Back to resultsHigh vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis (IMPI-3)
Primary Purpose
Tuberculous Pericarditis, HIV Status
Status
Recruiting
Phase
Phase 2
Locations
South Africa
Study Type
Interventional
Intervention
high dose Rifampicin (RIF)
Sponsored by
About this trial
This is an interventional basic science trial for Tuberculous Pericarditis
Eligibility Criteria
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
Sites / Locations
- Nelson Mandela Academic Hospital
- Groote Schuur HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
No Intervention
Experimental
Arm Label
Arm 1: Standard of care (RIF10)
Arm 2: High-dose RIF (RIF35)
Arm Description
Dosing of the daily oral RHZE fixed dose combination (FDC) will be according to WHO weight bands
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
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
Mortality between study arms
To investigate clinical outcome by mortality (attributable to PCTB and all cause)
re-accumulation of pericardial effusion between study arms
To investigate clinical outcome by comparing clinical evidence of constrictive pericarditis between study arms
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
Constrictive pericarditis between the study arms
Comparison of the incidence of constrictive pericarditis between the study arms
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04521803
Brief Title
High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis
Acronym
IMPI-3
Official Title
IMPI-3 - A Randomized Controlled Trial of High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 10, 2022 (Actual)
Primary Completion Date
October 31, 2024 (Anticipated)
Study Completion Date
October 31, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cape Town
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculous Pericarditis, HIV Status
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigator
Masking Description
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.
Allocation
Randomized
Enrollment
80 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Arm 1: Standard of care (RIF10)
Arm Type
No Intervention
Arm Description
Dosing of the daily oral RHZE fixed dose combination (FDC) will be according to WHO weight bands
Arm Title
Arm 2: High-dose RIF (RIF35)
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
high dose Rifampicin (RIF)
Intervention Description
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 Outcome Measure Information:
Title
Drug exposure in PCF and mediates in Mtb load
Description
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
Time Frame
72 hours and 52 weeks
Secondary Outcome Measure Information:
Title
Mortality between study arms
Description
To investigate clinical outcome by mortality (attributable to PCTB and all cause)
Time Frame
week 8 and 52 weeks
Title
re-accumulation of pericardial effusion between study arms
Description
To investigate clinical outcome by comparing clinical evidence of constrictive pericarditis between study arms
Time Frame
52 weeks
Title
TB-IRIS between study arms
Description
To investigate clinical outcome by comparison of the incidence of TB immune reconstitution inflammatory syndrome (TB-IRIS) between study arms
Time Frame
52 weeks
Title
Constrictive pericarditis between the study arms
Description
Comparison of the incidence of constrictive pericarditis between the study arms
Time Frame
52 weeks
Title
CMR evidence
Description
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
Time Frame
52 weeks
Other Pre-specified Outcome Measures:
Title
To investigate the safety and tolerability of RIF35 for PCTB by:
Description
The occurrence of Grade 3 or 4 transaminitis during ATT
Permanent discontinuation of the RIF10 or RIF35 ATT arm at week 8
Time Frame
week 8 and 52 weeks
Title
Discontinuation rate
Description
Comparison of discontinuation rates between study arms Comparison of discontinuation rates between study arms
Time Frame
52 weeks
Title
Change in Mtb bacterial load
Description
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
Time Frame
72 hours
Title
Relationships between pericardial Mtb-specific T cells with Mtb bacterial load
Description
To determine relationships between pericardial Mtb-specific T cells with Mtb bacterial load, treatment response and outcome in PCTB
Time Frame
52 weeks
Title
Mtb-induced markers of host cell death pathways and Mtb bacterial load in PCTB
Description
To assess whether there is association between Mtb-induced markers of host cell death pathways and Mtb bacterial load in PCTB
Time Frame
52 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mpumi U Maxebengula, BCom
Phone
0727633386
Email
mpumi.maxebengula@uct.ac.za
First Name & Middle Initial & Last Name or Official Title & Degree
Kishal Maxebengula, Dr
Phone
+27732515380
Ext
+27732515380
Email
kishal.lukhna@uct.ac.za
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mpiko U Ntsekhe, Professor
Organizational Affiliation
Department of Cardiology, Groote Schuur Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Nelson Mandela Academic Hospital
City
Mthatha
State/Province
Eastern Cape
ZIP/Postal Code
5099
Country
South Africa
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mpumi Maxebengula, BCom
Phone
0727633386
Email
mpumi.maxebengula@uct.ac.za
First Name & Middle Initial & Last Name & Degree
Samuel Yao Alomatu, Dr
Phone
+27475316257
Email
samalomatu@yahoo.com
First Name & Middle Initial & Last Name & Degree
Khulile Moeketsi, Dr
First Name & Middle Initial & Last Name & Degree
Samuel Alomatu, Dr
First Name & Middle Initial & Last Name & Degree
Thandazile Obed Fathuse, Dr
First Name & Middle Initial & Last Name & Degree
Pamela Mda, Dr
Facility Name
Groote Schuur Hospital
City
Cape Town
State/Province
Western Cape
ZIP/Postal Code
7925
Country
South Africa
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nompumelelo Maxebengula, Bcom
Phone
+27727633386
Email
mpumi.maxebengula@uct.ac.za
First Name & Middle Initial & Last Name & Degree
Kishal Lukhna, Dr
Phone
+27732515380
Email
kishal.lukhna@uct.ac.za
First Name & Middle Initial & Last Name & Degree
Mpiko Ntsekhe, PhD
First Name & Middle Initial & Last Name & Degree
Robert J Wilkinson, PhD
First Name & Middle Initial & Last Name & Degree
Sean Wasserman, PhD
First Name & Middle Initial & Last Name & Degree
Kishal Lukhna, Dr
First Name & Middle Initial & Last Name & Degree
Vanessa Mabiala, Dr
12. IPD Sharing Statement
Plan to Share IPD
Undecided
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High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis
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