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Using an External Control to Evaluate the Effectiveness of Posaconazole for Refractory Invasive Fungal Infections


Open-label, non-randomized, multinational, salvage therapy study ... Exclude control subjects who died within 72 hours of after the initiation of therapy ... – PowerPoint PPT presentation

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Title: Using an External Control to Evaluate the Effectiveness of Posaconazole for Refractory Invasive Fungal Infections

Using an External Control to Evaluate the
Effectiveness of Posaconazole for Refractory
Invasive Fungal Infections
  • Kenneth J. Koury
  • Jagadish P. Gogate
  • Schering-Plough Research Institute

Refractory Invasive Fungal Infections(rIFI)
  • Life-threatening infections
  • Limited therapeutic options, especially in
    salvage setting
  • Randomized study
  • straightforward interpretation of results
  • not practical to complete in a timely fashion
  • serious ethical issue potential enrollment of
    subjects into a failing regimen
  • No randomized trials completed for salvage
    therapy for any antifungal drug

Description of Study P00041
  • Open-label, non-randomized, multinational,
    salvage therapy study
  • Posaconazole oral suspension 400 mg bid
  • Subjects with invasive fungal infections
    refractory to standard antifungal therapies or
    subjects who were intolerant of standard
    antifungal agents
  • Started In January 1999 (compassionate use)
  • Enrollment expanded based on investigator
    interest, completed by April 2001

Advice from Regulatory Authorities
  • CPMP (Committee for Proprietary Medicinal
  • lack of randomized trial always makes it
    difficult to evaluate a new agent
  • well-conducted external-control study may provide
    a useful comparative reference
  • sponsor must demonstrate that any potential
    selection bias was minimized
  • show that two groups are clinically similar

Advice from Regulatory Authorities
  • FDA
  • treatment for rIFI may fulfill an unmet medical
  • response rates from a control group required
  • numerous discussions regarding design and
    analysis of external-control study (P02387)
  • comparability of patient populations
  • minimization of potential bias

External-Control Study (P02387)
  • Provide reference (benchmark) for comparison to
  • Procedures and methods prospectively implemented
    to minimize potential sources of bias
  • Exhaustive review of all cases of IFI at study
    centers over target time period
  • 2073 screened for possible enrollment
  • 279 fulfilled criteria

Control of Potential Bias
  • External Data Review Committee (DRC)
  • 15 independent clinical experts and 2
  • Concurrent, blinded review of data from 330
    posaconazole-treated subjects (P00041) and 279
    external-control subjects (P02387)
  • Determined patient eligibility
  • met MSG/EORTC criteria for proven or probable IFI
  • met criteria for refractory disease or
    intolerance of standard therapy or both
  • Determined patient outcome global response
    status at end of treatment

Selection Bias
  • Exhaustive review of all cases of IFI at study
    centers during comparable time period
  • Similar inclusion and exclusion criteria
  • Autopsy data not used for identifying control
  • Exclude control subjects who died within 72 hours
    of after the initiation of therapy

Information Bias
  • Inherent differences in the amount of data
    available in a retrospective study vs.
    prospective study
  • Develop uniform format for data presentation to
    maintain blinding of DRC
  • Outcome data from a given subject are not
    available for review by DRC until eligibility of
    that subject has been determined

Temporal and Geographic Bias
  • Use same time frame (almost concurrent rather
    than historical controls)
  • Use mostly same centers
  • Expect controls to have similar disease
    characteristics to posaconazole-treated subjects

Other Important Factors
  • Primary pathogen (type of fungus)
  • Infection site
  • Underlying disease and associated treatments
  • BMT, Solid Organ Transplant
  • Hematologic malignancies
  • HIV/Aids
  • Use of immune response modifiers, growth factors

Baseline and Disease Characteristics(With
Potential to Influence Outcome)
  • Demographic Variables Age, Gender, Race and
  • Refractory Status
  • Intolerance Status
  • Period of Enrollment
  • Primary Pathogen Aspergillus, Candida and Other
    Yeast, Fusarium, Cryptococcus, Zygomycetes, Other
    Filamentous Fungi, Other Endemic Fungi and
    Multiple Pathogens
  • Infection Site pulmonary, extra pulmonary,
    disseminated with pulmonary involvement and
    disseminated without pulmonary involvement

