Condition category
Infections and Infestations
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status

Plain English Summary

Background and study aims
Tuberculous meningitis accounts for 1-5 % of all TB infections and carries a high case-fatality (up to 50%) and many survivors are left with long-term disabilities. Rifampicin is the most important anti-TB drug but at the currently recommended dose (10 mg/kg) it fails to penetrate into the brain and spinal fluid adequately. This trial is testing whether giving a much higher dose of rifampicin by mouth, in addition to the normal anti-TB drugs, can reduce death and disability caused by TB meningitis.

Who can participate?
Patients aged 18 and over with first episode tuberculous meningitis suspected by attending physician and anti-TB treatment planned

What does the study involve?
Participants are allocated by chance to receive either four rifampicin 300 mg capsules in addition to standard fixed dose combination TB treatment, or standard fixed dose combination TB treatment. Participants are followed up in hospital until discharge and then as an outpatient for 12 months.

What are the possible benefits and risks of participating?
The high dose rifampicin may be more effective at treating the infection so the participants’ chance of dying or being left with a disability may be reduced (though this won’t be known until the end of the trial). More intensive monitoring of blood tests and clinical status may allow complications to be picked up and treated earlier than in they would in the normal care environment. Transport and costs of follow-up are covered by the study which may reduce financial burden on the participant. Possible risks of participation include: side effects or toxicity from the high-dose rifampicin; more frequent blood tests and an additional lumbar puncture; and the high dose rifampicin may not have an impact on clinical outcomes.

Where is the study run from?
1. Infectious Diseases Institute (Uganda)
2. University of KwaZulu Natal (South Africa)
3. Eijkman-Oxford Clinical Research Unit (Indonesia)
4. Universitas Padjadjaran (Indonesia)

When is the study starting and how long is it expected to run for?
November 2019 to December 2023

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Dr Fiona Cresswell

Trial website

Contact information



Primary contact

Dr Fiona Cresswell


Contact details

Infectious Diseases Institute
PO Box 22418
+256 (0)793420173

Additional identifiers

EudraCT number

Nil known number

Nil known

Protocol/serial number

MHREC 1554

Study information

Scientific title

High-dose oral rifampicin to improve survival from adult tuberculous meningitis: a double-blinded randomised placebo-controlled Phase III trial



Study hypothesis

High dose oral rifampicin (35 mg/kg) alongside other regular first-line antituberculous drugs will improve survival and neurological outcomes from Tuberculous meningitis compared to standard of care TB treatment.

Ethics approval

Current ethics approval as of 30/07/2019:
Approved 17/06/2019, Mulago Hospital IRB (Research Office, Kampala Women’s and Children’s Hospital, Mulago Hospital, Kampala, Uganda; Tel: +256 (0)752818584; Email:, ref: MHREC 1554.

Previous ethics approval:
Approval pending, Mulago Hospital IRB (Research Office, Kampala Women’s and Children’s Hospital, Mulago Hospital, Kampala, Uganda; Tel: +256 (0)752818584; Email:

Study design

Double-blinded parallel group randomised placebo-controlled Phase III trial

Primary study design


Secondary study design

Non randomised study

Trial setting


Trial type


Patient information sheet


Tuberculous meningitis


Participants are allocated by chance to receive either:
1. Four oral rifampicin 300-mg capsules in addition to standard fixed-dose combination TB treatment
2. Standard fixed-dose combination TB treatment
Participants are followed up in hospital until the time of discharge and then as an outpatient for 12 months.

