NCT03787940

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.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
676

participants targeted

Target at P75+ for not_applicable

Timeline
Completed

Started Mar 2019

Typical duration for not_applicable

Geographic Reach
1 country

4 active sites

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

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Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

November 19, 2018

Completed
1 month until next milestone

First Posted

Study publicly available on registry

December 27, 2018

Completed
2 months until next milestone

Study Start

First participant enrolled

March 4, 2019

Completed
2.8 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 31, 2021

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 31, 2021

Completed
Last Updated

February 1, 2021

Status Verified

January 1, 2021

Enrollment Period

2.8 years

First QC Date

November 19, 2018

Last Update Submit

January 28, 2021

Conditions

Tuberculous Meningitis

Keywords

N-Acetyltransferase Type 2 GenotypetreatmentTuberculous Meningitis

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (6)

  • days for coma-clearance time

    through study completion,up to 1 year

  • days for fever-clearance time

    through study completion,up to 1 year

  • difference of CSF protein concentration

    3 months after enrollment

  • difference of CSF glucose concentration

    3 months after enrollment

  • difference of CSF white cell counts

    3 months after enrollment

  • +1 more secondary outcomes

Study Arms (3)

Standard INH for Non-rapid acetylators

ACTIVE COMPARATOR

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)

Drug: Isoniazid

Standard INH for rapid acetylators

ACTIVE COMPARATOR

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 )

Drug: Isoniazid

High dose INH for rapid acetylators

EXPERIMENTAL

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)

Drug: Isoniazid

Interventions

IsoniazidDRUG

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

High dose INH for rapid acetylatorsStandard INH for Non-rapid acetylatorsStandard INH for rapid acetylators

Eligibility Criteria

Age18 Years - 65 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • to 65 years of age;
  • Clinical diagnosis of TBM;
  • Able and willing to provide informed consent to participate in the study.

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (4)

Beijing Chest Hospital affiliated to Capital Medical University

Beijing, China

RECRUITING

Jiamusi Infectious Disease Hospital

Jiamusi, China

RECRUITING

Jiangxi Provincial Chest Hospital

Nanchang, China

RECRUITING

Zunyi Medical College affiliated Hospital

Zunyi, China

RECRUITING

MeSH Terms

Conditions

Tuberculosis, Meningeal

Interventions

Isoniazid

Condition Hierarchy (Ancestors)

Meningitis, BacterialCentral Nervous System Bacterial InfectionsBacterial InfectionsBacterial Infections and MycosesInfectionsTuberculosis, Central Nervous SystemTuberculosis, ExtrapulmonaryTuberculosisMycobacterium InfectionsActinomycetales InfectionsGram-Positive Bacterial InfectionsCentral Nervous System InfectionsCentral Nervous System DiseasesNervous System DiseasesMeningitisNeuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

HydrazinesOrganic ChemicalsIsonicotinic AcidsAcids, HeterocyclicHeterocyclic CompoundsPyridinesHeterocyclic Compounds, 1-Ring

Study Officials

  • Hongfei Duan, MD

    Beijing Chest Hospital

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Hongfei Duan, MD

CONTACT

13520728402duanhongfei@hotmail.com

Lingling Shao, Master

CONTACT

15810187170shaolinglinglky@163.com

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
DOUBLE
Who Masked
PARTICIPANT, CARE PROVIDER
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

November 19, 2018

First Posted

December 27, 2018

Study Start

March 4, 2019

Primary Completion

December 31, 2021

Study Completion

December 31, 2021

Last Updated

February 1, 2021

Record last verified: 2021-01

Locations

CN(4)