Clinical trial NCT04521803: High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis
Official title: IMPI-3 - A Randomized Controlled Trial of High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Tuberculous Pericarditis
HIV Status
Lead sponsor: University of Cape Town
Sponsor class: OTHER
First posted: 2020-08-21
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: BASIC_SCIENCE

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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Drug exposure in PCF and mediates in Mtb load
timeFrame: 72 hours and 52 weeks
Secondary outcomes:
measure: Mortality between study arms
timeFrame: week 8 and 52 weeks
measure: re-accumulation of pericardial effusion between study arms
timeFrame: 52 weeks
measure: TB-IRIS between study arms
timeFrame: 52 weeks
measure: Constrictive pericarditis between the study arms
timeFrame: 52 weeks
measure: CMR evidence
timeFrame: 52 weeks
Other outcomes:
measure: To investigate the safety and tolerability of RIF35 for PCTB by:
timeFrame: week 8 and 52 weeks
measure: Discontinuation rate
timeFrame: 52 weeks
measure: Change in Mtb bacterial load
timeFrame: 72 hours
measure: Relationships between pericardial Mtb-specific T cells with Mtb bacterial load
timeFrame: 52 weeks
measure: Mtb-induced markers of host cell death pathways and Mtb bacterial load in PCTB
timeFrame: 52 weeks
Locations:
city: Mthatha
country: South Africa
facility: Nelson Mandela Academic Hospital
state: Eastern Cape
city: Cape Town
country: South Africa
facility: Groote Schuur Hospital
state: Western Cape
Study officials:
affiliation: Department of Cardiology, Groote Schuur Hospital
name: Mpiko U Ntsekhe, Professor
role: PRINCIPAL_INVESTIGATOR
References: