Clinical trial NCT05383742: 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)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Tuberculous Meningitis
Keywords: Tuberculosis, meningeal
Tuberculosis
CNS Disease
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2022-05-20
Enrollment: 330
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 British Medical Research Council (BMRC) Classification TBM Grade.

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 BMRC TBM grade 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).

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
* 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.
* 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 who are ART-naïve or who are not regularly taking ART, planned initiation or reinitiation of ART during screening or during the first 4 weeks after initiation of TB therapy
* 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).

Primary outcomes:
measure: 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)
timeFrame: At 48 weeks
Secondary outcomes:
measure: Modified Rankin Scale (all 7 levels)
timeFrame: At 0, 12, 24, 36, 48 and 72 weeks
measure: Modified Rankin Scale using collapsed categories: mRS (0 or 1), (2 or 3), (4 or 5), (6)
timeFrame: At 12, 24, 36, 48 and 72 weeks
measure: Modified Rankin Scale 5 or 6
timeFrame: At 12, 24, 36, 48 and 72 weeks
measure: Time to death through 48 and 72 weeks
timeFrame: At weeks 48 and 72
measure: Proportion of participants with Grade 3 or higher AEs
timeFrame: At 4, 8 and 24 weeks
measure: Proportion of participants with a serious adverse event (SAE)
timeFrame: At 4, 8 and 24 weeks
measure: Proportion of participants with study treatment discontinuations
timeFrame: At 4, 8 and 24 weeks
measure: Proportion of participants who complete study treatments
timeFrame: At 185 and 278 days
measure: Proportion of participants with TBM IRIS or paradoxical worsening
timeFrame: At 48 weeks
measure: Wechsler Adult Intelligence Scale Digit Symbol
timeFrame: At 24 and 48 weeks
measure: Color Trails 1
timeFrame: At 24 and 48 weeks
measure: Color Trails 2
timeFrame: At 24 and 48 weeks
measure: Category Fluency
timeFrame: At 24 and 48 weeks
measure: Hopkins Verbal Learning Test-Revised
timeFrame: At 24 and 48 weeks
measure: Grooved Pegboard Bilateral
timeFrame: At 24 and 48 weeks
measure: Finger-tapping Bilateral
timeFrame: At 24 and 48 weeks
measure: Patient Health Questionnaire (PHQ-9) total score
timeFrame: At 24, 48, and 72 weeks
measure: WHO DAS score
timeFrame: At 24, 48, and 72 weeks
measure: Change in BMRC TBM grade at week 1
timeFrame: At 1 week
measure: Time to coma clearance
timeFrame: At 4 weeks
measure: Time to new neurological event
timeFrame: At 48 weeks
Other outcomes:
measure: Proportion of participants with recurrence
timeFrame: At 36 and 48 weeks
measure: Positive or negative CSF Xpert Ultra
timeFrame: At screening, Day 3 and week 2 or week 6 or week 8
measure: Positive or negative CSF and urine LAM
timeFrame: At screening, Day 3 and week 2 or week 6 or week 8
measure: Functional outcomes and mortality in definite TBM patients
timeFrame: At 72 weeks
measure: Association of TBM host immune signatures and functional outcomes and treatment response
timeFrame: At 72 weeks
measure: Change in sterilization of CSF culture
timeFrame: At Weeks 2 and 6-8
measure: Change in CSF white blood cell count
timeFrame: At Weeks 2 and 6-8
measure: Change in CSF glucose
timeFrame: At Weeks 2 and 6-8
measure: Change in CSF blood glucose ratio
timeFrame: At Weeks 2 and 6-8
measure: Change in CSF protein
timeFrame: At Weeks 2 and 6-8
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao CRS (Site ID: 12201)
city: Rio De Janeiro
country: Brazil
facility: Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (Site ID: 12101)
city: Pune
country: India
facility: Byramjee Jeejeebhoy Government Medical College (BJMC) CRS (Site ID: 31441)
city: Eldoret
country: Kenya
facility: Moi University Clinical Research Center (MUCRC) CRS (Site ID: 12601)
city: Kericho
country: Kenya
facility: Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (Site ID: 12501)
city: Lilongwe
country: Malawi
facility: Malawi CRS (Site ID: 12001)
city: Mexico City
country: Mexico
facility: Nutrición-Mexico CRS (Site ID: 32078)
city: Lima
country: Peru
facility: Socios en Salud Sucursal Peru CRS (Site ID: 31985)
city: Lima
country: Peru
facility: Barranco CRS (Site ID:11301)
city: Cavite
country: Philippines
facility: TB HIV Innovations and Clinical Research Foundation Corp (Site ID: 31981)
city: Durban
country: South Africa
facility: Durban International CRS (Site ID:11201)
city: Johannesburg
country: South Africa
facility: University of the Witwatersrand Helen Joseph (WITS HJH) CRS (Site ID: 11101)
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118)
city: Bangkok
country: Thailand
facility: Siriraj Hospital, Mahidol University NICHD CRS (Site ID: 5115)
state: Bangkoknoi
city: Bangkok
country: Thailand
facility: Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site ID: 31802)
state: Pathumwan
city: Chiang Mai
country: Thailand
facility: Chiangrai Prachanukroh Hospital NICHD CRS (Site ID: 5116)
city: Vĩnh Phúc
country: Vietnam
facility: National Lung Hospital CRS (Site ID: 32483)
state: Hanoi
city: Harare
country: Zimbabwe
facility: Milton Park CRS (Site ID: 30313)
Study officials:
References: