Anidulafungin Plus Voriconazole Versus Voriconazole For The Treatment Of Invasive Aspergillosis

A Prospective, Randomized Trial Comparing The Efficacy Of Anidulafungin And Voriconazole In Combination To That Of Voriconazole Alone When Used For Primary Therapy Of Proven Or Probable Invasive Aspergillosis

This study compares the effectiveness and safety of the combination of anidulafungin and voriconazole compared to that of voriconazole alone (which is generally considered the standard of care) for the treatment of Invasive Aspergillosis.

Study Overview

• Status: Completed
• Conditions: Aspergillosis
• Intervention / Treatment: Drug: voriconazole; Drug: voriconazole; Drug: anidulafungin

• Study Type: Interventional
• Enrollment (Actual): 459
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Pfizer Investigational Site
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Pfizer Investigational Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Pfizer Investigational Site
• Belgium
  • Brugge, Belgium, 8000
    • Pfizer Investigational Site
  • Bruxelles, Belgium, 1000
    • Pfizer Investigational Site
  • Leuven, Belgium, 3000
    • Pfizer Investigational Site
  • Yvoir, Belgium, B-5530
    • Pfizer Investigational Site
• Brazil
  • PR
    • Curitiba, PR, Brazil, 80060-900
      • Pfizer Investigational Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 21941-913
      • Pfizer Investigational Site
  • RS
    • Porto Alegre, RS, Brazil, 90020-090
      • Pfizer Investigational Site
• Canada
  • Quebec, Canada, G1R 2J6
    • Pfizer Investigational Site
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Pfizer Investigational Site
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • Pfizer Investigational Site
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Pfizer Investigational Site
    • Hamilton, Ontario, Canada, L8V 1C3
      • Pfizer Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Pfizer Investigational Site
• Czech Republic
  • Praha 2, Czech Republic, 128 20
    • Pfizer Investigational Site
• France
  • Brest, France, 29609
    • Pfizer Investigational Site
  • Creteil, France, 94010
    • Pfizer Investigational Site
  • GRENOBLE Cedex 09, France, 38043
    • Pfizer Investigational Site
  • Paris, France, 75475
    • Pfizer Investigational Site
  • Rouen Cedex, France, 76038
    • Pfizer Investigational Site
  • Strasbourg, France, 67098
    • Pfizer Investigational Site
  • Cedex 01
    • Nantes, Cedex 01, France, 44093
      • Pfizer Investigational Site
  • Cedex 09
    • Marseille, Cedex 09, France, 13273
      • Pfizer Investigational Site
• Germany
  • Berlin, Germany, 12200
    • Pfizer Investigational Site
  • Berlin, Germany, 10117
    • Pfizer Investigational Site
  • Bremen, Germany, 28177
    • Pfizer Investigational Site
  • Dresden, Germany, 01307
    • Pfizer Investigational Site
  • Frankfurt (Oder), Germany, 15236
    • Pfizer Investigational Site
  • Hamburg, Germany, 20246
    • Pfizer Investigational Site
  • Heidelberg, Germany, 69120
    • Pfizer Investigational Site
  • Homburg/Saar, Germany, 66421
    • Pfizer Investigational Site
  • Koeln, Germany, 50937
    • Pfizer Investigational Site
  • Mainz, Germany, 55101
    • Pfizer Investigational Site
  • Muenchen, Germany, 81737
    • Pfizer Investigational Site
  • Wuerzburg, Germany, 97080
    • Pfizer Investigational Site
• Greece
  • Thessaloniki, Greece, 57010
    • Pfizer Investigational Site
• India
  • Maharashtra
    • Pune, Maharashtra, India, 411004
      • Pfizer Investigational Site
• Italy
  • Cuneo, Italy, 12100
    • Pfizer Investigational Site
  • Genova, Italy, 16132
    • Pfizer Investigational Site
  • Milano, Italy, 20132
    • Pfizer Investigational Site
  • Milano, Italy, 20162
    • Pfizer Investigational Site
  • Perugia, Italy, 06134
    • Pfizer Investigational Site
  • Pescara, Italy, 65100
    • Pfizer Investigational Site
  • Roma, Italy, 00168
    • Pfizer Investigational Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 120-752
    • Pfizer Investigational Site
  • Seoul, Korea, Republic of, 138-736
    • Pfizer Investigational Site
  • Seoul, Korea, Republic of, 110-744
    • Pfizer Investigational Site
  • Seoul, Korea, Republic of, 135-710
    • Pfizer Investigational Site
  • Seoul, Korea, Republic of, 150-713
    • Pfizer Investigational Site
• Netherlands
  • RC Leiden, Netherlands, NL-2300
    • Pfizer Investigational Site
• Peru
  • Lima, Peru, Lima 34
    • Pfizer Investigational Site
• Poland
  • Gdansk, Poland, 80-952
    • Pfizer Investigational Site
  • Warszawa, Poland, 02-097
    • Pfizer Investigational Site
• Portugal
  • Lisboa, Portugal, 1169-050
    • Pfizer Investigational Site
  • Lisboa, Portugal, 1649-035
    • Pfizer Investigational Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Pfizer Investigational Site
  • Moscow, Russian Federation, 105229
    • Pfizer Investigational Site
  • Moscow, Russian Federation, 125167
    • Pfizer Investigational Site
  • Saint Petersburg, Russian Federation, 197089
    • Pfizer Investigational Site
• Singapore
  • Singapore, Singapore, 119074
    • Pfizer Investigational Site
  • Singapore, Singapore, 169608
    • Pfizer Investigational Site
• Spain
  • Madrid, Spain, 28006
    • Pfizer Investigational Site
  • Madrid, Spain, 28050
    • Pfizer Investigational Site
  • Salamanca, Spain, 37007
    • Pfizer Investigational Site
  • Valencia, Spain, 46010
    • Pfizer Investigational Site
  • Valencia, Spain, 46026
    • Pfizer Investigational Site
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Pfizer Investigational Site
• Switzerland
  • Geneve 14, Switzerland, CH-1211
    • Pfizer Investigational Site
  • Lausanne, Switzerland, 1011
    • Pfizer Investigational Site
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Pfizer Investigational Site
  • Taipei, Taiwan, 112
    • Pfizer Investigational Site
  • Taoyuan County
    • Kuei-Shan Hsiang, Taoyuan County, Taiwan, 333
      • Pfizer Investigational Site
• Thailand
  • Bangkok, Thailand, 10330
    • Pfizer Investigational Site
  • Bangkok, Thailand, 10400
    • Pfizer Investigational Site
  • Bangkok, Thailand, 10700
    • Pfizer Investigational Site
• Turkey
  • Adana, Turkey, 01330
    • Pfizer Investigational Site
  • Ankara, Turkey, 06100
    • Pfizer Investigational Site
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Pfizer Investigational Site
  • Manchester, United Kingdom, M20 4BX
    • Pfizer Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Pfizer Investigational Site
    • Birmingham, Alabama, United States, 35249
      • Pfizer Investigational Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Pfizer Investigational Site
  • California
    • La Jolla, California, United States, 92037
      • Pfizer Investigational Site
    • LaJolla, California, United States, 92093
      • Pfizer Investigational Site
    • San Diego, California, United States, 92103-8976
      • Pfizer Investigational Site
    • San Francisco, California, United States, 94143
      • Pfizer Investigational Site
  • Florida
    • Gainesville, Florida, United States, 32610
      • Pfizer Investigational Site
    • Miami, Florida, United States, 33136
      • Pfizer Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Pfizer Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Pfizer Investigational Site
    • Chicago, Illinois, United States, 60612
      • Pfizer Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Pfizer Investigational Site
    • Baltimore, Maryland, United States, 21231-2410
      • Pfizer Investigational Site
    • Baltimore, Maryland, United States, 21231
      • Pfizer Investigational Site
    • Baltimore, Maryland, United States, 21287
      • Pfizer Investigational Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Pfizer Investigational Site
    • Detroit, Michigan, United States, 48201
      • Pfizer Investigational Site
  • New York
    • Rochester, New York, United States, 14642
      • Pfizer Investigational Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Pfizer Investigational Site
    • Winston-Salem, North Carolina, United States, 27157
      • Pfizer Investigational Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Pfizer Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Pfizer Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • Pfizer Investigational Site
  • Washington
    • Seattle, Washington, United States, 98195
      • Pfizer Investigational Site
    • Seattle, Washington, United States, 98109
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Immunocompromised state due to either 1. receipt of hematopoeitic stem cell transplantation or 2. hematologic malignancy;
• Diagnosis of possible, probable, or proven invasive aspergillosis.

