Slides - Clinical Trial Results

Report
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 nonpathogenic 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.
IMPI Trial: Study Design
PATIENTS WITH DEFINITE OR PROBABLE
TUBERCULOUS PERICARDIAL EFFUSION
RANDOMIZATION
M. w
X 5 Doses
PREDNISOLONE
PLACEBO
X 6 weeks
X 6 weeks
Placebo
X 5 Doses
M. w
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
Placebo
X 5 Doses
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 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
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
N
Age in yrs
Female %
HIV positive %
Centesis done %
Definite TB %
Probable TB pericarditis %
Non-TB cause %
On anti-retrovirals %
Prednisolone
706
38.8
44.9
67.1
60.6
26.7
71.7
1.5
14.0
Placebo
694
38.5
43.1
67.0
60.4
26.7
72.9
0.4
15.0
Effect of Prednisolone on Outcomes
Prednisolone
N(%)
Placebo
Hazard Ratio (95% CI)
P
N(%)
Primary efficacy outcome 168 ( 23.8)
170 (24.5 )
0.95 ( 0.77 -1.18)
0.66
Death
Tamponade
Constriction
Hospitalization
133 ( 18.8)
22 ( 3.1 )
31 ( 4.4 )
146 ( 20.7)
115
28
54
175
(16.6 )
( 4.0 )
( 7.8 )
(25.2 )
1.15
0.77
0.56
0.79
( 0.90
( 0.44
( 0.36
( 0.63
- 1.48 )
- 1.35 )
- 0.87 )
- 0.99 )
0.26
0.37
0.01
0.04
Opportunistic infection
Malignancy
AE, Not Hospitalized
Injection side effect
78 ( 11.0)
13 ( 1.8 )
171 ( 24.2)
140 ( 19.8)
68
4
149
137
( 9.8 )
( 0.6 )
(21.5 )
(19.7 )
1.16
3.27
1.15
0.98
( 0.84
( 1.07
( 0.93
( 0.77
- 1.61 )
-10.03 )
- 1.44 )
- 1.24 )
0.36
0.03
0.20
0.84
0.5
2
PrednisolonePlacebo
Better
Better
Effect of M. indicus pranii on Outcomes
Mycobacterium Placebo
Hazard Ratio (95% CI)
P
N(%)
N(%)
Primary efficacy outcome
156 ( 25.0)
152 (24.3)
1.03 ( 0.82 - 1.29 )
0.81
Death
Tamponade
Constriction
Hospitalization
119 ( 19.0)
22 ( 3.5 )
36 ( 5.8 )
152 ( 24.3)
111 (17.8)
22 ( 3.5 )
37 ( 5.9 )
141 (22.6)
1.07 ( 0.83
0.99 ( 0.55
0.97 ( 0.61
1.09 ( 0.87
0.59
0.98
0.89
0.46
Opportunistic infection
Malignancy
AE, Not Hospitalized
Injection side effect
75 ( 12.0)
11 ( 1.8 )
148 ( 23.7)
259 ( 41.4)
61 ( 9.8 )
3 ( 0.5 )
149 (23.8)
18 ( 2.9 )
- 1.39 )
- 1.79 )
- 1.53 )
- 1.37 )
1.25 ( 0.89 - 1.75 ) 0.20
3.69 ( 1.03 -13.24 ) 0.03
1.00 ( 0.79 - 1.25 ) 0.97
18.51(11.47 -29.87 ) <0.01
0.5
2
MycbacteriumPlacebo
Better
Better
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 HIVassociated 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.

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