High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Tuberculous Pericarditis, HIV Status

Intervention / Treatment
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* Drug: high dose Rifampicin (RIF)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Arm 1: Standard of care (RIF10)<br>Dosing of the daily oral RHZE fixed dose combination (FDC) will be according to WHO weight bands | |
| Experimental: Arm 2: High-dose RIF (RIF35)<br>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)<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality between study arms | To investigate clinical outcome by mortality (attributable to PCTB and all cause) | week 8 and 52 weeks | 
| re-accumulation of pericardial effusion between study arms | To investigate clinical outcome by comparing clinical evidence of constrictive pericarditis between study arms | 52 weeks | 
| TB-IRIS between study arms | To investigate clinical outcome by comparison of the incidence of TB immune reconstitution inflammatory syndrome (TB-IRIS) between study arms | 52 weeks | 
| Constrictive pericarditis between the study arms | Comparison of the incidence of constrictive pericarditis between the study arms | 52 weeks | 
| CMR evidence | 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 | 52 weeks |