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A Randomised Trial to Evaluate Toxicity and Efficacy of 1200mg and 1800mg Rifampicin for Pulmonary Tuberculosis (RIFASHORT)

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ClinicalTrials.gov Identifier: NCT02581527
Recruitment Status : Active, not recruiting
First Posted : October 21, 2015
Last Update Posted : July 13, 2022
Sponsor:
Collaborators:
London School of Hygiene and Tropical Medicine
University of Botswana
Information provided by (Responsible Party):
St George's, University of London

Brief 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 to those found in the World Health Organisation (WHO) recommended standard 6 month regimen.

Condition or disease Intervention/treatment Phase
Pulmonary Tuberculosis Drug: Rifampicin Drug: Isoniazid Drug: Ethambutol Drug: Pyrazinamide Phase 3

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:

  1. 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.
  2. 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.
  3. 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

  1. 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.
  2. The occurrence of grade 3 or 4 adverse events at any time during chemotherapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 654 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 1, 2017
Actual Primary Completion Date : January 1, 2022
Estimated Study Completion Date : July 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis
Drug Information available for: Rifampin

Arm Intervention/treatment
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)
Drug: Rifampicin
Rifampicin 150mg (Control arm); Rifampicin 1200mg (Regimen 1); Rifampicin 1800mg (Regimen 2)

Drug: Isoniazid
Isoniazid 75mg - all arms

Drug: Ethambutol
Ethambutol 275mg - all arms

Drug: Pyrazinamide
Pyrazinamide 400mg - all arms

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)
Drug: Rifampicin
Rifampicin 150mg (Control arm); Rifampicin 1200mg (Regimen 1); Rifampicin 1800mg (Regimen 2)

Drug: Isoniazid
Isoniazid 75mg - all arms

Drug: Ethambutol
Ethambutol 275mg - all arms

Drug: Pyrazinamide
Pyrazinamide 400mg - all arms

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)
Drug: Rifampicin
Rifampicin 150mg (Control arm); Rifampicin 1200mg (Regimen 1); Rifampicin 1800mg (Regimen 2)

Drug: Isoniazid
Isoniazid 75mg - all arms

Drug: Ethambutol
Ethambutol 275mg - all arms

Drug: Pyrazinamide
Pyrazinamide 400mg - all arms




Primary Outcome Measures :
  1. The occurrence of grade 3 or 4 adverse events at any time during chemotherapy. [ Time Frame: 18 months ]
  2. 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 ]

Secondary Outcome Measures :
  1. Sputum cultures positive for M.tuberculosis at 8 and 12 weeks from randomisation. [ Time Frame: 18 months ]
  2. 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 ]
  3. 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 ]
  4. 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) ) ]
  5. Time to unfavourable outcome in the modified intent-to-treat and per protocol sputum smear microscopy-positive population. [ Time Frame: 18 Months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. GeneXpert sputum positive, rifampicin susceptible, newly diagnosed pulmonary tuberculosis will be included even if they are microscopy negative.
  2. No previous anti-tuberculosis chemotherapy.
  3. Patients ≥ 18 years
  4. Consent to participation in the trial and to HIV testing
  5. Provide informed consent.
  6. Patient has a stable home address within easy reach of the treatment facility and likely to remain there for the next 18 months.
  7. 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:

  1. Patients with rifampicin resistance identified by GeneXpert or by direct susceptibility testing (late exclusions).
  2. Has any condition that may prove fatal during the study period.
  3. Has TB meningitis.
  4. 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
  5. Is female and known to be pregnant, or breast feeding.
  6. Is suffering from a condition likely to lead to uncooperative behaviour such as psychiatric illness or alcoholism.
  7. Has contraindications to any medications in the study regimens
  8. Is HIV positive
  9. Haemoglobin <7g/l
  10. Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 5 times the upper limit of normal (ULN) for that laboratory
  11. 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
  12. Has glucose in urine
  13. Weight < 35kg

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02581527


Locations
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Botswana
University of Botswana
Gaborone, Botswana
Guinea
Hopital National Ignace Deen
Conakry, Guinea
Nepal
GENETUP, National Anti-TB Association
Kathmandu, Nepal
Pakistan
Aga Khan University Hospital
Karachi, Pakistan
Peru
Hospital Nacional Dos de Mayo
Lima, Peru
Uganda
Epicentre
Mbarara, Uganda
Sponsors and Collaborators
St George's, University of London
London School of Hygiene and Tropical Medicine
University of Botswana
Investigators
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Principal Investigator: Amina Jindani, MD Professor
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Responsible Party: St George's, University of London
ClinicalTrials.gov Identifier: NCT02581527    
Other Study ID Numbers: 15.0190
First Posted: October 21, 2015    Key Record Dates
Last Update Posted: July 13, 2022
Last Verified: July 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Respiratory Tract Infections
Lung Diseases
Respiratory Tract Diseases
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Fatty Acid Synthesis Inhibitors