Duality%20of%20interests

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Duality of interests

• B.M. Mayosi has received research grants from
  AstraZeneca, Cadila Pharma, Novartis, Pfizer,
  Roche, and Servier

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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

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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.
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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.

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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.

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IMPI Organization
19 Centers in Africa
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
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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

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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)
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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)
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IMPI Time To Primary Outcome
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IMPI Prednisolone Time To Constriction
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IMPI Prednisolone Hospitalization
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IMPI Time To Malignancy
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IMPI Prednisolone Sub-group analysis
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IMPI Prednisolone Sub-group analysis
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IMPI Conclusions

• In those with definite or probable TB pericardial
  effusion
• 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.
• Both therapies were associated with an increased
  risk of HIV-associated malignancies.
• However, use of adjunctive steroids reduced the
  incidence of pericardial constriction and
  hospitalization.
• The beneficial effects of prednisolone on
  constriction and hospitalization were similar in
  HIV-positive and HIV-negative patients.