Pulmonary TuberculosisPhase 3RIFASHORTNCT02581527
A Randomised Trial to Evaluate Toxicity and Efficacy of 1200mg and 1800mg Rifampicin for Pulmonary Tuberculosis
A Phase 3 study testing Rifampicin, Isoniazid and Ethambutol in people with Pulmonary Tuberculosis, run by St George's, University of London at 6 sites in 6 countries.
Trial summary
In this trial, the investigators are assessing whether giving an increased dose of rifampicin to patients receiving the standard treatment for tuberculosis is safe and, when given for 4 months only, will also result in greater and faster killing of the tubercle bacillus in the lungs and result in relapse rates similar… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Pulmonary Tuberculosis
- What is being tested?
- Rifampicin, Isoniazid and Ethambutol
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 672 participants
- Where
- 6 sitesin 6 countries
- Study dates
- 1 Feb 2017to 31 Jul 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- GeneXpert sputum positive, rifampicin susceptible, newly diagnosed pulmonary tuberculosis will be included even if they are microscopy negative.
- No previous anti-tuberculosis chemotherapy.
- Patients ≥ 18 years
- Consent to participation in the trial and to HIV testing
- Provide informed consent.
- Patient has a stable home address within easy reach of the treatment facility and likely to remain there for the next 18 months.
- Pre-menopausal women must be using a barrier form of contraception or be surgically sterilised or have an Intrauterine Contraceptive Device (IUCD) in place for the duration of the treatment phase
Who cannot join
- Patients with rifampicin resistance identified by GeneXpert or by direct susceptibility testing (late exclusions).
- Has any condition that may prove fatal during the study period.
- Has TB meningitis.
- 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, and severe thrombocytopenia, rash, increase of bilirubin and other diseases that are likely to be contraindicated with rifampicin
- Is female and known to be pregnant, or breast feeding.
- Is suffering from a condition likely to lead to uncooperative behaviour such as psychiatric illness or alcoholism.
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- Has contraindications to any medications in the study regimens
- Is HIV positive
- Haemoglobin <7g/l
- Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 5 times the upper limit of normal (ULN) for that laboratory
- Creatinine clearance (CrCl) of < 30mls/min. Calculated as CrCl (mL/min) = N x [140-age (years)] x weight (kg) Serum creatinine (micromol/L) Where N = 1.23 males, 1.04 females
- Has glucose in urine
- Weight < 35kg
Trial locations and contacts
6 sites in 6 countries.
6 sites in 6 countries
About this study
Official title: An International Multicentre Controlled Clinical Trial to Evaluate 1200mg and 1800mg Rifampicin Daily for Four Months in the Reduction of the Duration of Standard Treatment of Pulmonary Tuberculosis
In this trial, the investigators are assessing whether giving an increased dose of rifampicin to patients receiving the standard treatment for tuberculosis is safe and, when given for 4 months only, will also result in greater and faster killing of the tubercle bacillus in the lungs and result in relapse rates similar to those found in the World Health Organisation (WHO) recommended standard 6 month regimen.
Read the detailed description
Type of design An open-label 3-arm trial to compare a standard 6-month control regimen with two 4-month treatment regimens for the treatment of tuberculosis (TB).
Disease/patients studied The trial will include 654 patients newly diagnosed with pulmonary TB with sputum positive or negative for TB on microscopy but with a positive result on a GeneXpert Test with organisms fully sensitive to rifampicin
The treatment regimens - Control and Experimental
Patients enrolled in the trial will be randomly allocated to receive one of the following three chemotherapy treatment regimens:
- Control regimen (R10): The standard regimen of isoniazid, pyrazinamide and ethambutol plus 10 mg/kg rifampicin for the initial 8 weeks, followed by isoniazid and rifampicin (at the same dose size) for an additional 4 months (2HRZE/4HR)A.
- Study regimen 1(SR1): 2 months of daily ethambutol, isoniazid, rifampicin, and pyrazinamide followed by 2 months of daily isoniazid and rifampicin. A supplement of either 450 mg (weight bands 35-39kg and 40-54kg) or 600mg (weight band 55-69kg and 70 and more kg) of rifampicin will be given throughout the four months (2EHR 1200Z/2HR1200)B.
- Study regimen 2(SR2): 2 months of daily ethambutol, isoniazid, rifampicin, and pyrazinamide followed by 2 months of daily isoniazid and rifampicin. A supplement of either 450 mg (weight bands 35-39kg and 40-54kg) or 600mg (weight band 55-69kg and 70 and more kg) of rifampicin will be given throughout the four months (2EHR1800Z/2HR1800)C.
