Plain English Summary
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
Trial website
Contact information
Type
Scientific
Primary contact
Dr Fiona Cresswell
ORCID ID
http://orcid.org/0000-0002-5070-532X
Contact details
Clinical Research Department
Infectious Diseases Institute
Kampala
PO Box 22418
Uganda
+256793420173
fiona.cresswell@lshtm.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
MHREC: 1260
Study information
Scientific title
High dose oral and intravenous rifampicin for improved survival of adult Tuberculous meningitis: a phase II open-label randomised controlled trial
Acronym
RifT
Study hypothesis
The 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
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
Study design
Parallel group open-label phase II randomized study
Primary study design
Interventional
Secondary study design
Randomised parallel trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
See additional files
Condition
Tuberculosis of nervous system
Intervention
Participants 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 type
Drug
Phase
Phase II
Drug names
Rifampicin
Primary outcome measure
1. 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 measures
1. 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 trial start date
01/09/2017
Overall trial end date
01/10/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. 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
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
60
Total final enrolment
61
Participant exclusion criteria
1. 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
Recruitment start date
01/06/2018
Recruitment end date
01/12/2019
Locations
Countries of recruitment
Uganda
Trial participating centre
Infectious Diseases Institute
Kampala
PO Box 22418
Uganda
Funders
Funder type
Research organisation
Funder name
Wellcome Trust
Alternative name(s)
Wellcome
Funding Body Type
private sector organisation
Funding Body Subtype
international
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Planned 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 statement:
The datasets generated during and/or analysed during the current study will be anonymised and stored in the LSHTM data compass repository.
Intention to publish date
01/04/2021
Participant level data
Stored in repository
Basic results (scientific)
Publication list
Publication citations
Additional files
- ISRCTN42218549_PIS_V1_26Mar18.pdf Uploaded 01/04/2019