Condition category
Infections and Infestations
Date applied
25/10/2012
Date assigned
26/10/2012
Last edited
26/05/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Clostridium difficile associated diarrhoea is a serious health problem with over 14,139 cases reported in 2015-16 in England and Wales. There are lots of beneficial gut bacteria which help suppress the growth of Clostridium difficile bacteria. However, taking antibiotics can kill these beneficial bacteria, allowing C. difficile to grow and causing inflammation of the bowel. Standard antibiotics used to treat C. difficile are vancomycin or metronidazole which kill C. difficile but also suppress the beneficial bacteria, meaning relapse of C. difficile occurs in around 1 in 3 patients. Rifaximin is an antibiotic which prevents C. difficile growth but only partly inhibits the growth of beneficial gut bacteria, allowing them to recover. A recent small study found that for patients successfully treated for C. difficile, relapse could be reduced from 31% to 15% by taking a course of Rifaximin. The aim of this study is to evaluate the effectiveness of Rifaximin for preventing relapse of C. difficile in a large study.

Who can participate?
Patients aged 18 or over who have been diagnosed with C. difficile infection and are currently being or have recently been successfully treated with a course of Metronidazole and/or Vancomycin. Adults who lack mental capacity who have a legal representative are also included.

What does the study involve?
Participants are randomly allocated to be treated with 2 weeks of Rifaximin 400mg three times daily, followed by 2 more weeks of 200mg three times daily or identical looking tablets which have no active ingredient (placebo). Blood and stool samples (serum to assess antibody response to C. difficile toxins, apart from participants with legal representative consent) are collected for those patients who have consented to provide these. Neither the doctors or the nurses or the patient know which treatment the patient received. Patients are interviewed at 12 weeks to see if they have had a relapse.

What are the possible benefits and risks of participating?
One in four patients completing a successful course of Metronidazole and Vancomycin may experience a return of their infection. It is anticipated that this will be lower in the group receiving Rifaximin but this cannot be guaranteed. Rifaximin works differently from other antibiotics because it passes through the stomach and into the intestines without being absorbed into the blood stream, so it is very safe. Most people have no side effects though rarely nausea and headache have been reported and there is a very low risk of an allergic reaction developing. Giving a blood sample may cause discomfort or bruising though this usually resolves within a few days. Adults who lack mental capacity are not required to provide a blood sample.

Where is the study run from?
The NIHR Nottingham Digestive Diseases Biomedical research unit at Nottingham University Hospitals is organising the research; trial coordination takes place at the Nottingham Clinical Trials Unit, University of Nottingham (UK).

When is the study starting and how long is it expected to run for?
December 2012 to June 2017

Who is funding the study?
NIHR Research for Patient Benefit Programme (UK)

Who is the main contact?
Kirsty Sprange
rapid@nottingham.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Ms Kirsty Sprange

ORCID ID

Contact details

Nottingham Clinical Trials Unit (NCTU)
Nottingham Health Science Partners (NHSP)
C Floor
South Block
Queens Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom
-
rapid@nottingham.ac.uk

Additional identifiers

EudraCT number

2012-003205-10

ClinicalTrials.gov number

Protocol/serial number

12990

Study information

Scientific title

A randomised placebo controlled trial of "follow on" Rifaximin for the prevention of relapse of Clostridium associated diarrhoea

Acronym

RAPID

Study hypothesis

Rifaximin is a poorly absorbed antibiotic which has been used for many years in Italy and the USA for the treatment of traveller's diarrhoea and IBS. It has an excellent safety record and has been shown to achieve high concentrations in the bowel. It has been used effectively to treat Clostridium difficile infection and has a low rate of antibiotic-resistance development. It has also been suggested as beneficial when used after an effective course of the antibiotic, metronidazole since it is said to disturb the normal gut bacteria less than metronidazole and vancomycin and hence might be predicted to reduce the incidence of relapse. This hypothesis is tested in this study. A reduction in recurrence rate of C. difficile from 30% to 10% would significantly reduce the burden of this disease in hospitals and the community and provide an inexpensive solution to this serious illness.

