The I nvestigation of the M anagement of P er i carditis

1. The Investigation of the Management of Pericarditis The IMPI Trial (‘ee-MP-ee’ means Warriors in Zulu)

2. Duality of interests B.M. Mayosi has received research grants from AstraZeneca, Cadila Pharma, Novartis, Pfizer, Roche, and Servier

3. Background • Tuberculous (TB) pericarditis affects a million people per year. • The case fatality rate is 26% despite anti-TB treatment. • Hypotheses: • Anti-inflammatory effect of Steroids may reduce morbidity (i.e., cardiac tamponade and constrictive pericarditis) and mortality in TB pericarditis. • Immunotherapy with Mycobacterium indicus pranii (Mw), a non-pathogenic environmental organism, may enhance cure of TB. • However, the effectiveness and safety of Steroids and Mwin TB pericarditis in uncertain.

4. IMPI: Primary Objectives To assess the effect of Prednisolone and Mw in definite or probable TB pericardial effusion on: • The composite outcome of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis; • The incidence of opportunistic infection and malignancy.

5. IMPI Trial: Study Design PATIENTS WITH DEFINITE OR PROBABLETUBERCULOUS PERICARDIAL EFFUSION RANDOMIZATION PREDNISOLONE X 6 weeks PLACEBO X 6 weeks M. w X 5 Doses Placebo X 5 Doses M. w X 5 Doses Placebo X 5 Doses Follow-up data at hospital discharge, at weeks 2, 4 and 6, and months 3, 6 and thereafter 6 monthly for 2 years, and annually up to 4 years

6. IMPI: Trial Interventions • Prednisolone or placebo • 120 mg/day in 1st wk, followed by 90 mg/day in 2nd wk, 60 mg/day in 3rdwk, 30 mg/day in 4thwk, 15 mg/day in 5thwk, and 5 mg/day in 6th wk. • M. winjection orplacebo • 5 doses of 0.1 ml intradermal injection at enrolment, then 2 wks, 4 wks, 6 wks, and 3 mo.

7. IMPI: Organization 19 centres, 8 countries African Coordinating Center University of Cape Town South Africa International Coordinating Center Population Health Research Institute HHS and McMaster University, Hamilton, Canada Sponsors: Canadian Institutes for Health Research, Cadila Pharma, South African Medical Research Council, Lily and Ernst Hausmann Trust

8. IMPI: Target Population • Inclusion Criteria • Age ≥ 18 years • Pericardial effusion on echocardiography • Evidence of definite or probable TB pericarditis • Within 1 week of starting of anti-TB treatment • Exclusion Criteria • Presence of an alternative cause of pericardial disease • Pregnancy • Use of corticosteroids in the previous month • Allergy to the M. indicus pranii

9. IMPI : Baseline Characteristics

12. IMPI Prednisolone: Time To Constriction

13. IMPI Prednisolone: Hospitalization

14. IMPI: Time To Malignancy

15. IMPI: Conclusions In those with definite or probable TB pericardial effusion: • Prednisolone for 6 weeks and M.wfor three months had no significant effect on the combined outcome of death from all causes, cardiac tamponade requiring pericardiocentesis or constrictive pericarditis. • Both therapies were associated with an increased risk of HIV-associated malignancy. • However, use of prednisolone reduced the incidence of constrictive pericarditis and hospitalization. • The beneficial effects of prednisolone on constriction and hospitalization were similar in HIV-positive and HIV-negative patients.