Intensified Short Course Regimen for TBM in Adults (INSHORT)

Comparative Evaluation of Intensified Short Course Regimen and Standard Regimen for Adults TB Meningitis : an Open-label Randomized Controlled Trial

Tuberculous meningitis (TBM) is the most lethal form of extra pulmonary tuberculosis. This devastating disease kills almost a third of its sufferers and disables a significant proportion of the survivors. TBM poses one of the most difficult diagnostic and therapeutic challenges in modern clinical practice. High-quality robust clinical trials have made a considerable contribution to the treatment of pulmonary tuberculosis in the last four decades. However, evidence from such clinical trials is lacking in TBM and the treatment remains uncertain. There is a significant variation in the choice, dose and duration of drugs between countries, institutions and clinicians. Investigators propose a multi-centric open-label clinical trial to assess the efficacy of short-course anti-TB drugs with high dose rifampicin, and moxifloxacin along with conventional anti-TB drugs and adjuvant therapy with aspirin and corticosteroids. Controls will receive standard treatment as per national guidelines for TBM. The investigators also aim to assess the safety and tolerability of high-dose Rifampicin and Moxifloxacin and the Pharmacodynamics and Pharmacokinetics parameters of ATT (Rifampicin, INH, Moxifloxacin and Pyrazinamide) in CSF between the two groups

Study Overview

• Status: Not yet recruiting
• Conditions: Tuberculous Meningitis
• Intervention / Treatment: Drug: High dose rifampicin (25mg/kg); Drug: Moxifloxacin 400mg; Drug: Aspirin 150 mg; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Steroid; Drug: Rifampicin; Drug: HRZE; Drug: HRE

• Study Type: Interventional
• Enrollment (Estimated): 372
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Dr Leeberk Raja Inbaraj, MBBS MD; Phone Number: 044-28369527; Email: leeberk.raja@icmr.gov.in
• Study Contact Backup: Name: Dr Bella Devaleenal, MBBS MPH; Phone Number: 044-28369538; Email: belladevalleenal.d@icmr.gov.in

Study Locations

• India
  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600031
      • ICMR- National Institute for Research in Tuberculosis
      • Contact: Dr Padmapriyadarsini Chandrasekaran, MBBS DNB MS PhD; Phone Number: 044-28369500; Email: nirtdirector@icmr.gov.in

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

A patient will be eligible for entry to the trial if ALL of the following conditions are satisfied

1. Adults (> 18 years) with or without HIV infection
2. Possible, probable or definite TBM according to Lancet consensus diagnostic criteria
3. Willing to give written informed consent
4. Is willing to have an HIV test.
5. Residing within 100 km of the study sites
6. Express willingness to attend the treatment centre for supervised treatment
7. Express willingness to adhere to the trial procedures and follow-up schedule.
8. Agrees to use effective barrier contraception during the period of the treatment in case of female participants

Exclusion Criteria:

Patients will not be eligible for the trial if they meet ANY of the following criteria

1. Known current/previous drug resistance to ATT (Rifampicin, INH, FQ)**
2. Concurrent or known diagnosis any other meningitis such as bacterial, viral, and fungal.
3. Currently having an uncontrolled cardiac arrhythmia or ECG abnormalities which are contradiction for the administration of moxifloxacin including prolonged QTc. QTc value define as >450 ms in males and >460 ms in females measured in lead II or V5 on a standard 12-lead ECG.
4. Has clinical icterus or hepatic impairment characterized by serum bilirubin level above the normal laboratory reference range with abnormal liver enzymes, or isolated alanine aminotransferase (ALT) and/ or aspartate aminotransferase (AST) levels above 5 times the upper limit of the normal laboratory reference range
5. Previous history of anti-TB treatment, If any, should not exceed one month in the past and not more than 7 days in the preceding one month.
6. pregnant or lactating women
7. rapid clinical deterioration or very sick and moribund during the screening process, renal failure, liver disease or any condition (social or medical) that in the opinion of the investigator would make trial participation unreliable or unsafe.