Ethics approval

NRES Committee East Midlands - Leicester, First MREC approval date 31/08/2012, ref:12/EM/0292

Study design

Multicentre two-arm parallel-group double-blind randomised placebo-controlled trial

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Trial setting

Hospitals

Trial type

Prevention

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Clostridium difficile-associated diarrhoea

Intervention

Patients randomised to receive either Rifaximin (200mg tablets) or placebo.

Dosage: Treatment is for 4 weeks. The initial trial daily dose will be 2 x 200mg tablets three times a day for first 2 weeks then, 1 x 200mg tablet three times a day for the final 2 weeks.

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

The difference in % relapse between Rifaximin and placebo at week 12

Secondary outcome measures

Current secondary outcome measures as of 30/04/2015:
Clinical:
1. Proportion with relapse of CDAD within 6 months
2. Proportion rehospitalised for CDAD within 6 months
3. Length of in-hospital stay following start of treatment

Exploratory:
1. Stool frequency and consistency during 12 weeks after start of treatment
2. Microbiological assessments

Previous secondary outcome measures:
1. Bowel symptoms measured at weeks 1-4 and weeks 11-12
2. Length of stay on active versus placebo measured at week 12
3. Microbiological exploratory assessments measured at week 12
4. Safety/Adverse events measured at 6 months
5. The difference in relapse of CDAD within 6 months of start of therapy

Overall trial start date

11/12/2012

Overall trial end date

11/06/2017

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 30/04/2015:
1. Men/women aged 18 and over (adults who lack mental capacity for whom there is a legal representative are included)
2. Successful treatment of clinically diagnosed CDAD using standard therapy (metronidazole or vancomycin given according to standard local hospital guidelines)

Previous inclusion criteria:
1. Men/women aged 18 and over (adults who lack mental capacity for whom there is a legal representative are included)
2. Successful treatment of clinically diagnosed C. difficile-associated diarrhea (CDAD) using standard therapy (metronidazole or vancomycin given according to standard local hospital guidelines
3. Able to swallow tablets
4. Able to stop chronic antibiotic use
5. Women of child bearing potential willing and able to use at least one highly effective contraceptive method throughout the study. Acceptable contraceptive methods include: established use of oral, injected or implanted hormonal methods; placement of an intrauterine device (IUD) or intrauterine system (IUS); condom or occlusive cap (diaphragm or cervical/vault caps) with spermicide; true abstinence (when this is in line with the preferred and usual lifestyle of the participant); or vasectomised partner.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 180; UK Sample Size: 180

Participant exclusion criteria

Current exclusion criteria as of 24/02/2016:
1. Woman of childbearing potential and not willing to use at least one highly effective contraceptive method throughout the study*
2. Male with spouse/partner of childbearing potential and not willing to use condoms
3. Pregnant or breastfeeding
4. Unable to swallow tablets
5. Life expectancy of <4 weeks
6. Hypersensitivity to the active substance, to any rifamycin (e.g. rifampicin or rifabutin) or to any of its excipients (tablet core: sodium starch glycolate type A, glycerol distearate, colloidal anhydrous, silica, talc and microcrystalline cellulose. Tablet coating: hypromellose, titanium dioxide (E171), disodium edentate, propylene glycol and red iron oxide E172)
7. >5 days post standard therapy (metronidazole or vancomycin) for clinically diagnosed CDAD
8. Taking ciclosporin

* Acceptable contraceptive methods include: established use of oral, injected or implanted hormonal methods; placement of an intrauterine device (IUD) or intrauterine system (IUS); condom or occlusive cap (diaphragm or cervical/vault caps) with spermicide; true abstinence (when this is in line with the preferred and usual lifestyle of the participant); or vasectomised partner.

