Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202306908320967 Date of Approval: 06/06/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public 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)
Official scientific 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 describing the background and objectives of the trial Tuberculosis meningitis (TBM) is a devastating illness, killing and disabling more patients than any other form of TB. TBM is characterized by a progressive granulomatous inflammation of the meninges, often at the base of the brain, resulting in hydrocephalus, brain infarction, and death, if left untreated. Even among treated patients, outcomes are poor. Mortality ranges from 25 to 50% in adults without HIV, and exceeds 50% in individuals living with HIV co-infection, with most deaths occurring within the first month of presentation. Among patients who survive TBM, the majority suffer from serious neurologic disability, resulting in lost productivity and decreased quality of life. Despite these bleak outcomes, a paucity of data exists on the optimal approach to TBM treatment. The WHO recommended regimen for TBM consists of the same drugs and dosing as those used to treat pulmonary TB, only for a prolonged course of 9 to 12 months instead of 6 months. A Cochrane review in 2016 showed that risk of relapse was low and virtually identical (0.8%) in TBM patients who received 6 months versus longer than 6 months of therapy. Thus, there is no evidence base to support prolonging TBM treatment beyond 6 months. 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). The Primary Objective is 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
Type of trial RCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Tuberculosis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/07/2023
Actual trial start date
Anticipated date of last follow up 31/12/2025
Actual Last follow-up date
Anticipated target sample size (number of participants) 330
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Permuted block randomization Central randomisation by phone/fax Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Rifampicin Isoniazid Linezolid Pyrazinamide Ethambutol 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 A will used the study drugs for 24 weeks 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 165
Control Group Rifampicin Isoniazid Pyrazinamide Ethambutol Arm B: WHO Standard of Care: RIF 10 mg/kg + INH 5 mg/kg + ethambutol (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 A total of 36 weeks of study treatment Arm B: WHO SOC: RIF 10 mg/kg + INH 5 mg/kg + ethambutol (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 165 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
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 pregnancy while receivingstudy treatment and for 30 days after stopping study treatment 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). 80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) 15 Year(s) 80 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 04/05/2023 KEMRI SERU
Ethics Committee Address
Street address City Postal code Country
Mbagati Road, P.O. Box 54840 Nairobi 00200 Kenya
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
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) at 48 weeks 48 weeks
Secondary Outcome Modified Rankin Scale (all 7 levels) at 12, 24, 36, and 72 weeks 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) Modified Rankin Scale 5 or 6 at 12, 24, 36, 48 and 72 weeks Change in mRS from baseline to each of 12, 24, 36, 48, and 72 weeks Time to death over 48 and 72 weeks Proportion of participants with Grade 3 or higher AEs over 8 weeks Proportion of participants with a serious adverse event (SAE) over 8 weeks Proportion of participants who complete study treatments, which is defined as completing 168 doses within 185 days for Arm A and 252doses in 278 days for Arm B Proportion of participants with TBM IRIS (as defined in section 8.3) over 48 weeks Neurocognitive battery performance (e.g., Wechsler Adult Intelligence Scale Digit Symbol or Symbol Digit Modalities, Color Trails 1, Color Trails 2, Category Fluency, Hopkins Verbal Learning Test-Revised, Grooved Pegboard Bilateral, Finger-tapping Bilateral) at 24 and 48 weeks Patient Health Questionnaire (PHQ-9) total score and WHO DAS score at 24, 48, and 72 weeks Change in BMRC TBM grade at week 1. Time to coma clearance, which is defined as Glasgow Coma Score of 15 for ≥48 hours for hospitalized participants, over 4 weeks. 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 participa 12, 24, 36, 48, 72 weeks for various outcomes as indicated above.
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
KEMRI Walter Reed Project Hospital Road, P.O Box 1357 Kericho 20200 Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
National Institute of Allergy and Infectious Diseases 5601 Fishers Lane Rockville MD 20852 United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor National Institute of Allergy and Infectious Diseases 5601 Fishers Lane Rockville MD 20852 United States of America Government Body
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Deborah Langat deborah.langat@usamru-k.org +254714059596 Hospital Road, P.O Box 1357
City Postal code Country Position/Affiliation
Kericho 20200 Kenya Principal Investigator KEMRI Walter Reed Project
Role Name Email Phone Street address
Public Enquiries Charles Kilel Charles.kilel@usamru-k.org +254701920951 Hospital Road, P.o Box 1357
City Postal code Country Position/Affiliation
Kericho 20200 Kenya KEMRI Walter Reed Project
Role Name Email Phone Street address
Scientific Enquiries Deborah Langat Deborah.langat@usamru-k.org +254714059596 Hospital Road, P.O Box 1357
City Postal code Country Position/Affiliation
Kericho 20200 Kenya KEMRI Walter Reed Project
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Individual participant data that underlie results in the publication, after deidentification Study Protocol Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group. For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group. By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information