1.1 Outcome measures Primary outcome measure
- Since the objective of the trial is to reduce treatment duration by increasing the dose of rifampicin, the primary outcome measure is the combined rate of failure at the end of treatment and relapse during the subsequent 12 months in smear positive patients.
- The occurrence of grade 3 or 4 adverse events at any time during chemotherapy.
- Conditions
- Pulmonary Tuberculosis
- Being tested
- Rifampicin, Isoniazid, Ethambutol, Pyrazinamide
- Medical subject headings
- Tuberculosis, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RifampicinDrug
Rifampicin 150mg (Control arm); Rifampicin 1200mg (Regimen 1); Rifampicin 1800mg (Regimen 2)
IsoniazidDrug
Isoniazid 75mg - all arms
EthambutolDrug
Ethambutol 275mg - all arms
PyrazinamideDrug
Pyrazinamide 400mg - all arms
| Study group | Role | What they receive |
|---|---|---|
| Rifampicin 150mg (Control) | Active comparator | 2 months daily 4FDC - Rifampicin 150mg, Isoniazid 75mg, Ethambutol 275mg and Pyrazinamide 400mg (intensive phase); followed by 4 months daily 2FDC - Rifampicin 150mg and Isoniazid 75mg (continuous phase) Receives: Drug: Rifampicin; Drug: Isoniazid; Drug: Ethambutol; Drug: Pyrazinamide |
| Rifampicin 1200mg (Regimen 1) | Experimental | 2 months daily 4FDC - high dose Rifampicin 1200mg, Isoniazid 75mg, Ethambutol 275mg and Pyrazinamide 400mg (intensive phase); followed by 2 months daily 2FDC - high dose Rifampicin 1200mg and Isoniazid 75mg (continuous phase) Receives: Drug: Rifampicin; Drug: Isoniazid; Drug: Ethambutol; Drug: Pyrazinamide |
| Rifampicin 1800mg (Regimen 2) | Experimental | 2 months daily 4FDC - high dose Rifampicin 1800mg, Isoniazid 75mg, Ethambutol 275mg and Pyrazinamide 400mg (intensive phase); followed by 2 months daily 2FDC - high dose Rifampicin 1800mg and Isoniazid 75mg (continuous phase) Receives: Drug: Rifampicin; Drug: Isoniazid; Drug: Ethambutol; Drug: Pyrazinamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
The occurrence of grade 3 or 4 adverse events at any time during chemotherapy.
Measured: 18 months
the primary outcome measure is the combined rate of failure at the end of treatment and relapse during the subsequent 12 months in smear positive patients in the modified intent to treat population.
Measured: 18 months
Secondary outcomes (5)
Sputum cultures positive for M.tuberculosis at 8 and 12 weeks from randomisation.
Measured: 18 months
Per protocol analysis of the primary efficacy outcome (the combined rate of failure at the end of treatment and relapse during the subsequent 12 months in smear positive patients)
Measured: 18 months
Combined unfavourable endpoint (rate of failure at the end of treatment and relapse) measured 18 months from randomisation in the Xpert MTB/RIF positive (i) modified intent-to-treat and (ii) per protocol populations
Measured: 18 months
Any adverse event, up to one month after completion of treatment, graded according to the DAIDS criteria
Measured: 1 month after end of treatment (7 months (Control), 5 months (Study regimens) )
Time to unfavourable outcome in the modified intent-to-treat and per protocol sputum smear microscopy-positive population.
Measured: 18 Months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2015 (estimated)
- Study start1 Feb 2017
- Primary completion1 Jan 2022
- Study completion31 Jul 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Pulmonary TuberculosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 672 participants (actual)
Sponsor and investigators
- Lead sponsor
- St George's, University of London
- Sponsor type
- University, hospital or other
- Collaborators
- London School of Hygiene and Tropical Medicine, University of Botswana
- Responsible party
- Sponsor
- Investigators
- Amina Jindani, MD, Principal investigator, Professor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02581527
- Sponsor's protocol ID
- 15.0190
- Acronym
- RIFASHORT
- Status last verified
- Jul 2022
- First submitted
- 19 Oct 2015
- Last updated
- 27 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Jindani A, Atwine D, Grint D, Bah B, Adams J, Ticona ER, Shrestha B, Agizew T, Hamid S, Jamil B, Byamukama A, Kananura K, Mugisha Taremwa I, Bonnet M, Camara LM, Bah-Sow OY, Bah KS, Bah NM, Sow M, Ticona Huaroto CE, Mugruza Pineda R, Tandukar B, Raya BB, Shrestha N, Mathoma A, Mathebula-Modongo UP, Basotli J, Irfan M, Begum D, Muzammil A, Ahmed I, Hasan R, Burgos MV, Sultan F, Hassan M, Masood I, Robb C, Decker J, Grubnic S, Butcher PD, Witney A, Dhillon J, Munshi T, Fielding K, Harrison TS. Four-Month High-Dose Rifampicin Regimens for Pulmonary Tuberculosis. NEJM Evid. 2023 Sep;2(9):EVIDoa2300054. doi: 10.1056/EVIDoa2300054. Epub 2023 Aug 22.
