Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy

An externally controlled trial

Thomas J. Walsh, Issam Raad, Thomas F. Patterson, Pranatharthi Chandrasekar, Gerald R. Donowitz, Richard Graybill, Reginald E. Greene, Ray Hachem, Susan Hadley, Raoul Herbrecht, Amelia Langston, Arnold Louie, Patricia Ribaud, Brahm H. Segal, David A. Stevens, Jo Anne H Van Burik, Charles S. White, Gavin Corcoran, Jagadish Gogate, Gopal Krishna & 3 others Lisa Pedicone, Catherine Hardalo, John R. Perfect

Research output: Contribution to journalArticle

Abstract

Background. Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. Methods. We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. Results. Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P = .006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. Conclusions. Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

Original languageEnglish (US)
Pages (from-to)2-12
Number of pages11
JournalClinical Infectious Diseases
Volume44
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

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Aspergillosis
Advisory Committees
Therapeutics
Echinocandins
Salvage Therapy
Triazoles
Mycoses
Hematopoietic Stem Cell Transplantation
Immunocompromised Host
Hematologic Neoplasms
Aspergillus
Prednisolone
Neutropenia
Population
Multicenter Studies
posaconazole
Suspensions
Pharmacokinetics
Odds Ratio
Demography

ASJC Scopus subject areas

  • Immunology

Cite this

Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy : An externally controlled trial. / Walsh, Thomas J.; Raad, Issam; Patterson, Thomas F.; Chandrasekar, Pranatharthi; Donowitz, Gerald R.; Graybill, Richard; Greene, Reginald E.; Hachem, Ray; Hadley, Susan; Herbrecht, Raoul; Langston, Amelia; Louie, Arnold; Ribaud, Patricia; Segal, Brahm H.; Stevens, David A.; Van Burik, Jo Anne H; White, Charles S.; Corcoran, Gavin; Gogate, Jagadish; Krishna, Gopal; Pedicone, Lisa; Hardalo, Catherine; Perfect, John R.

In: Clinical Infectious Diseases, Vol. 44, No. 1, 01.01.2007, p. 2-12.

Research output: Contribution to journalArticle

Walsh, TJ, Raad, I, Patterson, TF, Chandrasekar, P, Donowitz, GR, Graybill, R, Greene, RE, Hachem, R, Hadley, S, Herbrecht, R, Langston, A, Louie, A, Ribaud, P, Segal, BH, Stevens, DA, Van Burik, JAH, White, CS, Corcoran, G, Gogate, J, Krishna, G, Pedicone, L, Hardalo, C & Perfect, JR 2007, 'Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: An externally controlled trial', Clinical Infectious Diseases, vol. 44, no. 1, pp. 2-12. https://doi.org/10.1086/508774
Walsh, Thomas J. ; Raad, Issam ; Patterson, Thomas F. ; Chandrasekar, Pranatharthi ; Donowitz, Gerald R. ; Graybill, Richard ; Greene, Reginald E. ; Hachem, Ray ; Hadley, Susan ; Herbrecht, Raoul ; Langston, Amelia ; Louie, Arnold ; Ribaud, Patricia ; Segal, Brahm H. ; Stevens, David A. ; Van Burik, Jo Anne H ; White, Charles S. ; Corcoran, Gavin ; Gogate, Jagadish ; Krishna, Gopal ; Pedicone, Lisa ; Hardalo, Catherine ; Perfect, John R. / Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy : An externally controlled trial. In: Clinical Infectious Diseases. 2007 ; Vol. 44, No. 1. pp. 2-12.
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T1 - Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy

T2 - An externally controlled trial

AU - Walsh, Thomas J.

AU - Raad, Issam

AU - Patterson, Thomas F.

AU - Chandrasekar, Pranatharthi

AU - Donowitz, Gerald R.

AU - Graybill, Richard

AU - Greene, Reginald E.

AU - Hachem, Ray

AU - Hadley, Susan

AU - Herbrecht, Raoul

AU - Langston, Amelia

AU - Louie, Arnold

AU - Ribaud, Patricia

AU - Segal, Brahm H.

AU - Stevens, David A.

AU - Van Burik, Jo Anne H

AU - White, Charles S.

AU - Corcoran, Gavin

AU - Gogate, Jagadish

AU - Krishna, Gopal

AU - Pedicone, Lisa

AU - Hardalo, Catherine

AU - Perfect, John R.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Background. Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. Methods. We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. Results. Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P = .006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. Conclusions. Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

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