- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02581527
A Randomised Trial to Evaluate Toxicity and Efficacy of 1200mg and 1800mg Rifampicin for Pulmonary Tuberculosis (RIFASHORT)
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
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Gaborone, Botswana
- University of Botswana
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Conakry, Guinea
- Hopital National Ignace Deen
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Kathmandu, Nepal
- GENETUP, National Anti-TB Association
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Karachi, Pakistan
- Aga Khan University Hospital
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Lima, Peru
- Hospital Nacional Dos de Mayo
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Mbarara, Uganda
- Epicentre
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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.
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Active Comparator: Rifampicin 150mg (Control)
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)
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Rifampicin 150mg (Control arm); Rifampicin 1200mg (Regimen 1); Rifampicin 1800mg (Regimen 2)
Isoniazid 75mg - all arms
Ethambutol 275mg - all arms
Pyrazinamide 400mg - all arms
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Experimental: Rifampicin 1200mg (Regimen 1)
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)
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Rifampicin 150mg (Control arm); Rifampicin 1200mg (Regimen 1); Rifampicin 1800mg (Regimen 2)
Isoniazid 75mg - all arms
Ethambutol 275mg - all arms
Pyrazinamide 400mg - all arms
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Experimental: Rifampicin 1800mg (Regimen 2)
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)
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Rifampicin 150mg (Control arm); Rifampicin 1200mg (Regimen 1); Rifampicin 1800mg (Regimen 2)
Isoniazid 75mg - all arms
Ethambutol 275mg - all arms
Pyrazinamide 400mg - all arms
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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The occurrence of grade 3 or 4 adverse events at any time during chemotherapy.
Time Frame: 18 months
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18 months
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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
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18 months
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Sputum cultures positive for M.tuberculosis at 8 and 12 weeks from randomisation.
Time Frame: 18 months
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18 months
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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
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18 months
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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
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18 months
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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) )
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1 month after end of treatment (7 months (Control), 5 months (Study regimens) )
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Time to unfavourable outcome in the modified intent-to-treat and per protocol sputum smear microscopy-positive population.
Time Frame: 18 Months
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18 Months
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Collaborators and Investigators
Investigators
- Principal Investigator: Amina Jindani, MD, Professor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Lung Diseases
- Bacterial Infections
- Bacterial Infections and Mycoses
- Gram-Positive Bacterial Infections
- Actinomycetales Infections
- Mycobacterium Infections
- Tuberculosis
- Tuberculosis, Pulmonary
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Antimetabolites
- Hypolipidemic Agents
- Lipid Regulating Agents
- Anti-Bacterial Agents
- Leprostatic Agents
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 CYP3A Inducers
- Antitubercular Agents
- Antibiotics, Antitubercular
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2C8 Inducers
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C9 Inducers
- Fatty Acid Synthesis Inhibitors
- Rifampin
- Isoniazid
- Pyrazinamide
- Ethambutol
Other Study ID Numbers
- 15.0190
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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