| Protocol No: | ECCT/23/05/02 | Date of Protocol: | 03-11-2021 |
| Study 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) |
| 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 Objectives: |
1.2 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.
1.3 Secondary Objectives
1.3.1 To determine if a regimen of high-dose RIF, high-dose INH, LZD, and PZA improves functional outcomes measured by the mRS at 12, 24, 36, and 72 weeks compared with WHO SOC for the treatment of TBM.
1.3.2 To determine if a regimen of high-dose RIF, high-dose INH, LZD, and PZA improves longitudinal functional outcomes compared with WHO SOC for the treatment of TBM.
1.3.3 To determine if a regimen of high-dose RIF, high-dose INH, LZD, and PZA improves mortality at 48 and 72 weeks compared with WHO SOC for the treatment of TBM.
1.3.4 To determine the safety and tolerability of administration of high-dose RIF, high-dose INH, LZD, and PZA at 8 weeks for the treatment of TBM.
1.3.5 To compare neurocognitive outcomes at 24 and 48 weeks in participants randomized to high-dose RIF, high-dose INH, LZD, and PZA versus WHO SOC.
1.3.6 To evaluate the effect of high-dose RIF on the cerebrospinal fluid (CSF) and plasma pharmacokinetics (PK) of LZD.
1.3.7 To determine if RIF, INH, LZD, and PZA exposures in CSF and plasma predict functional outcomes and mortality.
1.3.8 To compare Patient Health Questionnaire (PHQ-9) total score and WHO Disability Assessment Schedule (WHO DAS) score at 24, 48, and 72 weeks.
1.3.9 To compare change in BMRC TBM grade at week 1.
1.3.10 To compare time to coma clearance, which is defined as Glasgow Coma Score of 15 for ≥48 hours for hospitalized participants over 4 weeks.
1.3.11 To compare 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 over 48 weeks.
1.3.12 To determine if a regimen of high-dose RIF, high-dose INH, LZD, and PZA improves functional outcomes measured by the mRS at 48 weeks compared with WHO SOC for the treatment of TBM among those with definite TB meningitis and among those with definite or probable TB meningitis.
1.4 Exploratory Objectives
1.4.1 To compare relapse rates 12 weeks after completion of study treatment between a 24-week treatment regimen versus the 36-week WHO SOC regimen.
1.4.2 To evaluate the CSF microbiologic, molecular and inflammatory response to high-dose RIF, high-dose INH, LZD, and PZA versus WHO SOC at 2 weeks and 6-8 weeks in TBM.
1.4.3 To investigate the value of Xpert Ultra and semiquantitative testing for lipoarabinomannan (LAM) in CSF and urine for the diagnosis and treatment monitoring of TBM.
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| Laymans Summary: | 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 the proposed 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. |
| 1 | A. Use of Feeding Tubes Reason: To address the necessity of feeding tubes, such as nasogastric (NG) tubes, for administering medications to patients with tuberculous meningitis (TBM). Details: • TBM patients often have impaired consciousness and cannot swallow, necessitating the use of NG tubes for medication administration. • Vital anti-TB medications and corticosteroids can be administered through these tubes. • Clinical trials (ClinicalTrials.gov IDs NCT04021121, NCT03537495, NCT04145258) and completed studies have routinely allowed and relied on the use of feeding tubes. • A significant percentage of participants in these trials have received medications via NG tubes, indicating its necessity for patient treatment. • Protocol sections 5.1.2, 5.2, and 11.2.1 have been updated to address the use of feeding tubes in the A5384 trial. B. Permitting Crushing of Study Drugs Reason: To include language allowing the crushing of study drugs for administration via feeding tubes. Details: • The practice of using NG tubes to administer crushed medications is common in both clinical and trial settings for TBM. • Although data is limited, existing studies suggest that crushing medications does not significantly impact pharmacokinetics for most anti-TB drugs. • Specific findings: • Rifampin: Studies show expected drug exposure levels even with crushed medications. • Isoniazid: Limited data suggest a lower absorption when crushed and mixed with water, but these studies did not involve TBM patients or NG tubes. • Linezolid, Pyrazinamide, Ethambutol: No significant impact on drug exposures when crushed. • No dose adjustments are necessary based on current data, but strategies like additional flushing of the NG tube can minimize drug loss. • Data on medication form (whole or crushed) and administration method (oral or NG tube) will be recorded to analyze their effects on drug exposure and clinical outcomes. C. Information in Consent Forms Reason: To inform participants and their guardians about the administration of study treatments via enteral feeding tubes. Details: • Changes in the sample informed consent, sample parental informed consent, and sample assent form will include information on the use of feeding tubes for participants unable to swallow medications. • These changes ensure transparency and provide necessary information for informed decision-making by participants and their families. These amendments aim to ensure effective and safe administration of essential medications to TBM patients, reflecting current clinical practices and trial protocols. |