PubMed 38320155
Study at a glance
From the registry record, last updated by the sponsor on 27 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An International Multicentre Controlled Clinical Trial to Evaluate 1200mg and 1800mg Rifampicin Daily for Four Months in the Reduction of the Duration of Standard Treatment of Pulmonary Tuberculosis
- ClinicalTrials.gov ID
- NCT02581527
- Acronym / sponsor ID
- RIFASHORT / 15.0190
- Conditions
- Pulmonary Tuberculosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 672 participants (actual)
- Lead sponsor
- St George's, University of LondonUniversity, hospital or other
- Collaborators
- London School of Hygiene and Tropical Medicine, University of Botswana
- Study start
- 1 Feb 2017 (actual)
- Primary completion
- 1 Jan 2022 (actual)
- Study completion
- 31 Jul 2022 (actual)
- First posted
- 21 Oct 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In this trial, the investigators are assessing whether giving an increased dose of rifampicin to patients receiving the standard treatment for tuberculosis is safe and, when given for 4 months only, will also result in greater and faster killing of the tubercle bacillus in the lungs and result in relapse rates similar to those found in the World Health Organisation (WHO) recommended standard 6 month regimen.
Detailed description
Type of design An open-label 3-arm trial to compare a standard 6-month control regimen with two 4-month treatment regimens for the treatment of tuberculosis (TB).
Disease/patients studied The trial will include 654 patients newly diagnosed with pulmonary TB with sputum positive or negative for TB on microscopy but with a positive result on a GeneXpert Test with organisms fully sensitive to rifampicin
The treatment regimens - Control and Experimental
Patients enrolled in the trial will be randomly allocated to receive one of the following three chemotherapy treatment regimens:
- Control regimen (R10): The standard regimen of isoniazid, pyrazinamide and ethambutol plus 10 mg/kg rifampicin for the initial 8 weeks, followed by isoniazid and rifampicin (at the same dose size) for an additional 4 months (2HRZE/4HR)A.
- Study regimen 1(SR1): 2 months of daily ethambutol, isoniazid, rifampicin, and pyrazinamide followed by 2 months of daily isoniazid and rifampicin. A supplement of either 450 mg (weight bands 35-39kg and 40-54kg) or 600mg (weight band 55-69kg and 70 and more kg) of rifampicin will be given throughout the four months (2EHR 1200Z/2HR1200)B.
- Study regimen 2(SR2): 2 months of daily ethambutol, isoniazid, rifampicin, and pyrazinamide followed by 2 months of daily isoniazid and rifampicin. A supplement of either 450 mg (weight bands 35-39kg and 40-54kg) or 600mg (weight band 55-69kg and 70 and more kg) of rifampicin will be given throughout the four months (2EHR1800Z/2HR1800)C.
1.1 Outcome measures Primary outcome measure
- Since the objective of the trial is to reduce treatment duration by increasing the dose of rifampicin, the primary outcome measure is the combined rate of failure at the end of treatment and relapse during the subsequent 12 months in smear positive patients.
- The occurrence of grade 3 or 4 adverse events at any time during chemotherapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Rifampicin 150mg (Control) | Active comparator | Drug: Rifampicin, Drug: Isoniazid, Drug: Ethambutol, Drug: Pyrazinamide2 months daily 4FDC - Rifampicin 150mg, Isoniazid 75mg, Ethambutol 275mg and Pyrazinamide 400mg (intensive phase); followed by 4 months daily 2FDC - Rifampicin 150mg and Isoniazid 75mg (continuous phase) |
| Rifampicin 1200mg (Regimen 1) | Experimental | Drug: Rifampicin, Drug: Isoniazid, Drug: Ethambutol, Drug: Pyrazinamide2 months daily 4FDC - high dose Rifampicin 1200mg, Isoniazid 75mg, Ethambutol 275mg and Pyrazinamide 400mg (intensive phase); followed by 2 months daily 2FDC - high dose Rifampicin 1200mg and Isoniazid 75mg (continuous phase) |
| Rifampicin 1800mg (Regimen 2) | Experimental | Drug: Rifampicin, Drug: Isoniazid, Drug: Ethambutol, Drug: Pyrazinamide2 months daily 4FDC - high dose Rifampicin 1800mg, Isoniazid 75mg, Ethambutol 275mg and Pyrazinamide 400mg (intensive phase); followed by 2 months daily 2FDC - high dose Rifampicin 1800mg and Isoniazid 75mg (continuous phase) |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- GeneXpert sputum positive, rifampicin susceptible, newly diagnosed pulmonary tuberculosis will be included even if they are microscopy negative.
