Intensified Short Course Regimen for TBM in Adults

NCT05917340 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: NIRT-IEC No:2023 003
• Study Type: interventional
• Target: 372
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Tuberculous Meningitis

Outcome Measures

Primary Outcomes (4)

• 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

• Mortality rate

  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 Outcomes (6)

• Maximum Plasma Concentration [Cmax] of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)

  Between week 1 & 2

• Time for maximal concentration of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)

  Between week 1 & 2

• Area Under the Curve (AUC) of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)

  Between week 1 & 2

• Grade 3 & 4 adverse events

  12 months

• Grade 3 & 4 adverse events

  24 months

Study Arms (3)

Arm- 1( Intervention arm with aspirin)

EXPERIMENTAL

Intensified with high dose rifampicin, moxifloxacin, aspirin and steroids in the initial two months.

Drug: High dose rifampicin (25mg/kg); Drug: Moxifloxacin 400mg; Drug: Aspirin 150 mg; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Steroid; Drug: Rifampicin

Arm -2 (Intervention arm without aspirin)

EXPERIMENTAL

Intensified with high dose rifampicin, moxifloxacin and steroids in the initial two months.

Drug: High dose rifampicin (25mg/kg); Drug: Moxifloxacin 400mg; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Steroid; Drug: Rifampicin

Arm -3 (Control)

ACTIVE COMPARATOR

Regimen as per the current National Tuberculosis Elimination Program in India.

Drug: HRZE; Drug: HRE

Interventions

High dose rifampicin (25mg/kg) DRUG

Given for 2 months

Arm -2 (Intervention arm without aspirin); Arm- 1( Intervention arm with aspirin)

Moxifloxacin 400mg DRUG

Given for 2 months

Arm -2 (Intervention arm without aspirin); Arm- 1( Intervention arm with aspirin)

Aspirin 150 mg DRUG

Given for 2 months

Arm- 1( Intervention arm with aspirin)

Isoniazid DRUG

Given for 6 months

Arm -2 (Intervention arm without aspirin); Arm- 1( Intervention arm with aspirin)

Pyrazinamide DRUG

Given for 6 months

Arm -2 (Intervention arm without aspirin); Arm- 1( Intervention arm with aspirin)

Steroid DRUG

Tapering dose of dexamethasone or prednisolone upto 8 weeks

Arm -2 (Intervention arm without aspirin); Arm- 1( Intervention arm with aspirin)

Rifampicin DRUG

Standard dose for 4 months after the initial treatment with high dose

Arm -2 (Intervention arm without aspirin); Arm- 1( Intervention arm with aspirin)

HRZE DRUG

2 months

Arm -3 (Control)

HRE DRUG

7-10 months as per TB program guidelines

Arm -3 (Control)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A patient will be eligible for entry to the trial if ALL of the following conditions are satisfied
• Adults (\> 18 years) with or without HIV infection
• Possible, probable or definite TBM according to Lancet consensus diagnostic criteria
• Willing to give written informed consent
• Is willing to have an HIV test.
• Residing within 100 km of the study sites
• Express willingness to attend the treatment centre for supervised treatment
• Express willingness to adhere to the trial procedures and follow-up schedule.
• Agrees to use effective barrier contraception during the period of the treatment in case of female participants

You may not qualify if:

• Patients will not be eligible for the trial if they meet ANY of the following criteria
• Known current/previous drug resistance to ATT (Rifampicin, INH, FQ)\*\*
• Concurrent or known diagnosis any other meningitis such as bacterial, viral, and fungal.
• 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.
• 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
• 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.
• pregnant or lactating women
• 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.
• 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.

Sponsors & Collaborators

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

Study Sites (1)

ICMR- National Institute for Research in Tuberculosis

Chennai, Tamil Nadu, 600031, India

Location

Related Publications (1)

• Inbaraj LR, Manesh A, Ponnuraja C, Bhaskar A, Srinivasalu VA, Daniel BD. Comparative evaluation of intensified short course regimen and standard regimen for adults TB meningitis: a protocol for an open label, multi-center, parallel arms, randomized controlled superiority trial (INSHORT trial). Trials. 2024 May 2;25(1):294. doi: 10.1186/s13063-024-08133-6.

  PMID: 38693583 DERIVED

MeSH Terms

Conditions

Tuberculosis, Meningeal

Interventions

Rifampin; Moxifloxacin; Aspirin; Isoniazid; Pyrazinamide; Steroids

Condition Hierarchy (Ancestors)

Meningitis, Bacterial; Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Tuberculosis, Central Nervous System; Tuberculosis, Extrapulmonary; Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Meningitis; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrazines; Fused-Ring Compounds

Central Study Contacts

Dr Leeberk Raja Inbaraj, MBBS MD

CONTACT

044-28369527; leeberk.raja@icmr.gov.in

Dr Bella Devaleenal, MBBS MPH

CONTACT

044-28369538; belladevalleenal.d@icmr.gov.in

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Scientist-E (Medical)

Study Record Dates

• First Submitted: June 8, 2023
• First Posted: June 23, 2023
• Study Start: March 1, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027
• Last Updated: December 21, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)