The Investigation of the Management of Pericarditis

The IMPI Trial

(‘ee-MP-ee’ means Warriors in Zulu)

Duality of interests

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

Pharma, Novartis, Pfizer, Roche, and Servier

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 Mw in TB pericarditis in uncertain.

IMPI: Primary Objectives

To assess the effect of Prednisolone and Mw in definite or probable TB pericardial effusion on:

(1)The composite outcome of death, cardiac tamponade requiring pericardiocentesis, or

constrictive pericarditis;

(2)The incidence of opportunistic infection and malignancy.

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

Placebo X 5 Doses

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

IMPI Trial: Study Design

IMPI: Trial Interventions

• Prednisolone or placebo

–120 mg/day in 1st wk, followed by 90 mg/day in 2nd wk, 60 mg/day in 3rd wk, 30 mg/day in 4th wk, 15 mg/day in 5th wk, and 5 mg/day in 6th wk.

• M. w injection or placebo

–5 doses of 0.1 ml intradermal injection at enrolment, then 2 wks, 4 wks, 6 wks, and 3 mo.

IMPI: Organization

19 centres, 8 countries

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• 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

IMPI : Baseline Characteristics

Characteristics Prednisolone Placebo

N 706 694

Age in yrs 38.8 38.5

Female % 44.9 43.1

HIV positive % 67.1 67.0

Centesis done % 60.6 60.4

Definite TB % 26.7 26.7

Probable TB pericarditis % 71.7 72.9

Non-TB cause % 1.5 0.4

On anti-retrovirals % 14.0 15.0

0.5 2Prednisolone

BetterPlacebo Better

Primary efficacy outcome

DeathTamponadeConstrictionHospitalization

Opportunistic infectionMalignancyAE, Not HospitalizedInjection side effect

Prednisolone Placebo Hazard Ratio (95% CI) P

N(%) N(%)

168 (23.8) 170 (24.5 ) 0.95 (0.77 - 1.18 ) 0.66

133 (18.8) 115 (16.6 ) 1.15 (0.90 - 1.48 ) 0.26 22 ( 3.1 ) 28 ( 4.0 ) 0.77 (0.44 - 1.35 ) 0.37 31 ( 4.4 ) 54 ( 7.8 ) 0.56 (0.36 - 0.87 ) 0.01146 (20.7) 175 (25.2 ) 0.79 (0.63 - 0.99 ) 0.04

78 (11.0 ) 68 ( 9.8 ) 1.16 (0.84 - 1.61 ) 0.36 13 ( 1.8 ) 4 ( 0.6 ) 3.27 (1.07 - 10.03 ) 0.03171 (24.2) 149 (21.5 ) 1.15 (0.93 - 1.44 ) 0.20140 (19.8) 137 (19.7 ) 0.98 (0.77 - 1.24 ) 0.84

Effect of Prednisolone on Outcomes

0.5 2Mycbacterium

BetterPlacebo Better

Primary efficacy outcome

DeathTamponadeConstrictionHospitalization

Opportunistic infectionMalignancyAE, Not HospitalizedInjection side effect

Mycobacterium Placebo Hazard Ratio (95% CI) P

N(%) N(%)

156 ( 25.0) 152 (24.3) 1.03 ( 0.82 - 1.29 ) 0.81

119 ( 19.0) 111 (17.8) 1.07 ( 0.83 - 1.39 ) 0.59 22 ( 3.5 ) 22 ( 3.5 ) 0.99 ( 0.55 - 1.79 ) 0.98 36 ( 5.8 ) 37 ( 5.9 ) 0.97 ( 0.61 - 1.53 ) 0.89152 ( 24.3) 141 (22.6) 1.09 ( 0.87 - 1.37 ) 0.46

75 ( 12.0) 61 ( 9.8 ) 1.25 ( 0.89 - 1.75 ) 0.20 11 ( 1.8 ) 3 ( 0.5 ) 3.69 ( 1.03 - 13.24 ) 0.03148 ( 23.7) 149 (23.8) 1.00 ( 0.79 - 1.25 ) 0.97259 ( 41.4) 18 ( 2.9 ) 18.51 (11.47 - 29.87 ) <0.01

Effect of M. indicus pranii on Outcomes

IMPI Prednisolone: Time To Constriction

IMPI Prednisolone: Hospitalization

IMPI: Time To Malignancy

IMPI: Conclusions

In those with definite or probable TB pericardial effusion:

1. Prednisolone for 6 weeks and M.w for three months had no 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 malignancy.

3. However, use of prednisolone reduced the incidence of constrictive pericarditis and hospitalization.

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