INSHORT: Intensified Short Course Regimen for TBM in Adults

Sponsor

Indian Council of Medical Research (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05917340

Collaborator

All India Institute of Medical Sciences, Jodhpur (Other), Christian Medical College, Vellore, India (Other), Jawaharlal Institute of Postgraduate Medical Education & Research (Other), North Eastern Indira Gandhi Regional Institute of Health ans Medical Sciences (Other), Madras Medical College (Other), Rural Development Trust Hospital (Other)

380

Enrollment

Location

Arms

Anticipated Duration (Months)

9.7

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Tuberculous Meningitis	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	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

380 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Oct 1, 2026

Anticipated Study Completion Date :

Jan 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intervention arm Intensified with high dose rifampicin, moxifloxacin and 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
Active Comparator: Control arm 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

Arm

Intervention/Treatment

Experimental: Intervention arm

Intensified with high dose rifampicin, moxifloxacin and 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

Active Comparator: Control arm

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

Outcome Measures

Primary Outcome Measures

Mortality rate [12 months]
Between two groups
Disability rate [12 months]
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
Mortality rate [12 months]
Disability rate [24 months]
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

Secondary Outcome Measures

Maximum Plasma Concentration [Cmax] of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients) [Between week 1 & 2]
Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio
Time for maximal concentration of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients) [Between week 1 & 2]
Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio
Area Under the Curve (AUC) of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients) [Between week 1 & 2]
Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio
Grade 3 & 4 adverse events [12 months]
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
Grade 3 & 4 adverse events [24 months]
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
Quality of life (QoL) in both the arms and change in QoL during the follow up [6,12 & 24 months]
Using WHO Short form -36 (SF-36), a questionnaire to assess health related outcomes

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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.