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Intensified Short Course Regimen for TBM in Adults (INSHORT)

Primary Purpose

Tuberculous Meningitis

Status
Not yet recruiting
Phase
Phase 3
Locations
India
Study Type
Interventional
Intervention
High dose rifampicin (25mg/kg)
Moxifloxacin 400mg
Aspirin 150 mg
Isoniazid
Pyrazinamide
Steroid
Rifampicin
HRZE
HRE
Sponsored by
Indian Council of Medical Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculous Meningitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • ICMR- National Institute for Research in Tuberculosis

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Arm- 1( Intervention arm with aspirin)

Arm -2 (Intervention arm without aspirin)

Arm -3 (Control)

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

Mortality rate
Between two groups
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
Mortality rate
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

Secondary Outcome Measures

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
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
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
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
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
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

Full Information

First Posted
June 8, 2023
Last Updated
July 31, 2023
Sponsor
Indian Council of Medical Research
Collaborators
All India Institute of Medical Sciences, Jodhpur, Christian Medical College, Vellore, India, Jawaharlal Institute of Postgraduate Medical Education & Research, North Eastern Indira Gandhi Regional Institute of Health ans Medical Sciences, Madras Medical College, Rural Development Trust Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05917340
Brief Title
Intensified Short Course Regimen for TBM in Adults
Acronym
INSHORT
Official Title
Comparative Evaluation of Intensified Short Course Regimen and Standard Regimen for Adults TB Meningitis : an Open-label Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 2023 (Anticipated)
Primary Completion Date
October 2026 (Anticipated)
Study Completion Date
January 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Indian Council of Medical Research
Collaborators
All India Institute of Medical Sciences, Jodhpur, Christian Medical College, Vellore, India, Jawaharlal Institute of Postgraduate Medical Education & Research, North Eastern Indira Gandhi Regional Institute of Health ans Medical Sciences, Madras Medical College, Rural Development Trust Hospital

4. Oversight

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
Data Monitoring Committee
Yes

5. 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculous Meningitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
372 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm- 1( Intervention arm with aspirin)
Arm Type
Experimental
Arm Description
Intensified with high dose rifampicin, moxifloxacin, aspirin and steroids in the initial two months.
Arm Title
Arm -2 (Intervention arm without aspirin)
Arm Type
Experimental
Arm Description
Intensified with high dose rifampicin, moxifloxacin and steroids in the initial two months.
Arm Title
Arm -3 (Control)
Arm Type
Active Comparator
Arm Description
Regimen as per the current National Tuberculosis Elimination Program in India.
Intervention Type
Drug
Intervention Name(s)
High dose rifampicin (25mg/kg)
Intervention Description
Given for 2 months
Intervention Type
Drug
Intervention Name(s)
Moxifloxacin 400mg
Intervention Description
Given for 2 months
Intervention Type
Drug
Intervention Name(s)
Aspirin 150 mg
Intervention Description
Given for 2 months
Intervention Type
Drug
Intervention Name(s)
Isoniazid
Intervention Description
Given for 6 months
Intervention Type
Drug
Intervention Name(s)
Pyrazinamide
Intervention Description
Given for 6 months
Intervention Type
Drug
Intervention Name(s)
Steroid
Intervention Description
Tapering dose of dexamethasone or prednisolone upto 8 weeks
Intervention Type
Drug
Intervention Name(s)
Rifampicin
Intervention Description
Standard dose for 4 months after the initial treatment with high dose
Intervention Type
Drug
Intervention Name(s)
HRZE
Intervention Description
2 months
Intervention Type
Drug
Intervention Name(s)
HRE
Intervention Description
7-10 months as per TB program guidelines
Primary Outcome Measure Information:
Title
Mortality rate
Description
Between two groups
Time Frame
12 months
Title
Disability rate
Description
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
Time Frame
12 months
Title
Mortality rate
Time Frame
12 months
Title
Disability rate
Description
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
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Maximum Plasma Concentration [Cmax] of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)
Description
Plasma Cmax, cerebrospinal fluid [CSF] Cmax, and plasma/CSF Cmax ratio
Time Frame
Between week 1 & 2
Title
Time for maximal concentration of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)
Description
Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio
Time Frame
Between week 1 & 2
Title
Area Under the Curve (AUC) of high dose rifampicin, isoniazid, pyrazinamide and moxifloxacin (Subset of patients)
Description
Plasma Tmax, cerebrospinal fluid [CSF] Tmax, and plasma/CSF Tmax ratio
Time Frame
Between week 1 & 2
Title
Grade 3 & 4 adverse events
Description
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
Time Frame
12 months
Title
Grade 3 & 4 adverse events
Description
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
Time Frame
24 months
Title
Quality of life (QoL) in both the arms and change in QoL during the follow up
Description
Using WHO Short form -36 (SF-36), a questionnaire to assess health related outcomes
Time Frame
6,12 & 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dr Leeberk Raja Inbaraj, MBBS MD
Phone
044-28369527
Email
leeberk.raja@icmr.gov.in
First Name & Middle Initial & Last Name or Official Title & Degree
Dr Bella Devaleenal, MBBS MPH
Phone
044-28369538
Email
belladevalleenal.d@icmr.gov.in
Facility Information:
Facility Name
ICMR- National Institute for Research in Tuberculosis
City
Chennai
State/Province
Tamil Nadu
ZIP/Postal Code
600031
Country
India
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr Padmapriyadarsini Chandrasekaran, MBBS DNB MS PhD
Phone
044-28369500
Email
nirtdirector@icmr.gov.in

12. IPD Sharing Statement

Plan to Share IPD
No

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Intensified Short Course Regimen for TBM in Adults

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