| 3 | Reasons for the Amendment: • Update secondary/exploratory objectives and outcomes. • Revise schedule of evaluations (SOE). • Add drug administration instructions for critically ill participants. • Update adverse event (AE) collection, including elevated creatinine. • Revise interim monitoring frequency by the Data and Safety Monitoring Board (DSMB). • Add toxicity management for DILI, hyperbilirubinemia, and lactic acidosis. • Update tuberculosis meningitis (TBM) immune reconstitution inflammatory syndrome (IRIS) management. • Clarify pharmacology study design and pharmacokinetic (PK) outcome measures. • Incorporate Amendment #1 (dated 10May2024). • Add informed consent attachments for optional procedures and parental consent. Key Changes: 1. Cover Page & Sections: Updated team roster, glossary, and study management. 2. Schema Revision: Corrected drug regimen for Arm B (Weeks 1-2, Weeks 3-8). 3. Secondary Objectives/Outcomes: Updated time points and added new objectives, including comparison of TBM-IRIS/paradoxical reactions. 4. Language Adjustments: Changed “relapse” to “recurrence” and added new exploratory objectives on metagenomic sequencing and transcriptomics. 5. Safety Information: Added background on RIF and LZD use, safety data on TBM, and medication inclusion/exclusion criteria. 6. Study Design: Allowed other TB medications for toxicity management, added language on nasogastric tubes for drug administration. 7. Eligibility Criteria: Clarified HIV-positive participants' ART requirements, and excluded co-enrollment in A5243. 8. Evaluations: Added diabetes screening, blood chemistry/electrolyte evaluations, and lactate tests. 9. Adverse Events (AEs): Updated AE collection guidelines and included language for rare toxicities (DILI, hyperbilirubinemia). 10. Pharmacokinetics (PK): Updated PK sampling details, including new options for sparse PK sampling. 11. Clinical Management: Added details for managing adverse effects (e.g., thrombocytopenia, gastrointestinal toxicity, and lactic acidosis). 12. Sample Informed Consent (SIC): Updated informed consent documents to reflect new risks, optional procedures (e.g., metagenomic testing), and sample collection guidelines. 2. State the justification/rationale for each amendment proposed: 3. • Update Secondary and Exploratory Objectives and Outcomes: Justification: To ensure the study objectives reflect current research needs and scientific understanding. This update ensures more accurate and meaningful data collection. 4. • Update the Schedule of Evaluations (SOE): Justification: To align the evaluation time points with updated study objectives and new clinical findings, ensuring more precise monitoring of participant outcomes. 5. • Add Study Drug Administration Instructions for Critically Ill Participants: Justification: Critical patients may require specific instructions for administering study drugs to ensure safety and efficacy. This amendment ensures proper management in such cases. 6. • Update Language on Collection and Reporting of Adverse Events (AEs), including Elevated Creatinine: Justification: To provide clearer guidelines on how adverse events should be tracked and reported, ensuring comprehensive safety monitoring throughout the study. 7. • Update Interim Monitoring Frequency by the Data and Safety Monitoring Board (DSMB): Justification: To enhance oversight and provide timely safety reviews, ensuring the study is conducted ethically and risks to participants are minimized. 8. • Add Toxicity Management for Drug-Induced Liver Injury (DILI), Hyperbilirubinemia without DILI, and Lactic Acidosis: Justification: To address specific risks associated with the study drugs, ensuring appropriate measures are in place to manage these potential side effects. 9. • Update Management of TBM IRIS and Paradoxical Reactions: Justification: To ensure that participants with TBM IRIS or paradoxical reactions receive the most effective and up-to-date treatment, improving patient safety and outcomes. 10. • Clarify Pharmacology Study Design and Analyses for Pharmacokinetic (PK) Outcome Measures: Justification: To improve the clarity and accuracy of pharmacokinetic studies, ensuring that PK outcomes are properly measured and analyzed. 