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.

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.

Inclusion Criteria:

1. Aged >18 years

2. Suspected PCTB with confirmed pericardial effusion on echocardiography (i.e., echo free space of ≥1 cm anterior to the right ventricle in diastole)

3. Consent to study participation including testing for HIV-1 (if HIV status is unknown)

4. 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:

   1. Evidence of pericarditis with microbiologic confirmation of Mtb- infection elsewhere in the body and/or
   2. Exudative, lymphocyte predominant effusion with elevated adenosine deaminase (≥35 U/L)

5. Participant will undergo pericardiocentesis (as per clinical indication)

6. Within 5 days of ATT initiation

Exclusion Criteria:

1. Glomerular filtration rate <30ml/min or renal failure requiring dialysis
2. Rifampin-resistant TB
3. Severe concurrent opportunistic infection
4. Contraindication to placement of intra-pericardial catheter
5. Failed pericardiocentesis procedure and/or failure of placement of intra-pericardial catheter
6. 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.
7. In females: a positive urine pregnancy test result
8. Confirmed autoimmune disorders (e.g. systemic lupus erythematosus)

Additional Exclusions for Gadolinium contrasted CMR

1. Any implanted devices that are not MR compatible (e.g. pacemaker, defibrillators, cerebral aneurysm clips, cochlear implants etc.)
2. Claustrophobia
3. Gadolinium allergy
4. Inability to lie on a flat surface for prolonged periods of time (e.g. severe congestive cardiac failure)
5. Breastfeeding

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.