Exclusion criteria from 30/04/2015 to 24/02/2016:
1. Woman of childbearing potential and not willing to use at least one highly effective contraceptive method throughout the study*
2. Male with spouse/partner of childbearing potential and not willing to use condoms
3. Pregnant or breastfeeding
4. Unable to swallow tablets
5. Life expectancy of <4 weeks
6. Hypersensitivity to the active substance, to any rifamycin (e.g. rifampicin or rifabutin) or to any of its excipients (tablet core: sodium starch glycolate type A, glycerol distearate, colloidal anhydrous, silica, talc and microcrystalline cellulose. Tablet coating: hypromellose, titanium dioxide (E171), disodium edentate, propylene glycol and red iron oxide E172)
7. >5 days post standard therapy (metronidazole or vancomycin) for clinically diagnosed CDAD

* Acceptable contraceptive methods include: established use of oral, injected or implanted hormonal methods; placement of an intrauterine device (IUD) or intrauterine system (IUS); condom or occlusive cap (diaphragm or cervical/vault caps) with spermicide; true abstinence (when this is in line with the preferred and usual lifestyle of the participant); or vasectomised partner.

Original exclusion criteria:
1. Pregnant or breast feeding
2. Hypersensitivity to the active substance, to any rifamycin (e.g. rifampicin or rifabutin) or to any of its excipients (Tablet core: Sodium starch glycolate type A, glycerol distearate, colloidal anhydrous, silica, talc and microcrystalline cellulose. Tablet coating: hypromellose, titanium dioxide (E171), disodium edentate, propylene glycol and red iron oxide E172)
3. >5 days post standard therapy (metronidazole or vancomycin) for clinically diagnosed CDAD

Recruitment start date

11/12/2012

Recruitment end date

10/03/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Nottingham University Hospitals
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

King’s Mill Hospital
Sutton-in-Ashfield
NG17 4JL
United Kingdom

Trial participating centre

Royal Derby Hospital
Derby
DE22 3NE
United Kingdom

Trial participating centre

Northern General Hospital
Sheffield
S5 7AU
United Kingdom

Trial participating centre

Chesterfield Royal Hospital
Chesterfield
S44 5BL
United Kingdom

Trial participating centre

Royal Shrewsbury Hospital
Shrewsbury
SY3 8XQ
United Kingdom

Trial participating centre

County Durham and Darlington NHS Foundation Trust
Darlington
DL3 6HX
United Kingdom

Trial participating centre

Sunderland Royal Hospital
Sunderland
SR4 7TP
United Kingdom

Trial participating centre

Kettering General Hospital
Kettering
NN16 8UZ
United Kingdom

Trial participating centre

Dorset County Hospital
Dorchester
DT1 2JY
United Kingdom

Trial participating centre

James Cook Hospital
Middlesbrough
TS4 3BW
United Kingdom

Trial participating centre

North Cumbria University Hospitals
Carlisle
CA2 7HY
United Kingdom

Trial participating centre

Hampshire Hospitals NHS Foundation Trust
Basingstoke
RG24 9NA
United Kingdom

Trial participating centre

University Hospitals Southampton
Southampton,
SO16 6YD
United Kingdom

Trial participating centre

New Cross Hospital
Wolverhampton
WV10 0QP
United Kingdom

Trial participating centre

Doncaster Royal Infirmary
Doncaster
DN2 5LT
United Kingdom

Trial participating centre

Russells Hall Hospital
Dudley
DY1 2HQ
United Kingdom

Trial participating centre

Stepping Hill Hospital
Stockport
SK2 7JE
United Kingdom

Trial participating centre

Queens Hospital
Romford
RM7 0AG
United Kingdom

Trial participating centre

King’s College Hospital
London
SE5 9RS
United Kingdom

Sponsor information

Organisation

University of Nottingham (UK)

Sponsor details

Research Innovation Services
Kings Meadow Campus
Lenton Lane
Nottingham
NG7 2NR
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

National Institute of Health Research (NIHR) (UK) - Research for Patient Benefit (RfPB) Grant Codes: PB-PG-1010-23257

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high impact peer reviewed journal, and dissemination of study results at scientific congresses.

IPD sharing statement
The current data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

11/06/2018

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

25/05/2017: The overall trial end date was changed from 11/09/2016 to 11/06/2017. 24/02/2016: The recruitment end date was changed from 11/12/2015 to 10/03/2016. 30/04/2015: The following changes were made to the trial record: 1. The overall start date was changed from 08/11/2012 to 11/12/2012. 2. The overall end date was changed from 31/12/2014 to 11/09/2016.