Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis

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