Improving diagnosis and treatment of HIV-associated Tuberculous meningitis

ISRCTN ISRCTN42218549
DOI https://doi.org/10.1186/ISRCTN42218549
Secondary identifying numbers MHREC: 1260
Submission date
09/03/2018
Registration date
24/04/2018
Last edited
07/05/2025
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Infections and Infestations
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Background and study aims
Tuberculous meningitis (TBM), the most severe form of Tuberculosis, is caused by bacteria and affects the brain and spine. Over 100,000 children and adults suffer from TBM yearly, of which up to half die and a quarter are left disabled. These appalling outcomes are driven by:
I. Delay in diagnosis - there is no reliable test;
II. Substandard antibiotic treatment – rifampicin, the key antibiotic, doesn’t reach an effective level in spinal fluid.
This study aims to assess the levels of rifampicin in blood and spinal fluid, and monitor the safety and effects of this on death and disability.

Who can participate?
Adults aged 18 years and over with Tuberculous Meningitis

What does the study involve?
Participants are randomly allocated to one of three groups. Those in the first group receive an antibiotic called rifampicin delivered through their veins for two weeks, and then take it orally for six weeks.
Those in the second group receive a higher than standard dose of oral rifampicin for eight weeks, whilst those in the control take the standard dose of rifampicin for eight weeks. Participants are treated in hospital for the first two weeks, then as an outpatient. They have blood samples taken, and physical and mental assessments throughout the trial.

What are the possible benefits and risks of participating?
Participants benefit from careful medical follow-up during the 24 week trial period including blood tests, additional diagnostic tests on spinal fluid and brain scans where required. This follow-up is likely to be more detailed than the normal medical care in the public hospitals in Uganda, so potentially complications can be detected and managed earlier if people are in the trial. Additionally, transport costs and expenses are covered by the trial for follow-up appointments.
Other studies using high dose rifampicin have shown that it is as safe as the standard dose, but these studies were in a different patient population. We will carefully monitor trial participants in case there are any safety issues with higher dose rifampicin in this patient population. Trial participants receive one to two additional lumbar punctures, which is likely to be more than they would have in routine hospital care in Uganda. This may have clinical benefits but lumbar punctures can rarely also cause harm (pain, infection, bleeding). Patients are counselled about these risks and lumbar punctures will be avoided if there are any concerns.

Where is the study run from?
Infectious Diseases Institute (Uganda)

When is the study starting and how long is it expected to run for?
September 2017 – October 2020

Who is funding the study?
Wellcome Trust (UK)

Who is the main contact?
Dr Fiona Cresswell (Scientific)
fiona.cresswell@lshtm.ac.uk

Contact information

Dr Fiona Cresswell
Scientific

Clinical Research Department
Infectious Diseases Institute
Kampala
PO Box 22418
Uganda

ORCiD logoORCID ID 0000-0002-5070-532X
Phone +256793420173
Email fiona.cresswell@lshtm.ac.uk

Study information

Study designParallel group open-label phase II randomized study
Primary study designInterventional
Secondary study designRandomised parallel trial
Study setting(s)Hospital
Study typeTreatment
Participant information sheet ISRCTN42218549_PIS_V1_26Mar18.pdf
Scientific titleHigh dose oral and intravenous rifampicin for improved survival of adult Tuberculous meningitis: a phase II open-label randomised controlled trial
Study acronymRifT
Study objectivesThe primary hypothesis is that intravenous rifampicin (20mg/kg) and high dose oral rifampicin (35mg/kg) will result in significantly increased plasma exposure and CSF penetration during the critical early days of TB treatment as compared to common control (10mg/kg oral rifampicin).
The secondary hypothesis is that this leads to improved early mycobacterial clearance from the CNS, reduced inflammatory response, and thereby will result in a reduction in neurocognitive disability, TBM-IRIS and mortality. It is hypothesised that the two investigational arms (IV 20mg/kg and oral 35mg/kg) will be equivalent to one another.
Ethics approval(s)1. Mulago Hospital Research Ethics Committee, 01/03/2018, ref: MHREC 1260
2. London School of Hygiene and Tropical Medicine Research Ethics Committee, 11/12/2017, ref: 14388
Health condition(s) or problem(s) studiedTuberculosis of nervous system
InterventionParticipants are randomised (stratified by site and MRC severity grade) into one of three arms:
1. Intravenous 20mg/kg/day rifampicin for 2 weeks (followed by oral rifampicin 35mg/kg/day for 6-weeks)
2. Oral 35mg/kg/day rifampicin for 8 weeks
3. Standard of care oral rifampicin (~10mg/kg/day) for 8-weeks
Other standard anti-TB drugs and steroids are given to all participants, as recommended by the World Health Organisation. Participants are treated in hospital for the first 14 days then followed up every 4 weeks as an outpatient, until 24 weeks.
Intervention typeDrug
Pharmaceutical study type(s)
PhasePhase II
Drug / device / biological / vaccine name(s)Rifampicin
Primary outcome measure1. Individual pharmacokinetic parameters (plasma and CSF AUC0-24h, Cmax) are measured using intensive PK sampling of blood at 0, 2, 4 and 8 hours and a single CSF sample on day 2 and by sparse PK sampling on day 12.
2. Safety composite endpoint is assessed during the intervention period by measuring:
2.1. Adverse Events, Clinical Grade 3-5 as classified by Division of AIDS Toxicity Scale, or
2.2. All serious adverse events, or
2.3. Drug-induced liver injury, grade 3-5, (ALT >5x ULN; or Bilirubin >2.6x ULN) or
2.4. Discontinuation of rifampicin for >5 days in the first 8 weeks for any cause
Secondary outcome measures1. Survival time is measured at 8 and 24 weeks after randomisation
2. Time to normalization of mental status is measured using the Glasgow Coma Scale score (GCS) of 15 which is maintained for >2 days
3. Degree of disability/dependence is measured using the Modified Rankin Scale score at 8 and 24 weeks
4. Neurocognitive performance is measured using detailed quantitative neurocognitive performance Z-score (QNPZ-8) at 8 and 24 weeks
5. Paradoxical TB-related immune reconstitution inflammatory syndrome (TB-IRIS) is assessed using published case definition at 4 weekly follow up.
Overall study start date01/09/2017
Completion date01/10/2020

