 dB at two adjacent frequencies, or an increase of ≥10 dB in the average threshold across three frequencies.
Time frame: Baseline to Day 8
Incidence of red man syndrome after randomization
Red man syndrome is defined as an infusion-related reaction occurring during or shortly after vancomycin administration, characterized by flushing/erythema and pruritus predominantly involving the face, neck, upper trunk, or upper extremities, with or without rash, and possibly accompanied by chest or back pain and/or hypotension, in the absence of features suggesting IgE-mediated anaphylaxis
Time frame: Baseline to Day 8
Incidence of skin hypersensitivity reactions after randomization
For example, rash and urticaria
Time frame: Baseline to Day 8
Incidence of gastrointestinal adverse reactions after randomization
For example, nausea and vomiting
Time frame: Baseline to Day 8
Length of stay in the intensive care unit (ICU) after randomization
Calculate the number of days of ICU stay
Time frame: From date of randomization until first ICU discharge or death, whichever comes first, assessed up to 3 months ± 7 days
Total length of hospital stay after randomization
Calculate the number of days from baseline to discharge
Time frame: From date of randomization until hospital discharge or death, whichever comes first, assessed up to 3 months ± 7 days
Duration of antibiotic use after randomization
Calculate the number of days from baseline to the discontinuation of antibiotics
Time frame: From date of randomization until discontinuation of systemic antibiotic therapy or death, whichever comes first, assessed up to 3 months ± 7 days
ICU costs after randomization
Costs from baseline to ICU discharge
Time frame: From date of randomization until first ICU discharge or death, whichever comes first, assessed up to 3 months ± 7 days
Total hospitalization costs after randomization
Total cost from baseline to discharge
Time frame: From date of randomization until hospital discharge or death, whichever comes first, assessed up to 3 months ± 7 days
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yilong Wang