Duality of interests

B.M. Mayosi has received research grants from AstraZeneca, Cadila

Pharma, Novartis, Pfizer, Roche, and Servier

Background

• Tuberculous (TB) pericarditis affects up to a million people per year worldwide.

• The case fatality rate associated with tuberculous pericarditis is as high as 40% despite anti-tuberculosis treatment.

• The use of adjunctive corticosteroids may reduce the inflammatory response to tuberculosis and reduce morbidity (i.e., cardiac tamponade and constrictive pericarditis) and mortality associated with the disease.

• There is also evidence that immunotherapy with Mycobacterium indicus pranii, a non-pathogenic environmental organism, may reduce inflammation associated with pulmonary TB.

•However, there is uncertainty about the safety and effectiveness of adjunctive steroids and Mycobacterium indicus pranii in TB pericarditis

IMPI: Primary Objective

The primary objective of the Investigation of the Management of Pericarditis (IMPI) Trial was to assess the safety and effectiveness of oral prednisolone and Mycobacterium indicus pranii immunotherapy in

reducing the composite outcome of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis in patients with definite or

probable tuberculous pericardial effusion.

IMPI: Study Design

• Randomized double-blind placebo-controlled 2x2 factorial multi-centre and multi-national trial;

• Enrol 1400 patients with definite or probable TB pericardial effusion over 36 months, and follow the last patient enrolled for 6 months;

•Eligible patients were randomly assigned to receive oral prednisolone or placebo for 6 weeks and Mycobacterium indicus pranii injection or placebo for 3 months;

• Patients were followed at weeks 2, 4, 6, and months 3 and 6, six-monthly follow-up was performed thereafter for up to four years.

IMPI: Trial Interventions

• Prednisolone and placebo were supplied as identical tablets (5mg, 30mg and 40mg) and given at a dosage of 120 mg/day in the first week, followed by 90 mg/day in the second week, 60 mg/day in the third week, 30 mg/day in the fourth week, 15 mg/day in the fifth week, and 5 mg/day in the sixth week.

• Patients enrolled in the Mycobacterium indicus pranii received 5 doses of 0.1 ml of the vaccine intradermally (on enrolment, at 2 weeks, 4 weeks, 6 weeks, and 3 months). Patients in the control arm received a similar regimen of placebo injections of normal saline in identically packaged vials.

IMPI: Organization

19 Centers in Africa

African Coordinating CenterUniversity 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

IMPI: Target Population

Inclusion Criteria: • Age ≥ 18 years• Confirmed pericardial effusion on echocardiography• Evidence of definite or probable TB pericarditis (Mayosi BM et al. Circulation 2005)• Within 1 week of starting of anti-TB treatment• Informed consent

Exclusion Criteria:• Presence of an alternative cause of pericardial disease• Pregnancy• Use of corticosteroids within the previous month• Hypersensitivity or allergy to the Mycobacterium indicus pranii

IMPI Prednisolone: Selected Baseline Characteristics

Characteristics Prednisolone Placebo

N= 706 694

Age (SD) 38.8 (13.5) 38.5 (13.3)

Female (n, %) 317 (44.9) 299 (43.1)

HIV positive (n, %) 474 (67.1) 465 (67.0)

Centesis done (n, %) 428 (60.6) 419 (60.4)

Definite TB (n, %) 189 (26.7) 185 (26.7)

Probable TB pericarditis 506 (71.7) 506 (72.9)

Non-TB cause (n, %) 11 (1.5) 3 (0.4)

On anti-retrovirals (n, %) 99 (14.0) 104 (15.0)

IMPI Mycobacterium : Selected Baseline Characteristics

Characteristics M. Indicus pranii Placebo

N= 625 625

Age (SD) 37.7 (12.5) 39.3 (14.1)

Female (n, %) 292 (46.7) 263 (42.1)

HIV positive (n, %) 437 (69.9) 403 (64.5)

Centesis done (n, %) 372 (59.5) 381(61.0)

Definite TB (n, %) 167 (26.7) 158 (25.3)

Probable TB pericarditis 450 (72.0) 462 (73.9)

Non-TB cause (n, %) 8 (1.3) 5 (0.8)

On anti-retrovirals (n, %) 88 (14.1) 84 (13.4)

IMPI: Time To Primary Outcome

IMPI Prednisolone: Time To Constriction

IMPI Prednisolone: Hospitalization

IMPI: Time To Malignancy

IMPI Prednisolone: Sub-group analysis

IMPI Prednisolone: Sub-group analysis

IMPI: Conclusions

In those with definite or probable TB pericardial effusion:

1. Adjunctive therapy with prednisolone for 6 weeks and Mycobacterium indicus pranii for three months did not have a significant effect on the combined outcome of death from all causes, cardiac tamponade requiring pericardiocentesis or constrictive pericarditis.

2. Both therapies were associated with an increased risk of HIV-associated malignancies.

3. However, use of adjunctive steroids reduced the incidence of pericardial constriction and hospitalization.

4. The beneficial effects of prednisolone on constriction and hospitalization were similar in HIV-positive and HIV-negative patients.