Clinical Study of ABCD in the Treatment of Cryptococcal Meningitis

Sponsor

Peking Union Medical College Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05471063

Collaborator

CSPC Ouyi Pharmaceutical Group Co., Ltd. (Other)

Enrollment

Location

Arm

8.2

Anticipated Duration (Months)

3.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cryptococcal Meningitis	Drug: Amphotericin B Colloidal Dispersion Drug: flucytosine Drug: fluconazole	N/A

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Aug 22, 2022

Anticipated Primary Completion Date :

Feb 28, 2023

Anticipated Study Completion Date :

Apr 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ABCD treatment 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 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. Other Names: Amphotericin B Cholesteryl Sulfate Complex for Injection Drug: flucytosine 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. Other Names: fluorocytosine Drug: fluconazole Fluconazole (400-600 mg/d) for consolidation therapy for at least 6 weeks. Other Names: Diflucan

Arm

Intervention/Treatment

Experimental: ABCD treatment

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

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.

Other Names:

Amphotericin B Cholesteryl Sulfate Complex for Injection

Drug: flucytosine

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.

Other Names:

fluorocytosine

Drug: fluconazole

Fluconazole (400-600 mg/d) for consolidation therapy for at least 6 weeks.

Other Names:

Diflucan

Outcome Measures

Primary Outcome Measures

Proportion of patients with complete or partial response at the end of induction therapy [From enrollment to the end of induction therapy (about 4-6 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.

Secondary Outcome Measures

Proportion of patients with complete or partial response at 4 weeks [At the 4 weeks of treatment]
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.
Proportion of patients with complete or partial response at 10 weeks [At the 10 weeks of treatment]
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.
Proportion of patients with complete or partial response at the end of consolidation therapy [At the end of the consolidation therapy (about 12 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.
Cryptococcus antigen titer [1,2,3,4,10 weeks]
Diachronic changes in antigenic titers of Cryptococcus
Duration of the cryptococcal meningitis [At the end of the consolidation therapy (about 12 weeks)]
The time from this hospitalization to the end of consolidation therapy.
Adverse events [about 12 weeks]
Incidence and severity of adverse events during treatment, evaluated according to NCI-CTCAE Ver. 5.0.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.