Tuberculous Pericarditis Clinical Trial
Official title:
A Trial of Adjunctive Prednisolone and Mycobacterium w Immunotherapy in Tuberculous Pericarditis
Human immunodeficiency virus (HIV) infection puts people at risk of opportunistic infections, such as tuberculosis. In Africa, the HIV epidemic has resulted in an increase in the number of cases of tuberculosis affecting various parts of the body, including the membrane surrounding the heart (i.e., pericardium). Pericardial tuberculosis is a serious form of tuberculosis that results in the death or disability of 1 in 2 affected people despite the use of antituberculosis medication. It has been suggested that the addition of corticosteroids to the antituberculosis medication could result in the reduction of the number of deaths caused by the disease, but this proposal remains to be confirmed in appropriately designed clinical trials. Similarly, vaccination with the Mycobacterium w injection is also proposed as a possible way of reducing the damage caused by the tuberculosis infection of the heart. The investigators are proposing to conduct a clinical trial in which people who are on antituberculosis treatment for pericardial tuberculosis will be randomly allocated to receive either prednisolone or a matching placebo tablet, or Mycobacterium w injection or placebo injection. The number of people who die or who develop hardening of the pericardium with compression of the heart (called pericardial constriction) or who need emergency evacuation of the pericardial fluid from pericardial sac for severe compression (called tamponade) will be compared in each group to determine whether the use of corticosteroids or Mycobacterium w injection is safe and results in reduction in the death rate. If corticosteroids and Mycobacterium w are shown to safely reduce the death rate, then they will be recommended for use in all patients with tuberculosis of the pericardium in the future.
Summary of research proposal Tuberculous pericarditis is one of the most severe forms of
infection with Mycobacterium tuberculosis, causing death or cardiac disability in nearly
half of those affected in spite of antituberculosis chemotherapy. Attenuation of the
inflammatory response in tuberculous pericarditis may improve outcome by reducing the
likelihood of cardiac tamponade and pericardial constriction. A meta-analysis of all
randomized controlled trials of corticosteroids for tuberculous pericarditis showed a trend
towards reduction of mortality, but the studies were too small to confirm any effect on
survival. Concern remains that corticosteroids might increase the frequency of opportunistic
infections and cancers in patients infected with the Human Immunodeficiency Virus (HIV). In
addition to the promising but inconclusive evidence on adjunctive steroids, there is
preliminary evidence suggesting that repeated doses of Mycobacterium w immunotherapy may
reduce the inflammation associated with extrapulmonary tuberculosis and increase the CD4
cell count in people infected with HIV. These early observations remain to be tested in a
large randomized trial with the hard endpoint of mortality.
The Investigation of the Management of Pericarditis in Africa (IMPI [pronounced as
'ee-mp-ee', for Zulu warriors]) Trial will assess effectiveness and safety of oral
prednisolone or placebo and Mycobacterium w immunotherapy or placebo in 1400 patients with
tuberculous pericardial effusion. This trial will also determine the feasibility of
conducting a large-scale multicentre clinical trial in patients with tuberculous
pericarditis in sub-Saharan Africa.
Hypothesis: We hypothesize that patients with suspected tuberculous pericarditis randomized
to adjunctive oral prednisolone for 6 weeks will have a 30% reduction in mortality compared
to placebo, and that patients randomized to Mycobacterium w injections for 6 months will
have a better survival compared to placebo.
Objectives: The primary objectives of the IMPI Trial are: a) to determine the effectiveness
of oral prednisolone and Mycobacterium w immunotherapy in reducing the composite outcome of
death, constriction or pericardial drainage for cardiac tamponade in patients with
tuberculous pericardial effusion, b) to assess the safety and interactive effects of the
co-administration of prednisolone and Mycobacterium w immunotherapy, and c) to demonstrate
the feasibility of conducting a study in patients with tuberculous pericardial effusion in
sub-Saharan Africa, and establish the infrastructure for conducting the full-scale IMPI
trial in an internal pilot phase of the first 200 participants.
If the internal pilot phase is positive, all the patients will be rolled-over into the
full-scale IMPI trial. The first occurrence of death will be recorded to improve estimates
of outcomes for the full-scale trial. Secondary outcomes of the full-scale trial will
include: 1) constriction, 2) rate of occurrence of cardiac tamponade requiring
pericardiocentesis, 3) rate of resolution of pericardial effusion, 4) improvement in
functional class.
Study Design: IMPI is a randomized double-blind placebo-controlled 2x2 factorial pilot trial
that will enroll 1400 patients from multiple centres in Kenya, Malawi, Mozambique, Nigeria,
Sierra Leone, South Africa, Uganda and Zimbabwe. Patients with tuberculous pericarditis who
fulfill the inclusion criteria will be randomly assigned to receive oral prednisolone or
placebo for 6 weeks and Mycobacterium w injection or placebo for 6 months. Patients will be
followed closely during the intervention period (at weeks 2, 4, 6, and months 3 and 6).
Six-monthly follow-up will be performed thereafter for up to two years. The recruitment of
the 1400 patients will be performed over 54 months, with a minimum follow-up period of 6
months for the last participants recruited in the trial. The Population Health Research
Institute at McMaster University will manage and coordinate the study in association with
the IMPI Project Office that is located in the Department of Medicine, Groote Schuur
Hospital, Cape Town, South Africa.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT04521803 -
High vs. Standard Dose Rifampicin for Effusive Tuberculous Pericarditis
|
Phase 2 |