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexBoth
Target number of participants60
Total final enrolment61
Key inclusion criteria1. Age ≥ 18 years
2. Provision of written informed consent by participant or surrogate
3. Clinical diagnosis of TBM: meningitis symptoms, clinical signs of meningism and antituberculous chemotherapy planned by the attending physician
AND
4. Bedside CSF glucose to plasma ratio <50%, or absolute CSF glucose <40mg/dl or 2.2 mmol/L
OR
5. Positive CSF AFB smear or Xpert MTB/ Rif or Ultra
Key exclusion criteria1. Presence of jaundice or known liver cirrhosis (Due to emergent need to begin TBM therapy to reduce mortality, enrolment will not be delayed and participants will be replaced a posteriori if baseline ALT>3x ULN)
2. Greater than 3 doses of TB treatment received within the previous 3 days (induction of cytochrome P450 enzymes occurs after 3-5 days of rifampicin therapy which would affect PK data)
3. Discontinued TB treatment in the prior 14 days (induction of cytochrome P450 enzymes persists for up to 2-weeks after cessation of R and would make interpretation of the PK data challenging)
4. Known allergy to Rifamycins, H, Z, E or study drug excipients
5. Known current/previous rifampicin drug-resistant M. tuberculosis infection
6. Current cryptococcal meningitis: India ink stain positive or culture positive or cryptococcal antigen positive in the absence of prior effective treatment and prophylaxis.
7. Use of any drug that has a clinically relevant interaction with rifampicin or other first-line TB drugs, including ritonavir, atazanavir or darunavir (see appendix 2 for further detail)
8. Cannot or unlikely to attend regular clinic visits
9. Pregnancy / Breastfeeding. Women of childbearing potential must agree to use barrier contraception or abstinence for 8 weeks. Hormonal contraception is unacceptable as rifampicin induces metabolism.
10. Lack of consent from participant or family member
11. Known porphyria
12. Known chronic renal failure with eGFR <10 ml/min
Date of first enrolment01/06/2018
Date of final enrolment01/12/2019

Locations

Countries of recruitment

  • Uganda

Study participating centre

Infectious Diseases Institute
Kampala
PO Box 22418
Uganda

Sponsor information

London School of Hygiene and Tropical Medicine
University/education

Keppel Street
London
WC1E 7HT
England
United Kingdom

ROR logo "ROR" https://ror.org/00a0jsq62

Funders

Funder type

Research organisation

Wellcome Trust
Private sector organisation / International organizations
Location
United Kingdom

Results and Publications

Intention to publish date01/04/2021
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryStored in repository
Publication and dissemination planPlanned dissemination of findings at conferences and by publication in a high-impact peer reviewed journal within 6 months of trial completion. We will also communicate results through the International TB meningitis research consortium.
IPD sharing planThe datasets generated during and/or analysed during the current study will be anonymised and stored in the LSHTM data compass repository.

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Participant information sheet version V1 26/03/2018 01/04/2019 No Yes
Protocol article protocol 10/07/2018 06/01/2021 Yes No
Results article 07/09/2021 08/11/2021 Yes No
Other publications Fujifilm SILVAMP TB LAM Assay on Cerebrospinal Fluid for the Detection of Tuberculous Meningitis in Adults With Human Immunodeficiency Virus 01/11/2021 07/05/2025 Yes No

Additional files

ISRCTN42218549_PIS_V1_26Mar18.pdf
Uploaded 01/04/2019

Editorial Notes

07/05/2025: Publication reference added.
08/11/2021: Publication reference added.
06/01/2021: Publication reference added.
08/01/2020: The total final enrolment number has been added.
24/04/2019: Internal review.
01/04/2019: The participant information sheet has been uploaded.