High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis

NCT04521803 | Recruiting Phase 2 DMC

• 1 other identifier: IMPI-3 DMID 20-0007
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

Brief Summary

The investigators hypothesise that high dose RIF (RIF35) will increase pericardial fluid RIF exposure and so enhance mycobacterial clearance, compared to standard of care dosing (RIF10). This Phase 2b randomized, placebo-controlled, double-blinded trial will evaluate the efficacy and safety of RIF 35mg/kg compared 10mg/kg, added to standard first-line ATT, for the treatment of PCTB.

Conditions

Tuberculous Pericarditis; HIV Status

Outcome Measures

Primary Outcomes (1)

• Drug exposure in PCF and mediates in Mtb load

  To determine whether higher dose rifampicin (35mg/kg) increases pericardial fluid (AUC) RIF levels and increases time to positivity of mycobacterial culture at 72 hours compared to standard dose Rifampicin

  72 hours and 52 weeks

Secondary Outcomes (5)

• Mortality between study arms

  week 8 and 52 weeks

• re-accumulation of pericardial effusion between study arms

  52 weeks

• TB-IRIS between study arms

  52 weeks

• Constrictive pericarditis between the study arms

  52 weeks

• CMR evidence

  52 weeks

Other Outcomes (5)

• To investigate the safety and tolerability of RIF35 for PCTB by:

  week 8 and 52 weeks

• Discontinuation rate

  52 weeks

• Change in Mtb bacterial load

  72 hours

Study Arms (2)

Arm 1: Standard of care (RIF10)

NO INTERVENTION

Dosing of the daily oral RHZE fixed dose combination (FDC) will be according to WHO weight bands

Arm 2: High-dose RIF (RIF35)

EXPERIMENTAL

Simulations were performed to determine the dose of RIF required to achieve the most equitable drug exposures across the weight range, 30 to 100 kg. Demographic data of a reference cohort of TB patients (n = 1225), with or without HIV-1 coinfection, recruited in clinical trials conducted in West Africa and South Africa were used for the simulations35-38. An additional 12 250 virtual patients were generated using the weight and height distributions of the 1225 patients to increase the number of patients with a weight close to the boundaries of the weight range. Parameter estimates of the population PK model for RIF were used to simulate (100 replicates) RIF exposures22. Four dosing scenarios were evaluated using the weight-band based dosing with 4-drug FDC tablets and extra RIF tablets with each tablet containing 150 mg or 600 mg RIF. The FDC tablets were assumed to have 20% reduced bioavailability based on data from a clinical trial where the same formulation was used39

Drug: high dose Rifampicin (RIF)

Interventions

high dose Rifampicin (RIF) DRUG

Simulations were performed to determine the dose of RIF required to achieve the most equitable drug exposures across the weight range, 30 to 100 kg. Demographic data of a reference cohort of TB patients (n = 1225), with or without HIV-1 coinfection, recruited in clinical trials conducted in West Africa and South Africa were used for the simulations35-38. An additional 12 250 virtual patients were generated using the weight and height distributions of the 1225 patients to increase the number of patients with a weight close to the boundaries of the weight range. Parameter estimates of the population PK model for RIF were used to simulate (100 replicates) RIF exposures22. Four dosing scenarios were evaluated using the weight-band based dosing with 4-drug FDC tablets and extra RIF tablets with each tablet containing 150 mg or 600 mg RIF. The FDC tablets were assumed to have 20% reduced bioavailability based on data from a clinical trial where the same formulation was used

Arm 2: High-dose RIF (RIF35)

Eligibility Criteria

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

You may qualify if:

• Aged \>18 years
• Suspected PCTB with confirmed pericardial effusion on echocardiography (i.e., echo free space of ≥1 cm anterior to the right ventricle in diastole)
• Consent to study participation including testing for HIV-1 (if HIV status is unknown)
• Microbiologically detected Mtb in PCF or diagnosis of probable PCTB. Probable PCTB (in the absence of a positive pericardial fluid culture) will be defined as per Mayosi et al.4:
• Evidence of pericarditis with microbiologic confirmation of Mtb- infection elsewhere in the body and/or
• Exudative, lymphocyte predominant effusion with elevated adenosine deaminase (≥35 U/L)
• Participant will undergo pericardiocentesis (as per clinical indication)
• Within 5 days of ATT initiation

You may not qualify if:

• Glomerular filtration rate \<30ml/min or renal failure requiring dialysis
• Rifampin-resistant TB
• Severe concurrent opportunistic infection
• Contraindication to placement of intra-pericardial catheter
• Failed pericardiocentesis procedure and/or failure of placement of intra-pericardial catheter
• Any disease or condition in which the use of the standard anti-TB drugs (or any of their components) are contraindicated. This includes, but is not limited to, allergy to any TB drug or their components.
• In females: a positive urine pregnancy test result
• Confirmed autoimmune disorders (e.g. systemic lupus erythematosus)
• Any implanted devices that are not MR compatible (e.g. pacemaker, defibrillators, cerebral aneurysm clips, cochlear implants etc.)
• Claustrophobia
• Gadolinium allergy
• Inability to lie on a flat surface for prolonged periods of time (e.g. severe congestive cardiac failure)
• Breastfeeding

Sponsors & Collaborators

• University of Cape Town: lead

Study Sites (2)

Nelson Mandela Academic Hospital

Mthatha, Eastern Cape, 5099, South Africa

NOT YET RECRUITING

Groote Schuur Hospital

Cape Town, Western Cape, 7925, South Africa

RECRUITING

MeSH Terms

Conditions

Pericarditis, Tuberculous

Interventions

Rifampin

Condition Hierarchy (Ancestors)

Tuberculosis, Cardiovascular; Tuberculosis, Extrapulmonary; Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Cardiovascular Infections; Cardiovascular Diseases; Pericarditis; Heart Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Mpiko U Ntsekhe, Professor

  Department of Cardiology, Groote Schuur Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mpumi U Maxebengula, BCom

CONTACT

0727633386; mpumi.maxebengula@uct.ac.za

Kishal Maxebengula, Dr

CONTACT

+27732515380; kishal.lukhna@uct.ac.za

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Neither participants nor the investigators will be aware of the participant's treatment allocation until the end of the study (double blinding). Blinding will be maintained by manufacture of placebo tablets similar in appearance and packaging to that of the study drug, with centralized dispensing by the study pharmacist. Unmasking procedures are detailed by SOP.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: National Principal Investigator

Model Details: Participant identification numbers (PID), assigned at the screening visit, will be used throughout the study. After signing the informed consent document; eligible participants will be stratified by HIV status and then further stratified by GX-Ultra status to ensure equal allocation regardless of HIV status and likely subsequent culture status. An electronic randomization tool will be used to randomize the subgroups in a 1:1 ratio. The randomization list will be generated and updated by the study coordinator, trial pharmacist, or statistician who will have no direct contact with trial participants or involvement with the assessment for eligibility in the trial.

Study Record Dates

• First Submitted: July 16, 2020
• First Posted: August 21, 2020
• Study Start: January 10, 2022
• Primary Completion: September 15, 2025
• Study Completion: February 28, 2026
• Last Updated: August 21, 2025

Record last verified: 2025-03

Locations

ZA (2)