Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis

NCT ID: NCT03787940

Last Updated: 2021-02-01

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 676 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-04
• Study Completion Date: 2021-12-31

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 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.

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 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.

Conditions

Tuberculous Meningitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Standard INH for Non-rapid acetylators

Participant with slow or intermediate acetylators(one of N-Acetyltransferase Type 2 Genotype) administered with standard chemotherapy (3 months HRZE followed by 9 months HRE with standard dose isoniazid)

Group Type: ACTIVE_COMPARATOR

Isoniazid

Intervention Type: DRUG

standard dose isoniazid or high dose isoniazid for participants with rapid acetylators

Standard INH for rapid acetylators

Participant with rapid acetylators(one of N-Acetyltransferase Type 2 Genotype) administered with standard chemotherapy (3 months HRZE followed by 9 months HRE with standard dose isoniazid )

Group Type: ACTIVE_COMPARATOR

Isoniazid

Intervention Type: DRUG

standard dose isoniazid or high dose isoniazid for participants with rapid acetylators

High dose INH for rapid acetylators

Participant with rapid acetylators(one of N-Acetyltransferase Type 2 Genotype) administered with high dose isonized treatment (3 months HRZE followed by 9 months HRE with high dose isoniazid)

Group Type: EXPERIMENTAL

Isoniazid

Intervention Type: DRUG

standard dose isoniazid or high dose isoniazid for participants with rapid acetylators

Interventions

Isoniazid

standard dose isoniazid or high dose isoniazid for participants with rapid acetylators

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Beijing Chest Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hongfei Duan, MD

Role: PRINCIPAL_INVESTIGATOR

Beijing Chest Hospital

Locations

Beijing Chest Hospital affiliated to Capital Medical University

Beijing, , China

Site Status: RECRUITING

Jiamusi Infectious Disease Hospital

Jiamusi, , China

Site Status: RECRUITING

Jiangxi Provincial Chest Hospital

Nanchang, , China

Site Status: RECRUITING

Zunyi Medical College affiliated Hospital

Zunyi, , China

Site Status: RECRUITING

Countries

China

Central Contacts

Hongfei Duan, MD

Role: CONTACT

duanhongfei@hotmail.com

13520728402

Lingling Shao, Master

Role: CONTACT

shaolinglinglky@163.com

15810187170

Facility Contacts

Hongfei Duan

Role: primary

Chao Qiu

Role: primary

Qilong Zhang

Role: primary

Jianyong Zhang

Role: primary

Other Identifiers

2018ZX10302302-004

Identifier Type: -

Identifier Source: org_study_id