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Intensified Short Course Regimen for TBM in Adults

ConditionTuberculous Meningitis
Trial statusNot yet recruiting
Trial phasePhase 3
Trial typeInterventional
Biological sexAll
Age18+
SponsorIndian Council of Medical Research

About this 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

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Disqualifiers

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

Trial design

Design model

Parallel

Treatments tested in this trial

  • High dose rifampicin (25mg/kg)

    Drug

    Given for 2 months

  • Moxifloxacin 400mg

    Drug

    Given for 2 months

  • Aspirin 150 mg

    Drug

    Given for 2 months

  • Isoniazid

    Drug

    Given for 6 months

  • Pyrazinamide

    Drug

    Given for 6 months

  • Steroid

    Drug

    Tapering dose of dexamethasone or prednisolone upto 8 weeks

  • Rifampicin

    Drug

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

  • HRZE

    Drug

    2 months

  • HRE

    Drug

    7-10 months as per TB program guidelines

Treatment groups

372 Participants
are divided into 3 treatment groups
Group A: Arm- 1( Intervention arm with aspirin)Experimental treatment 7 interventions
Group B: Arm -2 (Intervention arm without aspirin)Experimental treatment 6 interventions
Group C: Arm -3 (Control)Active comparator 2 interventions

Trial outcomes

Primary outcomes

1

Mortality rate

Between two groups

Time frame
12 months
2

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

Time frame
12 months
3

Mortality rate

Time frame
12 months
4

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

Time frame
24 months

Secondary outcomes

1

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 frame
Between week 1 & 2
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

Time frame
Between week 1 & 2
3

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

Time frame
Between week 1 & 2
4

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

Time frame
12 months

Other outcomes

Sponsors and contacts

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Indian Council of Medical Research

Lead sponsor

Tuberculosis Research Centre, India

Sponsor institution

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

Source ClinicalTrials.gov

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