Baseline and Disease Characteristics (With
Potential to Influence Outcome)
  • Underlying Disease 9 variables each with two
    categories (present and absent Hematologic
    Malignancies, Non-Hematologic Malignancies,
    Nonmalignant Hematologic Disorders, Bone Marrow
    Transplant, Solid Organ Transplant, Renal
    Disease, Hepatic Disease, Immunocompromised-
    Acquired, Immunocompromised-Congenital
  • Duration of prior effective antifungal therapy.
  • Baseline Neutropenia
  • Prior systemic corticosteroid use and Concurrent
    systemic corticosteroid use

Primary Efficacy Endpoint
  • DRC-adjudicated Global Response Status at the
    end of treatment
  • subject considered a responder if global
    response at EOT was classified as a complete or
    partial response
  • subject considered a non-responder if
    classified as stable disease, failure, or unable
    to determine

Global Response Status
  • Complete Response
  • Resolution of all attributable clinical signs
    and symptoms, radiological and mycological
    abnormalities, if present at baseline.
  • Partial Response
  • Clinically meaningful improvement in attributable
    clinical signs and symptoms, radiological and
    mycological abnormalities, if present at
  • Stable Disease
  • No improvement in attributable clinical signs
    symptoms, radiological and mycological
    abnormalities, if present at baseline
  • Failure
  • Deterioration in attributable clinical signs and
    symptoms, radiological and/or mycological
    abnormalities necessitating alternative
    antifungal therapy or resulting in death
  • Unable to Determine
  • If for any reason the global response cannot be
    assessed (e.g., insufficient medical records to
    determine outcome)

Primary Analysis
  • Modified ITT Population
  • subjects with proven or probable aspergillosis
  • refractory to standard therapy or intolerant
  • Analysis of Global Response Rate
  • Logistic regression model includes
  • treatment
  • key prognostic factors
  • other potential prognostic factors (with
    treatment imbalances at baseline)
  • Assessment of treatment differences based on
    odds ratio for treatment effect and its 95
    confidence interval

Prognostic Variables
  • Key Variables
  • Refractory status
  • Intolerance status
  • Site of infection
  • Presence of baseline neutropenia
  • Duration of prior antifungal therapy
  • Region
  • Other Variables
  • All other baseline and disease characteristics
    considered as potential prognostic variables
  • Included as covariates in primary statistical
    analysis if treatment imbalance at baseline is
    significant (plt0.10)

Supportive Analyses
  • Two step procedure
  • Preliminary analysis to identify prognostic
    indicators with potential to influence global
  • Based on a logistic regression procedure
  • All variables (except treatment) included
  • Variable selection option STEPWISE in PROC
    LOGISTIC of SAS (significance level 0.15 for
    entry and 0.10 for stay)
  • Statistical Modeling
  • Logistic regression on global response with
    treatment and other covariates selected from the
    above procedure.

Secondary Analyses
  • Survival Analyses
  • Time to Death (logrank test)
  • Cox Proportional Hazards Model
  • Treatment Group
  • Site of Infection
  • Refractory Status, Intolerance Status
  • Baseline Neutropenia

Additional Analyses
  • Forming cohorts based on a Prognosis Score (low,
    intermediate, high risk)
  • Use of Propensity scores

Baseline and Disease Characteristics
Baseline and Disease Characteristics
Baseline Comparisons
  • Both studies are comparable with respect to the
    distribution of demographic and almost all of the
    baseline disease characteristics
  • Majority of the subjects are refractory to prior
    antifungal therapies
  • Study P00041 has generally sicker patients (e.g.,
    hepatic disease and renal disease)

Global Response Rates (CompletePartial)
Region P00041 (N107) P02387 (N86)
US 38/94 (40.4) 16/68 (23.5)
Ex-US 7/13 (53.8) 6/18 (33.3)
All 45/107 (42.1) 22/86 (25.6)
  • Unadjusted OR2.11
  • Confidence Interval for OR(1.15, 3.92)
  • p-value 0.018

