HARVEST trial - improving outcomes from TB meningitis with high-dose oral rifampicin
| ISRCTN | ISRCTN15668391 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15668391 |
| Secondary identifying numbers | MHREC 1554 |
- Submission date
- 23/05/2019
- Registration date
- 17/06/2019
- Last edited
- 02/01/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
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 June 2025
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Dr Fiona Cresswell
fiona.cresswell@lshtm.ac.uk
Contact information
Scientific
Infectious Diseases Institute
Kampala
PO Box 22418
Uganda
 ORCID ID |
0000-0002-5070-532X |
|---|---|
| Phone | +256 (0)793420173 |
| fiona.cresswell@lshtm.ac.uk |
Study information
| Study design | Double-blinded parallel group randomised placebo-controlled Phase III trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet. |
| Scientific title | High-dose oral rifampicin to improve survival from adult tuberculous meningitis: a double-blinded randomised placebo-controlled Phase III trial |
| Study acronym | HARVEST |
| 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(s) | 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: evelynnamwase@gmail.com), 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: evelynnamwase@gmail.com) |
| 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | 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 study start date | 01/11/2019 |
| Overall study end date | 01/06/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 500 |
| 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 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 | 01/01/2020 |
| Recruitment end date | 01/06/2024 |
Locations
Countries of recruitment
- Indonesia
- South Africa
- Uganda
Study participating centres
PO Box 22418
Uganda
Durban
4001
South Africa
Jl Diponegoro 69
Jakarta
10430
Indonesia
40161
Indonesia
Sponsor information
University/education
Infectious Diseases Institute
Kampala
PO Box 22418
Uganda
| Phone | +256 (0)31 2211422 |
|---|---|
| research@idi.co.ug | |
| Website | https://www.idi-makerere.com |
"ROR" |
https://ror.org/03dmz0111 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/08/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| 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 plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Fiona Cresswell, IDI/LSHTM (fiona.cresswell@lshtm.ac.uk). |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 25/08/2020 | 23/10/2020 | Yes | No |
Editorial Notes
02/01/2024: The following changes have been made:
1. The intention to publish date has been changed from 01/07/2025 to 01/08/2025.
2. The IPD sharing plan has been changed from "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)." to "The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Fiona Cresswell, IDI/LSHTM (fiona.cresswell@lshtm.ac.uk).".
23/06/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/06/2022 to 01/06/2024.
2. The overall end date was changed from 31/12/2023 to 01/06/2025.
3. The intention to publish date was changed from 01/06/2024 to 01/07/2025.
4. The plain English summary was updated to reflect these changes.
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.
