A Trial of Adjunctive Prednisolone and Mycobacterium w Immunotherapy in Tuberculous Pericarditis

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.

Inclusion criteria

Patients admitted with suspected tuberculous pericarditis will be eligible if they meet all three of the following criteria:

• A confirmed pericardial effusion on echocardiography;
• Evidence of definite or probable tuberculous pericarditis; and
• Within 1 week of starting of antituberculosis treatment.

Exclusion criteria

• Presence of an alternative cause of pericardial disease, e.g., penetrating chest trauma in the previous 12 months and malignancy.
• Use of corticosteroids within the previous month.
• Hypersensitivity or allergy to the Mycobacterium w vaccine.
• Pregnancy.
• Age < 18 years.