Intervention type



Phase III

Drug names


Primary outcome measure

6-month survival

Secondary outcome measures

1. 12-month survival
2. Functional and neurocognitive outcomes measured using the following instruments:
2.1. Normalization of mental status with Glasgow coma scale score (GCS) of 15 and maintained for >2 days (among those with GCS <15 at study entry). A substantial proportion of TBM patients (~50%) present with altered mental status and depressed consciousness. In these participants, early response to treatment is assessed by determining the days from randomization until observation of a GCS of 15 which is achieved for >2 consecutive days
2.2. Functional outcomes assessed by Liverpool Outcome Score at month 6 (Appendix C)
2.3. Quantitative neurocognitive performance Z-scores (QNPZ-8) at 2 and 12 months (Uganda only). QNPZ-8 is derived from a test battery, which includes:
2.3.1. Grooved Pegboard test
2.3.2. Colour Trails 1 and 2 tests
2.3.3. WAIS-III Digit Symbol test
2.3.4. Finger Tapping test
2.3.5. WHO-UCLA Auditory Verbal Learning Test
2.3.6. Semantic Verbal Fluency test (category fluency)
3. Safety and tolerability endpoints:
3.1. Clinical AEs, grade 3-5 as classified by Division of AIDS (DAIDS) Toxicity Scale
3.2. Laboratory AEs, grade 3-5 as classified by DAIDS Toxicity Scale
3.3. All Serious AEs (SAEs)
3.4. Drug-induced liver injury (grade 3-5)
§ Alanine transaminase (ALT) or aspartate transaminase (AST) >5x upper limit of normal (ULN)
3.5. Discontinuation of TB treatment for >5 days in the first 8 weeks for any cause
4. Cumulative days of hospitalization (and re-hospitalization)
5. Incidence of re-hospitalization for neurologic deterioration
6. Incidence and management of drug-induced liver injury

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

1. First episode TBM suspected by attending physician (>3 days of meningitis symptoms and CSF abnormalities) and anti-TB treatment planned
2. Age ≥18 years
3. Provision of written informed consent by participant or surrogate

Participant type


Age group




Target number of participants


Participant exclusion criteria

1. Presence of jaundice, known liver cirrhosis, or known elevated ALT >5x ULN
2. More than 5 doses of any TB treatment received within the previous 7 days
3. Known allergy to: isoniazid, rifampicin, ethambutol, or pyrazinamide
4. Known current/previous rifampicin-resistant M.tb infection
5. Additional active and confirmed CNS infection
6. Corticosteroids contraindicated
7. Cannot or unlikely to attend regular clinic visits
8. Pregnancy or breastfeeding
9. Known renal failure with eGFR <30 ml/min by Modification of Diet in Renal Disease (MDRD) Study equation
10. HIV Protease Inhibitor ongoing use

Recruitment start date


Recruitment end date



Countries of recruitment

Indonesia, South Africa, Uganda

Trial participating centre

Infectious Diseases Institute
PO Box 22418

Trial participating centre

University of KwaZulu Natal
719 Umbilo Road
South Africa

Trial participating centre

Eijkman-Oxford Clinical Research Unit
University of Oxford; Faculty of Medicine Universitas Indonesia Jl Diponegoro 69

Trial participating centre

Universitas Padjadjaran

Sponsor information


Makerere College of Health Sciences

Sponsor details

Infectious Diseases Institute
PO Box 22418
+256 (0)31 2211422

Sponsor type




Funder type


Funder name

Medical Research Council

Alternative name(s)


Funding Body Type

government organisation

Funding Body Subtype

National government


United Kingdom

Results and Publications

Publication and dissemination plan

The researchers plan to publish the protocol in Wellcome Open Research once they have ethical approval.
The main trial paper will be published open access within 6 months of the last participant completing follow up.
Additional sub-studies will be published open access at the appropriate intervals.
The Meningitis Research Foundation is the researchers' communications partner to maximise the impact of the results. The researchers will engage other stakeholders in trial countries.

IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Kathy Huppler Hullsiek, Biostatistician, University of Minnesota (

Intention to publish date


Participant level data

Available on request

Basic results (scientific)

Publication list

2020 protocol in (added 23/10/2020)

Publication citations

Additional files

Editorial Notes

23/10/2020: Publication reference added. 30/07/2019: The following changes have been made: 1. The ethics approval information has been updated. 2. The recruitment start date has been changed from 02/11/2019 to 01/01/2020. 31/05/2019: Trial's existence confirmed by the MRC.