Exclusion Criteria:

• Patients with aspergilloma or chronic aspergillosis
• Receipt of 4 or more days of systemic antifungal treatment for the current episode of invasive aspergillosis
• Anticipated survival of less than 5 days or Karnofsky score <=20

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Voriconazole; Voriconazole monotherapy	Drug: voriconazole; First week: Voriconazole 6 mg/kg IV bid for the first 24 hours, followed by 4 mg/kg IV BID plus anidulafungin placebo IV qd. Second week: Voriconazole 4 mg/kg IV bid or 300 mg PO bid plus anidulafungin placebo IV qd. Third and fourth weeks: Voriconazole 4 mg/kg IV bid OR 300 mg PO bid plus anidulafungin placebo IV qd, OR Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy. Fifth and sixth weeks: Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy.; Other Names: Vfend; Drug: voriconazole; First week: Voriconazole 6 mg/kg IV bid for the first 24 hours, followed by 4 mg/kg IV bid plus anidulafungin 200 mg IV on day 1, followed by 100 mg IV qd thereafter. Second week: Voriconazole 4 mg/kg IV bid or 300 mg PO bid plus anidulafungin 100 mg IV qd. Third and fourth weeks: Voriconazole 4 mg/kg IV bid OR 300 mg PO bid plus anidulafungin 100 mg IV qd, OR Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy. Fifth and sixth weeks: Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy.; Other Names: Vfend
Experimental: Voriconazole and Anidulafungin; Combination therapy with voriconazole and anidulafungin	Drug: voriconazole; First week: Voriconazole 6 mg/kg IV bid for the first 24 hours, followed by 4 mg/kg IV BID plus anidulafungin placebo IV qd. Second week: Voriconazole 4 mg/kg IV bid or 300 mg PO bid plus anidulafungin placebo IV qd. Third and fourth weeks: Voriconazole 4 mg/kg IV bid OR 300 mg PO bid plus anidulafungin placebo IV qd, OR Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy. Fifth and sixth weeks: Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy.; Other Names: Vfend; Drug: voriconazole; First week: Voriconazole 6 mg/kg IV bid for the first 24 hours, followed by 4 mg/kg IV bid plus anidulafungin 200 mg IV on day 1, followed by 100 mg IV qd thereafter. Second week: Voriconazole 4 mg/kg IV bid or 300 mg PO bid plus anidulafungin 100 mg IV qd. Third and fourth weeks: Voriconazole 4 mg/kg IV bid OR 300 mg PO bid plus anidulafungin 100 mg IV qd, OR Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy. Fifth and sixth weeks: Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy.; Other Names: Vfend; Drug: anidulafungin; First week: Voriconazole 6 mg/kg IV bid for the first 24 hours, followed by 4 mg/kg IV bid plus anidulafungin 200 mg IV on day 1, followed by 100 mg IV qd thereafter. Second week: Voriconazole 4 mg/kg IV bid or 300 mg PO bid plus anidulafungin 100 mg IV qd. Third and fourth weeks: Voriconazole 4 mg/kg IV bid OR 300 mg PO bid plus anidulafungin 100 mg IV qd, OR Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy. Fifth and sixth weeks: Voriconazole 4 mg/kg IV bid or 300 mg PO bid monotherapy.; Other Names: Eraxis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Mortality at Week 6 in Participants With Proven or Probable Invasive Aspergillosis	Number of deaths measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1.	Day 1 to Day 42 (Week 6)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global Response at Week 6	Number of participants with a successful response (complete or partial global response). Complete response = resolution of all clinical signs and symptoms and >90% of lesions due to IA that were visible on radiologic studies at baseline (BL); partial response = clinical improvement and >50% improvement in radiological findings present at BL.	Baseline, Day 42 (Week 6)
All-cause Mortality at Week 6 in Participants With Possible, Probable, or Proven Invasive Aspergillosis (IA)	Number of deaths due to any cause measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1.	Day 1 to Day 42 (Week 6)
All-cause Mortality at Week 12 in Participants With Probable or Proven Invasive Aspergillosis (IA)	Number of deaths due to any cause measured 12 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1.	Day 1 to Day 84 (Week 12)
Mortality Due to Invasive Aspergillosis (IA) at Week 6 in Participants With Probable or Proven IA	Number of deaths due to Invasive Aspergillosis measured 6 weeks after start of treatment. Time to death defined as date of death minus first treatment date + 1.	Day 1 to Day 42 (Week 6)
Time to Death: All-Cause Mortality	Survival time from start of treatment. Time to death defined as date of death due to any cause minus first treatment date + 1.	Day 1 to Day 84 (Week 12)
Time to Death Due to Invasive Aspergillosis (IA)	Survival time from start of treatment. Time to death defined as date of death due to IA minus first treatment date + 1.	Day 1 to Day 84 (Week 12)

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, Heinz WJ, Jagannatha S, Koh LP, Kontoyiannis DP, Lee DG, Nucci M, Pappas PG, Slavin MA, Queiroz-Telles F, Selleslag D, Walsh TJ, Wingard JR, Maertens JA. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015 Jan 20;162(2):81-9. doi: 10.7326/M13-2508. Erratum In: Ann Intern Med. 2015 Mar 17;162(6):463. Ann Intern Med. 2019 Feb 5;170(3):220.
• Liu P, Mould DR. Population pharmacokinetic-pharmacodynamic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis. Antimicrob Agents Chemother. 2014 Aug;58(8):4727-36. doi: 10.1128/AAC.02809-13. Epub 2014 Jun 9.
• Liu P, Mould DR. Population pharmacokinetic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis. Antimicrob Agents Chemother. 2014 Aug;58(8):4718-26. doi: 10.1128/AAC.02808-13. Epub 2014 Jun 9.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: September 14, 2007
• First Submitted That Met QC Criteria: September 14, 2007
• First Posted (Estimate): September 18, 2007

Study Record Updates

• Last Update Posted (Estimate): April 30, 2012
• Last Update Submitted That Met QC Criteria: April 3, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Aspergillosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Anidulafungin; Voriconazole
• Other Study ID Numbers: A8851009

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No