Clinical Study of ABCD in the Treatment of Cryptococcal Meningitis

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of ABCD in the treatment of cryptococcal meningitis in non-HIV patients at week 4, the end of induction therapy, week 10 and the end of consolidation therapy.

Detailed Description
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This study is a multi-center, single-arm clinical study. The objective is to evaluate the efficacy and safety of ABCD in the treatment of cryptococcal meningitis in non-HIV patients. Qualified subjects shall receive cryptococcus induction therapy with ABCD combined with flucytosine for at least 4 weeks, or termination of treatment early at the investigator's discretion. Efficacy and safety are followed up at week 4 (day 28), the end of induction therapy, week 10 (day 70) and the end of consolidation therapy.

Official Title
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Clinical Study of Amphotericin B Colloidal Dispersion (ABCD) in the Treatment of Cryptococcal Meningitis

Conditions
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Cryptococcal Meningitis

Intervention / Treatment
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* Drug: Amphotericin B Colloidal Dispersion
* Drug: flucytosine
* Drug: fluconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old and ≤70 years old, no gender limitation; Diagnosis of cryptococcal meningitis (with or without other cryptococcal lesions) based on CSF culture and/or CSF ink staining smear and/or CSF antigen testing; The researcher believes that patients can benefit from participating in this study; The subjects voluntarily participated in the study and signed the informed consent. Exclusion Criteria: Patients with other invasive fungal diseases; HIV infected patients; Patients who received intravenous polyene treatment within the past 6 months; Allergic to Amphotericin B Colloidal Dispersion or other ingredients in this product; Patients with abnormal liver function [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >＝5 times the upper limit of normal value (ULN) without total bilirubin elevation, or ALT or AST >＝ 3 times ULN with total bilirubin >＝ 1.5 times]; Patients with impaired renal function (renal function index blood creatinine (Cr) is more than 2 times higher than ULN, or 24-hour urine creatinine clearance rate （Ccr） is less than 50ml/min), or patients requiring/undergoing hemodialysis or peritoneal dialysis; Pregnant women, breast-feeding women and women of childbearing age who were unable to take effective contraceptive measures during the study period; Conditions considered unsuitable for the study by the investigator, such as concomitancy of severe organ insufficiency, clinically significant laboratory abnormalities, comprehension or compliance problems, etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABCD treatment<br>In this single-arm research, patients were treated with ABCD 3.0-4.0 mg/kg/d (subject to adjustment, maximum dose not exceeding 6.0 mg/kg/d) combined with flucytosine 100 mg/kg/d for induction therapy of cryptococcal meningitis. The course of induction therapy is at least four weeks. Then, patients were treated with Fluconazole (400-600 mg/d) ± flucytosine (100 mg/kg/d) for consolidation therapy for at least 6 weeks. | Drug: Amphotericin B Colloidal Dispersion<br>* Amphotericin B Colloidal Dispersion 3.0-4.0 mg/kg/d (subject to adjustment, maximum dose not exceeding 6.0 mg/kg/d) . The course of induction therapy is at least four weeks.<br>* Other names: Amphotericin B Cholesteryl Sulfate Complex for Injection;Drug: flucytosine<br>* Flucytosine 100 mg/kg/d for induction therapy and consolidation therapy of cryptococcal meningitis. The course of induction therapy is at least four weeks, and consolidation therapy for at least 6 weeks.<br>* Other names: fluorocytosine;Drug: fluconazole<br>* Fluconazole (400-600 mg/d) for consolidation therapy for at least 6 weeks.<br>* Other names: Diflucan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with complete or partial response at the end of induction therapy | Complete response: live during the observation period, patients with cryptococcus meningitis all the clinical signs and symptoms disappeared, a significant reduction in the cerebrospinal fluid cryptococcal antigen test results and/or CSF cryptococcus training and/or ink staining (two consecutive tests, one week interval) results overcast, and abnormal head MRI/CT (if exist in baseline) improved or stable. Partial response: patient survival during the observation period, cryptococcal meningitis clinical signs and symptoms improved, all the significant reduction in the cerebrospinal fluid cryptococcal antigen test results and/or CSF cryptococcus training and/or ink staining (two consecutive tests, one week interval) results overcast, and abnormal head MRI/CT (if exist in baseline) improved or stable. | From enrollment to the end of induction therapy (about 4-6 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with complete or partial response at 4 weeks | Complete response: live during the observation period, patients with cryptococcus meningitis all the clinical signs and symptoms disappeared, a significant reduction in the cerebrospinal fluid cryptococcal antigen test results and/or CSF cryptococcus training and/or ink staining (two consecutive tests, one week interval) results overcast, and abnormal head MRI/CT (if exist in baseline) improved or stable. Partial response: patient survival during the observation period, cryptococcal meningitis clinical signs and symptoms improved, all the significant reduction in the cerebrospinal fluid cryptococcal antigen test results and/or CSF cryptococcus training and/or ink staining (two consecutive tests, one week interval) results overcast, and abnormal head MRI/CT (if exist in baseline) improved or stable. | At the 4 weeks of treatment | 
| Proportion of patients with complete or partial response at 10 weeks | Complete response: live during the observation period, patients with cryptococcus meningitis all the clinical signs and symptoms disappeared, a significant reduction in the cerebrospinal fluid cryptococcal antigen test results and/or CSF cryptococcus training and/or ink staining (two consecutive tests, one week interval) results overcast, and abnormal head MRI/CT (if exist in baseline) improved or stable. Partial response: patient survival during the observation period, cryptococcal meningitis clinical signs and symptoms improved, all the significant reduction in the cerebrospinal fluid cryptococcal antigen test results and/or CSF cryptococcus training and/or ink staining (two consecutive tests, one week interval) results overcast, and abnormal head MRI/CT (if exist in baseline) improved or stable. | At the 10 weeks of treatment | 
| Proportion of patients with complete or partial response at the end of consolidation therapy | Complete response: live during the observation period, patients with cryptococcus meningitis all the clinical signs and symptoms disappeared, a significant reduction in the cerebrospinal fluid cryptococcal antigen test results and/or CSF cryptococcus training and/or ink staining (two consecutive tests, one week interval) results overcast, and abnormal head MRI/CT (if exist in baseline) improved or stable. Partial response: patient survival during the observation period, cryptococcal meningitis clinical signs and symptoms improved, all the significant reduction in the cerebrospinal fluid cryptococcal antigen test results and/or CSF cryptococcus training and/or ink staining (two consecutive tests, one week interval) results overcast, and abnormal head MRI/CT (if exist in baseline) improved or stable. | At the end of the consolidation therapy (about 12 weeks) | 
| Cryptococcus antigen titer | Diachronic changes in antigenic titers of Cryptococcus | 1,2,3,4,10 weeks | 
| Duration of the cryptococcal meningitis | The time from this hospitalization to the end of consolidation therapy. | At the end of the consolidation therapy (about 12 weeks) | 
| Adverse events | Incidence and severity of adverse events during treatment, evaluated according to NCI-CTCAE Ver. 5.0. | about 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cryptococcal meningitis, Amphotericin B Colloidal Dispersion, non-HIV patients