Primary Efficacy Analysis
  • Logistic Regression on Global Response
  • Key Prognostic Factors included
  • Refractory Status, Intolerance Status, Site of
    Infection, Neutropenia, Duration of Prior
    Antifungal Therapy, Age and Region of
  • Potential Prognostic Factors with Baseline
  • Enrollment Time, Race, Non-malignant Hematologic
    Disorders, Renal Disease and Hepatic Disease

Results of Primary Efficacy Analysis
  • Only two significant variables in the model
  • Treatment and Baseline Neutropenia
  • No interaction between Treatment and Neutropenia
    based on a logistic regression model with
    Treatment, Neutropenia and interaction between
  • Odds Ratio for Treatment 4.06
  • P-value for the Treatment Effect 0.006
  • 95 Confidence Interval (1.50, 11.04)

Impact on Odds Ratio for Treatment Effect
Sequential Addition of Prognostic Variables
Variable Added in the Model Sequentially Odds Ratio P-value
No covariate 2.11 0.0178
Neutropenia 1.94 0.040
Region 2.10 0.025
Hepatic Disease 2.55 0.010
Refractory Status 2.64 0.007
Intolerance Status 2.80 0.005
Infection Site 2.70 0.008
Non-malignant Hematologic Disorders 2.89 0.006
Age 2.88 0.007
Renal Disease 3.05 0.008
Prior AF duration 3.34 0.006
Enrollment Time 4.05 0.006
Race Group 4.06 0.006
Supportive Analysis
  • Variables associated with the Global Response
    selected using the Stepwise Logistic Regression
  • Baseline Neutropenia, Prior Corticosteroid Use,
    Solid Organ Transplant
  • Logistic regression on Global Response with
    Treatment and the above variables in the Model
  • Odds Ratio for Treatment 2.05
  • P-value for the Treatment Effect 0.034
    Confidence Interval (1.06, 3.97)

Sensitivity Analyses
No. Variations of the Prognostic Factors OR CI/P-value
1 Excluded Non-malignant Hematologic Disorders, Renal and Hepatic Disease 2.68 (1.15, 6.27)/ 0.023
2 Binary infection site, Continuous Age and Prior AF duration 3.67 (1.41, 9.54)/0.008
3 Binary Enrollment and Infection site, Continuous Age and Ordinal Prior AF duration 3.73 (1.51, 9.21)/0.004
4 Binary Enrollment and Infection Site, Continuous Age and Prior AF duration 3.45 (1.42, 8.41)/0.006
5 Ordinal Enrollment, Binary Infection site, Continuous Age and Ordinal Prior AF duration 3.48 (1.39, 8.72)/0.008
6 Ordinal Enrollment, Binary Infection site, Binary Prior AF duration (lt30, gt30) and Continuous Age 3.69 (1.46, 9.35)/0.006
Global Response Rates by Baseline Neutropenia
Study protocol Study protocol Study protocol Study protocol
P00041 P00041 P02387 P02387
Neutropenia Status 1/3 33.3
Missing 1/3 33.3
Neutropenia 5/21 23.8 2/26 7.7
No Neutropenia 35/78 44.9 19/58 32.8
Unable to Determine 4/5 80.0 1/2 50.0
Total 45/107 42.1 22/86 25.6
Global Response Rates by Corticosteroid Use
Study protocol Study protocol Study protocol Study protocol
P00041 P00041 P02387 P02387
Prior Corticosteroid 15/29 51.7 12/26 46.2
No prior use 15/29 51.7 12/26 46.2
Prior use 30/78 38.5 10/60 16.7
Concomitant Corticosteroid 13/23 56.5 7/27 25.9
No Concomitant use 13/23 56.5 7/27 25.9
Concomitant use 32/84 38.1 15/59 25.4
Total 45/107 42.1 22/86 25.6
Global Response Rates by Infection Site
Study protocol Study protocol Study protocol Study protocol
P00041 P00041 P02387 P02387
Infection Site
Pulmonary 31/79 39.2 17/67 25.4
Extra-Pulmonary 10/19 52.6 5/11 45.5
Disseminated with Pulmonary Involvement 1/3 33.3 0/3 0
Disseminated w/o Pulmonary Involvement 3/6 50 0/5 0
Total 45/107 42.1 22/86 25.6
Global Response Rates by Underlying Disease
Study protocol Study protocol Study protocol Study protocol
P00041 (n107) P00041 (n107) P02387 (n86) P02387 (n86)
Bone Marrow Transplant 21/55 38.2 7/38 18.4
Solid Organ Transplant 7/12 58.3 5/7 71.4
Hematologic Malignancies 29/79 36.7 16/70 22.9
Non-malignant Hematologic Disorders 36/91 39.6 11/52 21.2
Non-hematologic malignancies 6/13 46.2 1/5 20.0
Immunosuppressive-acquired 13/28 46.4 6/19 31.6
Immunosuppressive-congenital 1/2 50.0 0/3 0.0
Renal Disease 27/68 39.7 5/21 23.8
Hepatic Disease 16/43 37.2 0/6 0.0
No Identifiable Risk Factors 1/1 100.0
(No Transcript)
Variables used for Prognosis Score
  • BMT, Solid Organ Transplant, Acquired
    Immunodeficiency, Congenital Immunodeficiency,
    Hematologic Malignancy, Non-hematologic
    Malignancy, Non-malignant Hematologic Disorder,
    Renal disease risk factor OR Creatinine gt Grade
    1, Liver disease risk factor OR Total Bilirubin
    gt Grade 1 OR SGOT gt Grade 1 OR SGPT gt Grade 1,
    Prior Systemic Steroid use, Prior
    Immunosuppressive therapy, Prior Myelosuppressive
    therapy, Baseline Neutropenia, Baseline
    Mechanical Ventilation, and Baseline GVHD
  • Prognosis Score one point added to subjects
    score for each condition that is present

