Condition category
Infections and Infestations
Date applied
23/05/2019
Date assigned
17/06/2019
Last edited
31/05/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

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
fiona.cresswell@lshtm.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Dr Fiona Cresswell

ORCID ID

http://orcid.org/0000-0002-5070-532X

Contact details

Infectious Diseases Institute
Kampala
PO Box 22418
Uganda
+256 (0)793420173
fiona.cresswell@lshtm.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov 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

Acronym

Harvest

Study hypothesis

High dose oral rifampicin (35mg/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

Approval pending, Mulago Hospital IRB (Research Office, Kampala Women’s and Children’s Hospital, Mulago Hospital, Kampala, Uganda; Tel: +256 (0)752818584; Email: evelynnamwase@gmail.com)

Study design

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

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Tuberculous meningitis

Intervention

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

Drug

Phase

Phase III

Drug names

Rifampicin

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

01/11/2019

Overall trial end date

31/12/2023

Reason abandoned (if study stopped)

Eligibility

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

Patient

Age group

Adult

Gender

Both

Target number of participants

500

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

02/11/2019

Recruitment end date

01/06/2022

Locations

Countries of recruitment

Indonesia, South Africa, Uganda

Trial participating centre

Infectious Diseases Institute
Kampala
PO Box 22418
Uganda

Trial participating centre

University of KwaZulu Natal
719 Umbilo Road
Durban
4001
South Africa

Trial participating centre

Eijkman-Oxford Clinical Research Unit
University of Oxford; Faculty of Medicine Universitas Indonesia Jl Diponegoro 69
Jakarta
10430
Indonesia

Trial participating centre

Universitas Padjadjaran
Bandung
40161
Indonesia

Sponsor information

Organisation

Makerere College of Health Sciences

Sponsor details

Infectious Diseases Institute
Kampala
PO Box 22418
Uganda
+256 (0)31 2211422
research@idi.co.ug

Sponsor type

University/education

Website

https://www.idi-makerere.com

Funders

Funder type

Government

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

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 (hulls003@umn.edu).

Intention to publish date

01/06/2024

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

31/05/2019: Trial's existence confirmed by the MRC.