Ignite Creation Date:
2024-05-06 @ 12:31 PM
Last Modification Date:
2024-10-26 @ 1:00 PM
Study NCT ID:
NCT03787940
Status:
UNKNOWN
Last Update Posted:
2021-02-01
First Post:
2018-11-19
Brief Title:
Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis
Sponsor:
Beijing Chest Hospital
Organization:
Beijing Chest Hospital
Study Overview
Official Title:
Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis Based on N-Acetyltransferase Type 2 Genotyping
Status:
UNKNOWN
Status Verified Date:
2021-01
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The genetically polymorphic N-acetyltransferase type 2 NAT2 is responsible for isoniazid metabolism and rapid acetylators were associated with low concentrations of isoniazid based on previous studies The investigators hypothesize that among rapid acetylators high dose isoniazid would result in lower rates of death and disability in patients with tuberculous meningitis than the rates with the standard regimen The investigators recruited patients between the ages of 18 and 65 years with newly diagnosed TBM then NAT2 genotype will be characterized by using High-Resolution Melting Kit Zeesan Company Xiamen Participants with slow or intermediate acetylators will be administered with standard chemotherapy For participants with rapid acetylators patients were stratified at study entry according to the modified British Medical Research Council criteria MRC grade then randomly assigned in a 11 ratio to receive either standard or with high dose isoniazid treatment All patients received antituberculosis treatment which consisted of isoniazid standard dose or high dose rifampin pyrazinamide ethambutol for 3 months followed by isoniazid rifampin and ethambutol at the same doses for an additional 9 months All patients received adjunctive treatment with dexamethasone for the first 6 to 8 weeks of treatment 338 participants with rapid acetylators were randomly assigned to group B standard treatment and group C high dose isoniazid respectively At the same time 338 participants with slow or intermediate acetylators were recruited to group A standard treatment The primary outcome was death or severe disability 12 months after enrollment Secondary outcome measures were coma-clearance time fever-clearance time and difference of laboratory examination protein concentration chloride glucose and white cell counts of cerebrospinal fluid
Detailed Description:
Tuberculous meningitis TBM is the most lethal form of tuberculosis causing death or severe neurologic deficits in more than half of those affected in spite of antituberculosis chemotherapy Among the first line drugs isoniazid is the only bactericidal agent that easily crossed blood-brain barrier achieving concentrations in cerebrospinal fluid CSF similar to those in serum The genetically polymorphic N-acetyltransferase type 2 NAT2 is responsible for isoniazid metabolism and individuals can be classified as rapid acetylators intermediate acetylators or slow acetylators based on NAT2 genotyping Rapid acetylators were associated with low concentrations of isoniazid based on previous studies The investigators hypothesize that among rapid acetylators high dose isoniazid would result in lower rates of death and disability in patients with tuberculous meningitis than the rates with the standard regimen
The investigators recruited patients between the ages of 18 and 65 years with newly diagnosed TBM Patients could not enter the trial if they have been using any other second line antituberculosis drug if they had received anti-tuberculosis therapy in the past 3 yearsif they have positive CSF Gram or India ink stain if they have received more than 14 days of anti-tuberculosis drugs for the current infection if they were known or suspected hypersensitivity to or unacceptable side effects from any oral first line antituberculosis drug if the plasma creatinine concentration was more than the upper limit of the normal range if the plasma bilirubin concentration was more than 2 times the upper limit of the normal range or if the plasma alanine aminotransferase level was more than three times the upper limit of the normal range if they were known or suspected pregnancy if they were known or suspected isoniazid andor rifampin resistant if they were lack of consent if they were any participant for whom investigators judge this study is not appropriated
Participants will be recruited from four sites in China including Beijing Chest Hospital affiliated to Capital Medical University Zunyi Medical College affiliated Hospital Jiangxi Provincial Chest Hospital and Jiamusi Infectious Disease Hospital All hospitals serve the local community and act as tertiary referral centers for patients with severe tuberculosis or infectious diseases in China
Written informed consent to participate in the study was obtained from all patients Then NAT2 genotype will be characterized by using High-Resolution Melting Kit Zeesan Company Xiamen Participants with slow or intermediate acetylators will be administered with standard chemotherapy 3 months HRZE followed by 9 months HRE For participants with rapid acetylators patients were stratified at study entry according to the modified British Medical Research Council criteria MRC grade then randomly assigned in a 11 ratio to receive either standard or high dose isoniazid treatment