Global Response Rate by Prognosis Score
Prognosis Score Group P00041 Posaconazole P02387 Control
Low Risk (0-1) 2/2 (100) -
Intermediate Risk (2-4) 10/21 (58) 8/25 (32)
High Risk (gt5) 33/48 (39) 14/61 (23)
All 45/107 (42) 22/86 (26)
P-value 0.0202 based on CMH stratified analysis
for general association.
Propensity Scores
  • Propensity Score is defined as the conditional
    probability of being treated given the
  • Estimated propensity score can be used to reduce
    the bias through matching, stratification,
    regression adjustment or some combination of all
  • Advantage of using propensity scores in
    estimating treatment effect is its simplicity in
    interpreting the results.
  • Quantiles of the distribution of the propensity
    scores can be used as covariates in logistic
    regression analysis or as strata in assessing the
    treatment effect.

Global Response Rate by Propensity Score Group
Propensity Score Group P0041 P02387
lt0.177 0/1 (0) 18/57(32)
0.177- lt0.608 10/16 (63) 3/18 (17)
0.608- lt0.936 12/33 (36) 1/9 (11)
gt0.936 23/57 (40) 0/2 (0)
All 45/107 (42) 22/86 (26)
P-value using the logistic regression is
0.0223 P value based on the CMH analysis is
Summary and Conclusions
  • Posaconazole is substantially more effective than
    control for treatment of rIFI due to aspergillus
  • The adjusted odds ratio obtained from the primary
    analysis is almost twice as large as the
    unadjusted odds ratio
  • The treatment effect based on primary analysis is
    robust in the sense that it is not sensitive to
    the classification of baseline and disease
    characteristics used to specify the way in which
    the prognostic factors were incorporated in the

Summary and Conclusions
  • The treatment effect is statistically significant
    even when the influential factors non-malignant
    hematologic disorders, hepatic disease and renal
    disease are excluded from the primary model (odds
    ratio2.70, p-value0.0227).
  • Alternate methods of controlling for prognostic
    factors confirm effectiveness of posaconazole.
  • Survival (based on the Kaplan-Meier estimates) is
    substantially longer in subjects treated with
    Posaconazole than control subjects. Kaplan-Meier
    estimates of the survival rates at the end of one
    year are 38 and 22 in P0041 and P02387
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