Trial of a Six-Month Regimen of High-Dose Rifampicin, High-Dose Isoniazid, Linezolid, and Pyrazinamide Versus a Standard Nine-Month Regimen for the Treatment of Adults and Adolescents With Tuberculous Meningitis

Learn more about:
Related Clinical Trial
Trial of a Six-Month Regimen of High-Dose Rifampicin, High-Dose Isoniazid, Linezolid, and Pyrazinamide Versus a Standard Nine-Month Regimen for the Treatment of Adults and Adolescents With Tuberculous Meningitis Cyclophosphamide in the Treatment of Refractory Proliferative Arachnoiditis in CNS Tuberculosis Evaluation of New Biomarker-based Approaches for Improving the Diagnosis of Childhood Tuberculous Meningitis Retrospective Real-word Study of Linezolid for the Treatment of Tuberculous Meningitis Study Of The Long Term Outcome Of Tuberculous Meningitis In Vietnamese Adults Treated With Adjunctive Dexamethasone Adjunctive Corticosteroids for Tuberculous Meningitis in HIV-infected Adults (The ACT HIV Trial) The Relationships Between Gene Polymorphisms of LTA4H and Dexamethasone Treatment for Tuberculous Meningitis Linezolid, Aspirin and Enhanced Dose Rifampicin in HIV-TBM Leukotriene A4 Hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-uninfected Adults With Tuberculous Meningitis Diagnosis of Tuberculous Meningitis by ESAT-6 in CSF Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis Optimizing Antituberculosis Therapy in Adults With Tuberculous Meningitis A Pilot Study of Adjunctive Aspirin for the Treatment of HIV Negative Adults With Tuberculous Meningitis Rifampicin Explorative PK Study for Tuberculous Meningitis Comparing Oral and Intravenous Preparation Immediate Versus Deferred Antiretroviral Therapy for HIV-Associated Tuberculous Meningitis

Brief Title

Trial of a Six-Month Regimen of High-Dose Rifampicin, High-Dose Isoniazid, Linezolid, and Pyrazinamide Versus a Standard Nine-Month Regimen for the Treatment of Adults and Adolescents With Tuberculous Meningitis

Official Title

A Phase II, Randomized, Open-Label Trial of a Six-Month Regimen of High-Dose Rifampicin, High-Dose Isoniazid, Linezolid, and Pyrazinamide Versus a Standard Nine-Month Regimen for the Treatment of Adults and Adolescents With Tuberculous Meningitis: Improved Management With Antimicrobial AGents Isoniazid rifampiciN LinEzolid for TBM (IMAGINE-TBM)

Brief Summary

      The purpose of this study is to compare a 6-month regimen of high-dose rifampicin (RIF),
      high-dose isoniazid (INH), linezolid (LZD), and pyrazinamide (PZA) versus the World Health
      Organization (WHO) standard of care (SOC) treatment for tuberculosis meningitis (TBM).
    

Detailed Description

      Rationale: TBM is a devastating illness with high risk of mortality and severe neurologic
      morbidity. Although recent data suggest that significant dose increases in RIF may improve
      outcomes in TBM, mortality remains high, and enhanced treatment strategies are needed. In
      addition, limited data are available to guide treatment duration in adults with TBM. The
      overall goal of this Phase II, randomized, open-label trial is to assess the PK, safety, and
      longitudinal treatment outcomes of an optimized 6-month regimen of high-dose RIF, high-dose
      INH, LZD, and PZA to the WHO 9-month SOC regimen for the treatment of TBM.

      Primary objective: To determine if a regimen of high-dose RIF, high-dose INH, LZD, and PZA
      improves functional outcomes measured by the modified Rankin Scale (mRS) at 48 weeks compared
      with WHO SOC for the treatment of TBM.

      Design: Participants with definite, probable, or possible TBM will be randomized to one of
      the two study arms below and randomization will be stratified by HIV status and stage of
      disease as defined by the modified BMRC criteria.

