Brief Title
Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis
Official Title
Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis Based on N-Acetyltransferase Type 2 Genotyping
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.
Study Type
Interventional
Primary Outcome
Number of Participants with death or severe disability
Secondary Outcome
days for coma-clearance time
Condition
Tuberculous Meningitis
Intervention
Isoniazid
Study Arms / Comparison Groups
Standard INH for Non-rapid acetylators
Description: 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)
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
676
Start Date
March 4, 2019
Completion Date
December 31, 2021
Primary Completion Date
December 31, 2021
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.
Gender
All
Ages
18 Years - 65 Years
Accepts Healthy Volunteers
No
Contacts
Hongfei Duan, MD, 13520728402, [email protected]
Location Countries
China
Location Countries
China
Administrative Informations
NCT ID
NCT03787940
Organization ID
2018ZX10302302-004
Responsible Party
Sponsor
Study Sponsor
Beijing Chest Hospital
Study Sponsor
Hongfei Duan, MD, Principal Investigator, Beijing Chest Hospital
Verification Date
January 2021