8. Has a known allergy to any of the drugs proposed to be used in the trial regimen

   • All participants with Rifampicin resistance will be excluded at baseline from the study. Participants with H, FQ and Z resistance identified from MGIT results done at baseline will be referred back to NTEP for appropriate management and their numbers will be compensated.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm- 1( Intervention arm with aspirin); Intensified with high dose rifampicin, moxifloxacin, aspirin and steroids in the initial two months.	Drug: High dose rifampicin (25mg/kg); Given for 2 months; Drug: Moxifloxacin 400mg; Given for 2 months; Drug: Aspirin 150 mg; Given for 2 months; Drug: Isoniazid; Given for 6 months; Drug: Pyrazinamide; Given for 6 months; Drug: Steroid; Tapering dose of dexamethasone or prednisolone upto 8 weeks; Drug: Rifampicin; Standard dose for 4 months after the initial treatment with high dose
Experimental: Arm -2 (Intervention arm without aspirin); Intensified with high dose rifampicin, moxifloxacin and steroids in the initial two months.	Drug: High dose rifampicin (25mg/kg); Given for 2 months; Drug: Moxifloxacin 400mg; Given for 2 months; Drug: Isoniazid; Given for 6 months; Drug: Pyrazinamide; Given for 6 months; Drug: Steroid; Tapering dose of dexamethasone or prednisolone upto 8 weeks; Drug: Rifampicin; Standard dose for 4 months after the initial treatment with high dose
Active Comparator: Arm -3 (Control); Regimen as per the current National Tuberculosis Elimination Program in India.	Drug: HRZE; 2 months; Drug: HRE; 7-10 months as per TB program guidelines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate		12 months
Mortality rate	Between two groups	12 months
Disability rate	Measured by Modified Rankin scale. A score of 0 to 2 will be considered as no disability and 3-5 will be considered as disability. 0 - no symptoms ; 5 - severe disability	12 months
Disability rate	Measured by Modified Rankin scale. A score of 0 to 2 will be considered as no disability and 3-5 will be considered as disability. 0 - no symptoms ; 5 - severe disability	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration [Cmax] of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)	Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio	Between week 1 & 2
Time for maximal concentration of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)	Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio	Between week 1 & 2
Area Under the Curve (AUC) of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)	Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio	Between week 1 & 2
Grade 3 & 4 adverse events	Comparison of the number of participants who develop Grade 3 or Grade 4 adverse events (according to Division of AIDS (DAIDS) criteria) during treatment. Grade 1 - mild event ; Grade 2 - moderate event; Grade 3- severe event ;Grade 4 - potentially life-threatening	12 months
Grade 3 & 4 adverse events	Comparison of the number of participants who develop Grade 3 or Grade 4 adverse events (according to Division of AIDS (DAIDS) criteria) during treatment. Grade 1 - mild event ; Grade 2 - moderate event; Grade 3- severe event ;Grade 4 - potentially life-threatening	24 months
Quality of life (QoL) in both the arms and change in QoL during the follow up	Using WHO Short form -36 (SF-36), a questionnaire to assess health related outcomes	6,12 & 24 months

Collaborators and Investigators

• Sponsor: Indian Council of Medical Research
• Collaborators: Christian Medical College, Vellore, India; Jawaharlal Institute of Postgraduate Medical Education & Research; Madras Medical College; Rural Development Trust Hospital; North Eastern Indira Gandhi Regional Institute of Health ans Medical Sciences; All India Institute of Medical Sciences, Jodhpur

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: June 8, 2023
• First Submitted That Met QC Criteria: June 15, 2023
• First Posted (Actual): June 23, 2023

Study Record Updates

• Last Update Posted (Actual): December 21, 2023
• Last Update Submitted That Met QC Criteria: December 20, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Central Nervous System Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Meningitis, Bacterial; Central Nervous System Bacterial Infections; Tuberculosis; Tuberculosis, Central Nervous System; Neuroinflammatory Diseases; Tuberculosis, Extrapulmonary; Meningitis; Tuberculosis, Meningeal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Aspirin; Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide
• Other Study ID Numbers: NIRT-IEC No:2023 003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No