Condition category
Infections and Infestations
Date applied
09/03/2018
Date assigned
24/04/2018
Last edited
24/04/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

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

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 measures

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

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

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

Sponsor information

Organisation

London School of Hygiene and Tropical Medicine

Sponsor details

Keppel Street
London
WC1E 7HT
United Kingdom

Sponsor type

University/education

Website

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

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes