Evaluation of high dose rifampicin toxicity in pulmonary tuberculosis

ISRCTN	ISRCTN55670677
DOI	https://doi.org/10.1186/ISRCTN55670677
Secondary identifying numbers	Version 2.1

Submission date: 12/10/2010
Registration date: 09/11/2010
Last edited: 20/09/2017

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

Not provided at time of registration

Contact information

Dr Amina Jindani
Scientific

St George's University of London
Infection and Immunity Research Centre
Cranmer Terrace
London
SW17 0RE
United Kingdom

Phone	+44 (0)20 8725 2810
Email	ajindani@sgul.ac.uk

Study information

Study design	Open-label three-arm trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a patient information sheet
Scientific title	An international multicentre controlled clinical trial to evaluate the toxicity of high dose rifampicin in the treatment of pulmomary tuberculosis (RIFATOX)
Study acronym	RIFATOX
Study hypothesis	The current treatment of tuberculosis involves taking drugs daily for 6 or 8 months. Although the drugs are free to patients in low income countries, this still involves a substantial cost, in terms of time and administration, to both the patient and the treatment services. If the length of treatment could be shortened to 3, or even, 4 months, this would be of great benefit to the patients and the treatment services. A shorter treatment could also result in greater cure rates and, perhaps, a reduction in the emergence of resistance to the drugs. One of the drugs given in treatment is called rifampicin. Laboratory experiments suggest that increasing the dose of rifampicin results in a greater killing of the tubercle bacillus both in liquid suspensions and in animals. This trial assesses whether giving an increased dose of rifampicin to patients receiving the standard treatment for tuberculosis is safe and does not result in greater bad effects from the higher dose. If it is found to be safe, another trial would be carried out to see if the increased dose can increase the elimination of the tubercle bacillus from the lungs and if so, whether, eventually, the treatment can be shortened to 3, or even, 4 months.
Ethics approval(s)	1. UK: 1.1. The Oxford Tropical Research Ethics Committee (OXTREC), 02/08/2010, ref: 31-01 1.2. The St. George's University of London R&D Office, 20/09/2010, ref: 10.005 2. Bolivia: 2.1. The Ministry of Health and Sports (Ministerio de Salud y Deportes), April 2010, ref: MSD/DESP./0733/2010 2.2. The Commission for Ethics of Investigations (Comision de Ethica de la Investigation), 19/07/2010 3. Nepal: The National Health Research Council, 15/04/2010, ref: 1192 4. India: Approval pending at time of registration
Condition	Infectious Diseases; Tuberculosis
Intervention	All patients enrolled will receive treatment for 6 months. The duration of the study will be the first 4 months of treatment. For the last 2 months of treatment, the patients will be transferred to the National Treatment Programme to complete 6 months. Control Regimen : 2 months of daily ethambutol, isoniazid, rifampicin, and pyrazinamide followed by 4 months of daily isoniazid and rifampicin (2EHRZ/4HR)A. Study Regimen 1: The regimen as above but with an increase in the dose of rifampicin to 15mg/kg body weight daily for the first 4 months. (2EHR15Z/2HR15/2HR)B For the first 4 months, the dose of rifampicin will be 15mg/kg. Study Regimen 2: The regimen as above but with an increase in the dose of rifampicin to 20mg /kg body weight daily for the first 4 months. (2EHR20Z/2HR20/2HR)C For the first 4 months, the dose of rifampicin will be 20mg/kg.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Ethambutol, isoniazid, rifampicin, pyrazinamide
Primary outcome measure	Occurrence of grade 3 or 4 adverse events at any time during chemotherapy
Secondary outcome measures	1. Culture conversion at the end of 8 weeks of chemotherapy 2. Per protocol analysis of the primary outcome. 3. Any adverse event graded according to the modified Division of Aids (DAIDS) criteria 4. Rate of completion of chemotherapy according to the protocol 5. Number of observed doses of chemotherapy ingested
Overall study start date	01/10/2010
Overall study end date	01/10/2012

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	300
Participant inclusion criteria	1. Newly diagnosed pulmonary tuberculosis 2. Two sputum specimens positive for tubercle bacilli on direct smear microscopy 3. No previous anti-tuberculosis chemotherapy 4. Aged 18 years and over 5. A firm home address that is readily accessible for visiting and be intending to remain there or within the recruitment area for the entire treatment period 6. Agree to participate in the study and to give a sample of blood for HIV testing 7. Pre-menopausal women must be using a barrier form of contraception or be surgically sterilised or have an interuterine contraceptive device (IUCD) in place for the duration of the treatment phase
Participant exclusion criteria	1. Has any condition (except HIV infection) that may prove fatal during the study period 2. Has TB meningitis 3. Has pre-existing non-tuberculous disease likely to prejudice the response to, or assessment of, treatment e.g. insulin-dependent diabetes, liver or kidney disease, blood disorders, peripheral neuritis 4. Is female and known to be pregnant, or breast feeding 5. Is suffering from a condition likely to lead to uncooperative behaviour such as psychiatric illness or alcoholism 6. Has contraindications to any medications in the study regimens 7. Requires anti-retro viral treatment (ART) at diagnosis 8. Haemoglobin <7g/l 9. Asparate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 5 times the upper limit of normal (ULN) for that laboratory 10. Creatinine clearance of < 30mls/min Calculated as ((140-age) x weight x 1.23 x (0.85 if female))/Creat[micromol/l) 11. Has glucose in urine 12. Is HIV positive with a CD4 count of less than 350/mm3 13. Weight < 35kg
Recruitment start date	01/10/2010
Recruitment end date	01/10/2012

Locations

Countries of recruitment

Bolivia
England
India
Nepal
United Kingdom

Study participating centre

St George's University of London

London
SW17 0RE
United Kingdom

Sponsor information

St George's University of London (UK)
University/education

Cranmer Terrace
London
SW17 0RE
England
United Kingdom

Phone	+44 (0)20 8725 2810
Email	ajindani@sgul.ac.uk
"ROR"	https://ror.org/040f08y74

Funders

Funder type

University/education

St. George's, University of London
Private sector organisation / Universities (academic only)

Alternative name(s): St. George's
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	sub-study results	24/04/2017		Yes	No

Editorial Notes

19/09/2017: Funder confirmed as St. George's, University of London.
26/04/2017: Publication reference added.