11. • Incorporate Previous Letter of Amendment #1, dated 10May2024: Justification: To include any previously approved amendments that were not integrated into the main protocol at the time of initial approval. 12. • Add Sample Informed Consent (SIC) Attachments for Optional Procedures and Parental Consent for Optional Procedures: Justification: To provide participants with clear, updated consent forms for optional procedures and to include necessary parental consent where required, ensuring ethical study conduct. 13. • Cover Page, Team Roster, Study Management, and Glossary Updates: Justification: To ensure all administrative and logistical details are current and clearly defined, promoting study organization and clarity. 14. • Correction to Drug Regimen in Schema Figure 1 (Arm B, Weeks 1-2, and Weeks 3-8): Justification: To correct any discrepancies in the dosing schedule to ensure accuracy and consistency in drug administration throughout the study. 15. • Update Secondary Objectives and Outcome Measures: Justification: To ensure that all secondary outcomes align with study objectives and scientific goals, providing more accurate results. 16. • Division of Secondary Objective 1.3.4 into Two Objectives: Justification: To separate safety and tolerability measures into distinct objectives for clearer data collection and analysis. 17. • Addition of Objective to Compare TBM-IRIS or Paradoxical Worsening over 48 Weeks: Justification: To explore long-term outcomes of TBM-IRIS and provide valuable data for managing these conditions over extended periods. 18. • Update Language for "Relapse" to "Recurrence": Justification: To standardize terminology throughout the protocol and ensure consistency in the study language. 19. • Addition of Exploratory Objectives for Metagenomic Sequencing, Transcriptomics, and Profiling: Justification: To include advanced diagnostic and research techniques that could provide deeper insights into TBM and the study's pharmacological effects. 20. • Add Background Information on High-Dose RIF and LZD: Justification: To provide updated scientific justification for the use of these drugs in the treatment of TBM, improving the study’s clinical relevance. 21. • Add Information on RIF Safety, Tolerability, DILI, and Hyperbilirubinemia: Justification: To ensure comprehensive monitoring of potential drug-related side effects, enhancing participant safety. 22. • Clarify Rationale for Including Pregnant Women and Adolescents: Justification: To provide justification for including these vulnerable populations, ensuring that their participation is both safe and necessary for the study. 23. • Allow Use of Alternative TB Medications for Toxicity Management: Justification: To ensure that participants receive effective treatment in case of adverse reactions to study medications. 24. • Updated Exclusion Criterion for ART-Naïve HIV Participants: Justification: To clarify the eligibility of HIV-positive participants who are not consistently on ART, ensuring participant safety. 25. • Removal of Co-enrollment in A5243 for Non-US Sites: Justification: A5243 study has closed to accrual, so participants can no longer be co-enrolled, ensuring compliance with study guidelines. 26. • Changes to Weight and Medication Dosing for Participants: Justification: To ensure accurate drug dosing based on weight, particularly for participants in critical conditions. 27. • Updated Informed Consent for Optional and Research Procedures: Justification: To ensure participants have clear, updated information about optional procedures and research activities, protecting their autonomy and informed consent rights. |
| Abstract of Study: |
DESIGN
A5384 is a Phase II randomized, open-label trial to compare a 6-month regimen of high-dose rifampicin (RIF), high-dose isoniazid (INH), linezolid (LZD), and pyrazinamide (PZA) to the World Health Organization (WHO) 9-month standard of care (SOC) regimen for the treatment of tuberculous meningitis (TBM).
DURATION
72 weeks
SAMPLE SIZE
330 participants
POPULATION
Participants living with and without HIV co-infection, with definite, probable, or possible TBM, aged ≥15 years.
STRATIFICATION
Participants will be stratified by HIV status and TBM disease stage, as defined by the modified British Medical Research Council (BMRC) Classification 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
REGIMEN
Participants will be randomized 1:1 to one of two arms:
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 + 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.
All participants will receive pyridoxine, while on INH, and adjunctive corticosteroids (as provided by standard of care [SOC], not provided by the study) according to disease severity for at least 6 weeks.
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