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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03787940
Other study ID # 2018ZX10302302-004
Secondary ID
Status Recruiting
Phase N/A
First received
Last updated
Start date March 4, 2019
Est. completion date December 31, 2021

Study information

Verified date January 2021
Source Beijing Chest Hospital
Contact Hongfei Duan, MD
Phone 13520728402
Email duanhongfei@hotmail.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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 1:1 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.


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 years;if 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 and/or 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 1:1 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 1:1. 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.


Recruitment information / eligibility

Status Recruiting
Enrollment 676
Est. completion date December 31, 2021
Est. primary completion date December 31, 2021
Accepts healthy volunteers No
Gender All
Age group 18 Years to 65 Years
Eligibility Inclusion Criteria: - 18 to 65 years of age; - Clinical diagnosis of TBM; - Able and willing to provide informed consent to participate in the study. Exclusion Criteria: - Using any other second line antituberculosis drug; - Received anti-tuberculosis therapy in the past 3 years; - Positive CSF Gram or India ink stain; - Received more than 14 days of anti-tuberculosis drugs for the current infection; - Known or suspected hypersensitivity to or unacceptable side effects from any oral first line antituberculosis drug; - Plasma creatinine concentration was more than the upper limit of the normal range, or the plasma bilirubin concentration was more than 2 times the upper limit of the normal range, or the plasma alanine aminotransferase level was more than three times the upper limit of the normal range; - Known or suspected pregnancy; - Known or suspected isoniazid and/or rifampin resistant; - Lack of consent; - Any participant for whom investigators judge this study is not appropriate.

Study Design


Intervention

Drug:
Isoniazid
standard dose isoniazid or high dose isoniazid for participants with rapid acetylators

Locations

Country Name City State
China Beijing Chest Hospital affiliated to Capital Medical University Beijing
China Jiamusi Infectious Disease Hospital Jiamusi
China Jiangxi Provincial Chest Hospital Nanchang
China Zunyi Medical College affiliated Hospital Zunyi

Sponsors (1)

Lead Sponsor Collaborator
Beijing Chest Hospital

Country where clinical trial is conducted

China, 

Outcome

Type Measure Description Time frame Safety issue
Primary Number of Participants with death or severe disability Number of Participants with death or severe disability 12 months after enrollment up to 12 months after enrollment
Secondary days for coma-clearance time days for coma-clearance time through study completion through study completion,up to 1 year
Secondary days for fever-clearance time days for fever-clearance time through study completion through study completion,up to 1 year
Secondary difference of CSF protein concentration difference of CSF protein concentration (g/L) 3 months after enrollment
Secondary difference of CSF glucose concentration difference of CSF glucose concentration (mmol/L) 3 months after enrollment
Secondary difference of CSF white cell counts difference of CSF white cell counts (per milliliter) 3 months after enrollment
Secondary difference of CSF chloride concentration difference of CSF chloride concentration (mmol/L) 3 months after enrollment
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