High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis (IMPI-3)

IMPI-3 - A Randomized Controlled Trial of 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.

Study Overview

• Status: Recruiting
• Conditions: HIV Status; Tuberculous Pericarditis
• Intervention / Treatment: Drug: high dose Rifampicin (RIF)

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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mpumi U Maxebengula, BCom; Phone Number: 0727633386; Email: mpumi.maxebengula@uct.ac.za
• Study Contact Backup: Name: Kishal Maxebengula, Dr; Phone Number: +27732515380 +27732515380; Email: kishal.lukhna@uct.ac.za

Study Locations

• South Africa
  • Eastern Cape
    • Mthatha, Eastern Cape, South Africa, 5099
      • Not yet recruiting
      • Nelson Mandela Academic Hospital
      • Contact: Mpumi Maxebengula, BCom; Phone Number: 0727633386; Email: mpumi.maxebengula@uct.ac.za
      • Contact: Samuel Yao Alomatu, Dr; Phone Number: +27475316257; Email: samalomatu@yahoo.com
      • Principal Investigator: Khulile Moeketsi, Dr
      • Sub-Investigator: Samuel Alomatu, Dr
      • Sub-Investigator: Thandazile Obed Fathuse, Dr
      • Sub-Investigator: Pamela Mda, Dr
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • Recruiting
      • Groote Schuur Hospital
      • Principal Investigator: Mpiko Ntsekhe, PhD
      • Contact: Nompumelelo Maxebengula, Bcom; Phone Number: +27727633386; Email: mpumi.maxebengula@uct.ac.za
      • Contact: Kishal Lukhna, Dr; Phone Number: +27732515380; Email: kishal.lukhna@uct.ac.za
      • Sub-Investigator: Robert J Wilkinson, PhD
      • Sub-Investigator: Sean Wasserman, PhD
      • Sub-Investigator: Kishal Lukhna, Dr
      • Sub-Investigator: Vanessa Mabiala, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate the safety and tolerability of RIF35 for PCTB by:	The occurrence of Grade 3 or 4 transaminitis during ATT; Permanent discontinuation of the RIF10 or RIF35 ATT arm at week 8	week 8 and 52 weeks
Discontinuation rate	Comparison of discontinuation rates between study arms Comparison of discontinuation rates between study arms	52 weeks
Change in Mtb bacterial load	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	72 hours
Relationships between pericardial Mtb-specific T cells with Mtb bacterial load	To determine relationships between pericardial Mtb-specific T cells with Mtb bacterial load, treatment response and outcome in PCTB	52 weeks
Mtb-induced markers of host cell death pathways and Mtb bacterial load in PCTB	To assess whether there is association between Mtb-induced markers of host cell death pathways and Mtb bacterial load in PCTB	52 weeks

Collaborators and Investigators

• Sponsor: University of Cape Town
• Investigators: Principal Investigator: Mpiko U Ntsekhe, Professor, Department of Cardiology, Groote Schuur Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2022
• Primary Completion (Estimated): September 15, 2025
• Study Completion (Estimated): February 28, 2026

Study Registration Dates

• First Submitted: July 16, 2020
• First Submitted That Met QC Criteria: August 17, 2020
• First Posted (Actual): August 21, 2020

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Cardiovascular Infections; Tuberculosis, Cardiovascular; Tuberculosis, Extrapulmonary; Tuberculosis; Pericarditis; Pericarditis, Tuberculous; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin
• Other Study ID Numbers: IMPI-3 DMID 20-0007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No