- No previous anti-tuberculosis chemotherapy.
- Patients ≥ 18 years
- Consent to participation in the trial and to HIV testing
- Provide informed consent.
Key exclusion criteria (13 listed)
- Patients with rifampicin resistance identified by GeneXpert or by direct susceptibility testing (late exclusions).
- Has any condition that may prove fatal during the study period.
- Has TB meningitis.
- 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, and severe thrombocytopenia, rash, increase of bilirubin and other diseases that are likely to be contraindicated with rifampicin
- Is female and known to be pregnant, or breast feeding.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RifampicinRifampicin 150mg (Control arm); Rifampicin 1200mg (Regimen 1); Rifampicin 1800mg (Regimen 2) | Drug | Rifampicin 1200mg (Regimen 1), Rifampicin 150mg (Control), Rifampicin 1800mg (Regimen 2) |
| IsoniazidIsoniazid 75mg - all arms | Drug | Rifampicin 1200mg (Regimen 1), Rifampicin 150mg (Control), Rifampicin 1800mg (Regimen 2) |
| EthambutolEthambutol 275mg - all arms | Drug | Rifampicin 1200mg (Regimen 1), Rifampicin 150mg (Control), Rifampicin 1800mg (Regimen 2) |
| PyrazinamidePyrazinamide 400mg - all arms | Drug | Rifampicin 1200mg (Regimen 1), Rifampicin 150mg (Control), Rifampicin 1800mg (Regimen 2) |
Primary outcome
The occurrence of grade 3 or 4 adverse events at any time during chemotherapy.
Time frame: 18 months
the primary outcome measure is the combined rate of failure at the end of treatment and relapse during the subsequent 12 months in smear positive patients in the modified intent to treat population.
Time frame: 18 months
5 secondary outcomes
Sputum cultures positive for M.tuberculosis at 8 and 12 weeks from randomisation.
Time frame: 18 months
Per protocol analysis of the primary efficacy outcome (the combined rate of failure at the end of treatment and relapse during the subsequent 12 months in smear positive patients)
Time frame: 18 months
Combined unfavourable endpoint (rate of failure at the end of treatment and relapse) measured 18 months from randomisation in the Xpert MTB/RIF positive (i) modified intent-to-treat and (ii) per protocol populations
Time frame: 18 months
Any adverse event, up to one month after completion of treatment, graded according to the DAIDS criteria
Time frame: 1 month after end of treatment (7 months (Control), 5 months (Study regimens) )
Time to unfavourable outcome in the modified intent-to-treat and per protocol sputum smear microscopy-positive population.
Time frame: 18 Months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Apr 2023.
- Derived from this study: PubMed 38320155Jindani A, Atwine D, Grint D, Bah B, Adams J, Ticona ER, Shrestha B, Agizew T, Hamid S, Jamil B, Byamukama A, Kananura K, Mugisha Taremwa I, Bonnet M, Camara LM, Bah-Sow OY, Bah KS, Bah NM, Sow M, Ticona Huaroto CE, Mugruza Pineda R, Tandukar B, Raya BB, Shrestha N, Mathoma A, Mathebula-Modongo UP, Basotli J, Irfan M, Begum D, Muzammil A, Ahmed I, Hasan R, Burgos MV, Sultan F, Hassan M, Masood I, Robb C, Decker J, Grubnic S, Butcher PD, Witney A, Dhillon J, Munshi T, Fielding K, Harrison TS. Four-Month High-Dose Rifampicin Regimens for Pulmonary Tuberculosis. NEJM Evid. 2023 Sep;2(9):EVIDoa2300054. doi: 10.1056/EVIDoa2300054. Epub 2023 Aug 22.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Amina Jindani, MD principal investigator
Professor
6 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Rifampicin, Isoniazid and Ethambutol in people with Pulmonary Tuberculosis, run by St George's, University of London at 6 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Botswana, Guinea, Nepal, Pakistan, Peru and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The occurrence of grade 3 or 4 adverse events at any time during chemotherapy. (time frame: 18 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02581527, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Apr 2023.