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NCT Number: NCT04521803

High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis

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.

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Key information

Conditions

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

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Nelson Mandela Academic Hospital, Mthatha, Eastern Cape, South Africa

Loading trial locations.

About this study

IMPI-3 - A Randomized Controlled Trial of High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis

Phase 2b Randomized, placebo-controlled, double-blinded clinical trial

The trial will enroll 100 adult participants with pericardial TB from two research sites in South Africa, with no exclusions being made on the basis of sex/gender, racial or ethnic group.

Consenting participants will be stratified by HIV status and PCF GX-Ultra status, then randomized 1:1 to receive either standard of care anti-tuberculosis treatment (ATT) or standard of care plus high dose Rifampicin (RIF), both administered orally for 2 months, followed by a continuation phase of 4 months' RH at standard doses.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Exclusion criteria

  • 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)

Additional Exclusions for Gadolinium contrasted CMR

  • 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

Treatment and study plan

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

Primary outcomes

  1. Drug exposure in PCF and mediates in Mtb load

    Time frame: 72 hours and 52 weeks

    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

Secondary outcomes

  1. Mortality between study arms

    Time frame: week 8 and 52 weeks

    To investigate clinical outcome by mortality (attributable to PCTB and all cause)

  2. re-accumulation of pericardial effusion between study arms

    Time frame: 52 weeks

    To investigate clinical outcome by comparing clinical evidence of constrictive pericarditis between study arms

  3. TB-IRIS between study arms

    Time frame: 52 weeks

    To investigate clinical outcome by comparison of the incidence of TB immune reconstitution inflammatory syndrome (TB-IRIS) between study arms

  4. Constrictive pericarditis between the study arms

    Time frame: 52 weeks

    Comparison of the incidence of constrictive pericarditis between the study arms

  5. CMR evidence

    Time frame: 52 weeks

    To investigate clinical outcome by evidence on week 52 CMR of:

    • Constrictive physiology
    • Pericardial inflammation
    • Pericardial thickening
    • Pericardial fibrosis
    • Inflammatory exudative or hemorrhagic pericardial effusion

Other outcomes

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

    Time frame: week 8 and 52 weeks

    • The occurrence of Grade 3 or 4 transaminitis during ATT
    • Permanent discontinuation of the RIF10 or RIF35 ATT arm at week 8

  2. Discontinuation rate

    Time frame: 52 weeks

    Comparison of discontinuation rates between study arms Comparison of discontinuation rates between study arms

  3. Change in Mtb bacterial load

    Time frame: 72 hours

    To investigate early change in Mtb bacterial load by measures other than culture TTP (CFU, Xpert ct values, ddPCR, CEQ, Mtb RNA, FujiLAM) in PCF over 72 hours by treatment allocation

  4. Relationships between pericardial Mtb-specific T cells with Mtb bacterial load

    Time frame: 52 weeks

    To determine relationships between pericardial Mtb-specific T cells with Mtb bacterial load, treatment response and outcome in PCTB

  5. Mtb-induced markers of host cell death pathways and Mtb bacterial load in PCTB

    Time frame: 52 weeks

    To assess whether there is association between Mtb-induced markers of host cell death pathways and Mtb bacterial load in PCTB

Study contacts

Contact information is provided by the study sponsor or research team.

Kishal Maxebengula, Dr

CONTACT

[email protected]

+27732515380 ext. +27732515380

Mpumi U Maxebengula, BCom

CONTACT

[email protected]

0727633386

Sponsors and collaborators

Lead sponsor

University of Cape Town

Other

Registry information

Official study title

IMPI-3 - A Randomized Controlled Trial of High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis

Acronym: IMPI-3

Important dates

Study start
2022
Primary completion
2025
Study completion
2026
First posted
Aug 21, 2020
Registry last updated
Aug 21, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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