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

NCT02581527 | Completed Phase 3 DMC

• 1 other identifier: 15.0190
• Study Type: interventional
• Target: 672
• Locations: 6 countries
• Sites: 6

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.

Conditions

Pulmonary Tuberculosis

Outcome Measures

Primary Outcomes (2)

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

  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.

  18 months

Secondary Outcomes (5)

• Sputum cultures positive for M.tuberculosis at 8 and 12 weeks from randomisation.

  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)

  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

  18 months

• Any adverse event, up to one month after completion of treatment, graded according to the DAIDS criteria

  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.

  18 Months

Study Arms (3)

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)

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)

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)

Drug: Rifampicin; Drug: Isoniazid; Drug: Ethambutol; Drug: Pyrazinamide

Interventions

Rifampicin DRUG

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

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

Isoniazid DRUG

Isoniazid 75mg - all arms

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

Ethambutol DRUG

Ethambutol 275mg - all arms

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

Pyrazinamide DRUG

Pyrazinamide 400mg - all arms

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

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• St George's, University of London: lead
• London School of Hygiene and Tropical Medicine: collaborator
• University of Botswana: collaborator

Study Sites (6)

University of Botswana

Gaborone, Botswana

Location

Hopital National Ignace Deen

Conakry, Guinea

Location

GENETUP, National Anti-TB Association

Kathmandu, Nepal

Location

Aga Khan University Hospital

Karachi, Pakistan

Location

Hospital Nacional Dos de Mayo

Lima, Peru

Location

Epicentre

Mbarara, Uganda

Location

Related Publications (1)

• 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.

  PMID: 38320155 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Rifampin; Isoniazid; Ethambutol; Pyrazinamide

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Ethylenediamines; Diamines; Polyamines; Amines; Pyrazines

Study Officials

• Amina Jindani, MD

  Professor

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 19, 2015
• First Posted: October 21, 2015
• Study Start: February 1, 2017
• Primary Completion: January 1, 2022
• Study Completion: July 31, 2022
• Last Updated: April 27, 2023

Record last verified: 2022-07

Locations

PE (1); NE (1); UG (1); GU (1); PA (1); BO (1)