All patients received antituberculosis treatment which consisted of isoniazid 300 mg for standard treatment and 900 mg for high dose treatment rifampin 450 mg for weight no more than 50 kg 600 mg for weight more than 50 kg pyrazinamide 1500 mg for weight no more than 50 kg 1750 mg for weight more than 50 kg ethambutol 750 mg for weight no more than 50 kg 1000 mg for weight more than 50 kg for 3 months followed by isoniazid rifampin and ethambutol at the same doses for an additional 9 months All patients received adjunctive treatment with dexamethasone for the first 6 to 8 weeks of treatment as recommend by British Infection Society
338 participants with rapid acetylators will be randomly assigned to group B standard treatment and group C high dose isoniazid respectively The calculation assumes an overall mortality and severe disability of 50 vs 70 in the two arms a power of 80 and a two-sided significance level of 5 Randomization ration is 11 At the same time 338 participants with slow or intermediate acetylators were recruited to group A standard treatment
The primary outcome was death or severe disability 12 months after enrollment Secondary outcome measures were coma-clearance time fever-clearance time and difference of CSF laboratory examination protein concentration chloride glucose and white cell counts of cerebrospinal fluid after 3 months treatment
The investigators recruited patients between the ages of 18 and 65 years with newly diagnosed TBM Patients could not enter the trial if they have been using any other second line antituberculosis drug if they had received anti-tuberculosis therapy in the past 3 yearsif they have positive CSF Gram or India ink stain if they have received more than 14 days of anti-tuberculosis drugs for the current infection if they were known or suspected hypersensitivity to or unacceptable side effects from any oral first line antituberculosis drug if the plasma creatinine concentration was more than the upper limit of the normal range if the plasma bilirubin concentration was more than 2 times the upper limit of the normal range or if the plasma alanine aminotransferase level was more than three times the upper limit of the normal range if they were known or suspected pregnancy if they were known or suspected isoniazid andor rifampin resistant if they were lack of consent if they were any participant for whom investigators judge this study is not appropriated
Participants will be recruited from four sites in China including Beijing Chest Hospital affiliated to Capital Medical University Zunyi Medical College affiliated Hospital Jiangxi Provincial Chest Hospital and Jiamusi Infectious Disease Hospital All hospitals serve the local community and act as tertiary referral centers for patients with severe tuberculosis or infectious diseases in China
Written informed consent to participate in the study was obtained from all patients Then NAT2 genotype will be characterized by using High-Resolution Melting Kit Zeesan Company Xiamen Participants with slow or intermediate acetylators will be administered with standard chemotherapy 3 months HRZE followed by 9 months HRE For participants with rapid acetylators patients were stratified at study entry according to the modified British Medical Research Council criteria MRC grade then randomly assigned in a 11 ratio to receive either standard or high dose isoniazid treatment
All patients received antituberculosis treatment which consisted of isoniazid 300 mg for standard treatment and 900 mg for high dose treatment rifampin 450 mg for weight no more than 50 kg 600 mg for weight more than 50 kg pyrazinamide 1500 mg for weight no more than 50 kg 1750 mg for weight more than 50 kg ethambutol 750 mg for weight no more than 50 kg 1000 mg for weight more than 50 kg for 3 months followed by isoniazid rifampin and ethambutol at the same doses for an additional 9 months All patients received adjunctive treatment with dexamethasone for the first 6 to 8 weeks of treatment as recommend by British Infection Society
338 participants with rapid acetylators will be randomly assigned to group B standard treatment and group C high dose isoniazid respectively The calculation assumes an overall mortality and severe disability of 50 vs 70 in the two arms a power of 80 and a two-sided significance level of 5 Randomization ration is 11 At the same time 338 participants with slow or intermediate acetylators were recruited to group A standard treatment
The primary outcome was death or severe disability 12 months after enrollment Secondary outcome measures were coma-clearance time fever-clearance time and difference of CSF laboratory examination protein concentration chloride glucose and white cell counts of cerebrospinal fluid after 3 months treatment
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None