Tuberculous Meningitis Clinical Trial
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)
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).
Status | Recruiting |
Enrollment | 330 |
Est. completion date | May 10, 2027 |
Est. primary completion date | May 10, 2027 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 15 Years and older |
Eligibility | 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). |
Country | Name | City | State |
---|---|---|---|
Brazil | Hospital Nossa Senhora da Conceicao CRS (12201) | Porto Alegre | |
Brazil | Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (12101) | Rio De Janeiro | |
India | Byramjee Jeejeebhoy Government Medical College (BJMC) CRS (31441) | Pune | |
Kenya | Moi University Clinical Research Center (MUCRC) CRS (12601) | Eldoret | |
Kenya | Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (12501) | Kericho | |
Malawi | Malawi CRS | Lilongwe | |
Mexico | Nutrición-Mexico CRS | Mexico City | |
Peru | Barranco CRS | Lima | |
Philippines | De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC) (Site ID: 31981) | Cavite | |
South Africa | Durban International CRS | Durban | |
South Africa | University of the Witwatersrand Helen Joseph (WITS HJH) CRS | Johannesburg | |
Tanzania | Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118) | Moshi | |
Thailand | Siriraj Hospital, Mahidol University NICHD CRS (Site ID: 5115) | Bangkok | Bangkoknoi |
Thailand | Chiangrai Prachanukroh Hospital NICHD CRS | Chiang Mai | |
Vietnam | National Lung Hospital CRS (Site ID: 32483) | Vinh Phúc | Hanoi |
Zimbabwe | Milton Park CRS | Harare |
Lead Sponsor | Collaborator |
---|---|
National Institute of Allergy and Infectious Diseases (NIAID) |
Brazil, India, Kenya, Malawi, Mexico, Peru, Philippines, South Africa, Tanzania, Thailand, Vietnam, Zimbabwe,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Proportion of participants who relapsed by 12 and 24 weeks after completion of study treatments | At week 12 and 24 | ||
Other | Positive or negative CSF Xpert Ultra | At Day 3, week 2 and week 8 | ||
Other | Positive or negative CSF and urine LAM | At Day 3, weeks 2, 8 and 12 | ||
Other | Change in sterilization of CSF culture | At Weeks 2 and 6-8 | ||
Other | Change in CSF white blood cell count | At Weeks 2 and 6-8 | ||
Other | Change in CSF glucose | At Weeks 2 and 6-8 | ||
Other | Change in CSF blood glucose ratio | At Weeks 2 and 6-8 | ||
Other | Change in CSF protein | At Weeks 2 and 6-8 | ||
Primary | 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) | At 48 Weeks | ||
Secondary | Modified Rankin Scale (all 7 levels) | At weeks 12,24,36 and 72 | ||
Secondary | Modified Rankin Scale using collapsed categories at 12, 24, 36, 48 and 72 weeks: mRS (0 or 1), (2 or 3), (4 or 5), (6) | 12, 24, 36, 48 and 72 weeks | ||
Secondary | Modified Rankin Scale 5 or 6 | At 12, 24, 36, 48 and 72 weeks | ||
Secondary | Change in mRS from baseline to each of 12, 24, 36, 48, and 72 weeks | At 12, 24, 36, 48, and 72 weeks | ||
Secondary | Time to death over 48 and 72 weeks | At weeks 48 and 72 | ||
Secondary | Proportion of participants with Grade 3 or higher AEs over 8 weeks | At 8 weeks | ||
Secondary | Proportion of participants with a serious adverse event (SAE) over 8 weeks | At 8 weeks | ||
Secondary | Proportion of participants who complete study treatments, which is defined as completing 168 doses within 185 days for Arm A and 252 doses in 278 days for Arm B | At day 185 and day 278 | ||
Secondary | Proportion of participants with TBM IRIS (as defined in protocol) over 48 weeks | At week 48 | ||
Secondary | Wechsler Adult Intelligence Scale Digit Symbol or Symbol Digit Modalities | Neurocognitive battery performance | At week 24 and 48 | |
Secondary | Color Trails 1, 2 | Neurocognitive battery performance | At week 24 and 48 | |
Secondary | Category Fluency | Neurocognitive battery performance | At week 24 and 48 | |
Secondary | Hopkins Verbal Learning Test-Revised | Neurocognitive battery performance | At week 24 and 48 | |
Secondary | Grooved Pegboard Bilateral | Neurocognitive battery performance | At week 24 and 48 | |
Secondary | Finger-tapping Bilateral | Neurocognitive battery performance | At week 24 and 48 | |
Secondary | Patient Health Questionnaire (PHQ-9) total score | defined as Glasgow Coma Score of 15 for =48 hours for hospitalized participants over 4 weeks | At 24, 48, and 72 weeks | |
Secondary | WHO DAS score | defined as Glasgow Coma Score of 15 for =48 hours for hospitalized participants over 4 weeks | At 24, 48, and 72 weeks | |
Secondary | Change in BMRC TBM grade at week 1. BMRC TBM grade is defined as: | 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 |
At week 1 | |
Secondary | Time to coma clearance, which is defined as Glasgow Coma Score of 15 for =48 hours for hospitalized participants, over 4 weeks. | At week 4 | ||
Secondary | Time to new neurological event, which is defined as fall in Glasgow Coma Score of =2 points for =48 hours for hospitalized participants or since last visit for non-hospitalized participants, new onset seizures, new focal neurologic deficit | At week 48 | ||
Secondary | CSF to plasma ratio | At Day 3, Week 2, 6 or 8 | ||
Secondary | Rate of CSF uptake | At Day 3, Week 2, 6 or 8 | ||
Secondary | Plasma absorption rate constant (ka) | At Day 3, Week 2, 6 or 8 | ||
Secondary | Drug clearance (Cl/F) | At Day 3, Week 2, 6 or 8 | ||
Secondary | Volume of distribution (Vd) | At Day 3, Week 2, 6 or 8 | ||
Secondary | Post-hoc Bayesian predictions of secondary parameters Cmax | At Day 3, Week 2, 6 or 8 | ||
Secondary | Time to Cmax | At Day 3, Week 2, 6 or 8 | ||
Secondary | Time to AUC0-24 | At Day 3, Week 2, 6 or 8 | ||
Secondary | Time to plasma elimination half-life | At Day 3, Week 2, 6 or 8 | ||
Secondary | Time to CSF elimination half-life | At Day 3, Week 2, 6 or 8 |
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