      Arm A: RIF 35 mg/kg + INH 15 mg/kg + LZD 1200 mg + PZA 25 mg/kg for 2 weeks, followed by RIF
      35 mg/kg + INH 10 mg/kg + LZD 1200 mg + PZA 25 mg/kg for 6 weeks, and then RIF 35 mg/kg and
      INH 10 mg/kg for 16 weeks, for a total of 24 weeks of study treatment.

      Arm B: WHO SOC: RIF 10 mg/kg + INH 5 mg/kg + EMB 20 mg/kg + PZA 25 mg/kg for 8 weeks,
      followed by RIF 10 mg/kg and INH 5 mg/kg for 28 weeks, for a total of 36 weeks of study
      treatment. Up to 15 mg/kg or a maximum of 900 mg daily of oral RIF will be permitted in this
      arm at clinician's discretion.

      All participants in Arms A and B will receive pyridoxine, while receiving INH, and adjunctive
      corticosteroids according to disease severity for at least 6 weeks.

      All participants in Arms A and B will be followed from randomization to week 72.

      Procedures: Study visits will include interval history, blood collection for laboratory
      testing, peripheral neuropathy screening, visual acuity, color vision, and contrast
      sensitivity visual testing to monitor for AEs. Lumbar puncture will be performed for
      assessments of CSF microbiology, LAM and other biomarkers. Optional collection and storage of
      blood and storage of remaining CSF for future testing will occur. Urine will be obtained for
      LAM assessment. Plasma and CSF PK assessments will be performed. Participants will undergo
      assessment of functional status with the mRS and WHO DAS 2.0. Participants will also be
      assessed with a neurocognitive battery and depression questionnaire (PHQ-9).
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Modified Rankin Scale (6-death, 5-severe disability, 4-moderately severe disability, 3-moderate disability, 2-slight disability, 1-no significant disability, 0-no symptoms)

Secondary Outcome

 Modified Rankin Scale (all 7 levels)

Condition

Tuberculous Meningitis

Intervention

Rifampicin (RIF)

Study Arms / Comparison Groups

 Arm A
Description:  RIF 35 mg/kg + INH 15 mg/kg + LZD 1200 mg + PZA 25 mg/kg for 2 weeks, followed by RIF 35 mg/kg + INH 10 mg/kg + LZD 1200 mg + PZA 25 mg/kg for 6 weeks, and then RIF 35 mg/kg and INH 10 mg/kg for 16 weeks, for a total of 24 weeks of study treatment.

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

330

Start Date

October 14, 2022

Completion Date

August 2, 2026

Primary Completion Date

August 2, 2026

Eligibility Criteria

        Inclusion Criteria:

          -  Definite, probable, or possible TBM diagnosis wherein the participant is being
             committed to a full course of SOC anti-TB treatment for TBM in the setting of routine
             care. CSF, imaging, laboratory, and other results used to determine definite,
             probable, or possible TBM can be from testing performed as part of routine care, as
             long as obtained within 21 days prior to study entry

          -  Persons aged ≥15 years

          -  Absence of HIV-1 infection, as documented by any licensed rapid HIV test or HIV-1
             enzyme or chemiluminescence immunoassay (E/CIA) test kit, within 30 days prior to
             study entry, OR

          -  HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test kit at
             any time prior to entry and confirmed by a licensed Western blot or a second antibody
             test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or
             plasma HIV-1 RNA viral load. Two or more HIV-1 RNA viral loads of >1,000 copies/mL are
             also acceptable as documentation of HIV-1 infection, or documentation of HIV diagnosis
             in the medical record by a healthcare provider

          -  Documentation within 3 days prior to study entry of stage of disease using BMRC TBM
             grade:

          -  Grade I: Glasgow Coma Score 15, no focal neurological deficits

          -  Grade II: Glasgow Coma Score 11-14 or 15 with focal neurological deficits

          -  Grade III: Glasgow Coma Score ≤10

          -  The following laboratory values obtained within 3 days prior to study entry:

               -  Serum creatinine ≤1.8 times upper limit of normal (ULN)

               -  Hemoglobin ≥8.0 g/dL for men, ≥7.5 g/dL for women

               -  Absolute neutrophil count ≥600/mm3

               -  Platelet count ≥60,000/mm3

               -  Alanine aminotransferase (ALT) ≤3 x ULN

               -  Total bilirubin ≤2 x ULN

          -  For participants of reproductive potential who have not been post-menopausal for at
             least 24 consecutive months (i.e., no menses within the preceding 24 months), or
             participants who have not undergone surgical sterilization, hysterectomy, bilateral
             salpingectomy, bilateral oophorectomy, or tubal ligation, documentation of a serum or
             urine pregnancy test result (positive or negative; see protocol for test sensitivity
             requirement) within 21 days prior to study entry

          -  Participants with documentation of a positive pregnancy test will be consented using
             the consent form for pregnant participants.

        Participants of reproductive potential with documentation of a negative pregnancy test must
        agree to use at least one acceptable form of contraception, or abstain from sexual activity
        that could lead to pregnancy while receiving study treatment and for 30 days after stopping
        study treatment.

        Participants who are not of reproductive potential or whose partner(s) has documented
        azoospermia are not required to use contraception. Any statement of self-reported sterility
        or that of the partner's must be entered in the source documents

          -  Ability and willingness of participant or parent or legally authorized representative
             (for adolescents or participants unable to provide consent) to provide informed
             consent/assent

          -  Ability to comply with the protocol requirements in the opinion of the site
             investigator

        Exclusion Criteria:

          -  More than 14 cumulative days of first-line TB medications, including but not limited
             to INH, RIF, EMB, and PZA, received within 90 days prior to study entry

          -  Known current or previous drug resistant TB infection (i.e., resistance to one or more
             first-line TB medications, including but not limited to INH, RIF, EMB, LZD and PZA)

          -  Known allergy/sensitivity or any hypersensitivity to components of study TB drugs
             (INH, RIF, LZD, PZA, and EMB) or their formulation

          -  For participants who are able to undergo the Brief Peripheral Neuropathy Screen (BPNS)
             within 21 days prior to study entry, Grade 3 subjective peripheral neuropathy score on
             the BPNS AND EITHER vibratory loss OR absent ankle jerks

          -  Expected concomitant use or use up to 21 days prior to study entry of monoamine
             oxidase inhibitors or selective serotonin reuptake inhibitors, or concomitant use of
             any other drug with significant interaction with the study drugs (See protocol)

          -  For participants with HIV and ART-naïve, planned initiation of ART during the first 4
             weeks after randomization

          -  For participants with HIV and on ART that includes a protease inhibitor, nevirapine,
             or other prohibited ART (see protocol), contraindication to switching to an acceptable
             alternative regimen (e.g., efavirenz, high-dose raltegravir or dolutegravir with
             nucleoside reverse transcriptase inhibitors, as per local SOC) prior to randomization.
             TB treatment, including study drugs, should be started as soon as possible

          -  Contraindication to LP at discretion of treating clinician (e.g., unequal pressures
             between intracranial compartments due to mass lesion, non-communicating hydrocephalus)

          -  Positive cryptococcal antigen, gram stain, bacterial culture, or other test result
             obtained from a CSF specimen collected within 21 days prior to entry as part of
             routine care indicating CNS infection with a pathogen other than Mtb (e.g.,
             cryptococcal meningitis, bacterial meningitis).
      

Gender

All

Ages

15 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, (301) 628-3348, [email protected]

Location Countries

Brazil

Location Countries

Brazil

Administrative Informations


NCT ID

NCT05383742

Organization ID

A5384


Responsible Party

Sponsor

Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

, , 


Verification Date

September 2022