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VFEND® (voriconazole) Clinical Studies

14 CLINICAL STUDIES

Voriconazole, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp., and Scedosporium spp.

14.1 Invasive Aspergillosis (IA)

Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

Study 307/602 – Primary Therapy of Invasive Aspergillosis

The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute IA was demonstrated in 277 patients treated for 12 weeks in a randomized, controlled study (Study 307/602). The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation. The study also included patients with solid organ transplantation, solid tumors, and AIDS. The patients were mainly treated for definite or probable IA of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable IA was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID MSG/EORTC).

Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2–85 days). After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2–232 days).

Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0–1.5 mg/kg/day. Median duration of IV amphotericin therapy was 12 days (range 1–85 days). Treatment was then continued with OLAT, including itraconazole and lipid amphotericin B formulations. Although initial therapy with conventional amphotericin B was to be continued for at least two weeks, actual duration of therapy was at the discretion of the investigator. Patients who discontinued initial randomized therapy due to toxicity or lack of efficacy were eligible to continue in the study with OLAT treatment.

A satisfactory global response at 12 weeks (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole treated patients compared to 32% of amphotericin B treated patients (Table 15). A benefit of voriconazole compared to amphotericin B on patient survival at Day 84 was seen with a 71% survival rate on voriconazole compared to 58% on amphotericin B (Table 13).

Table 13 also summarizes the response (success) based on mycological confirmation and species.

Table 13: Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive Aspergillosis Study 307/602
Voriconazole Ampho B* Stratified Difference
(95% CI)
*
Amphotericin B followed by other licensed antifungal therapy
Difference and corresponding 95% confidence interval are stratified by protocol
Assessed by independent Data Review Committee (DRC)
§
Proportion of subjects alive
Not all mycologically confirmed specimens were speciated
#
Some patients had more than one species isolated at baseline
n/N (%) n/N (%)
Efficacy as Primary Therapy
    Satisfactory Global Response 76/144 (53) 42/133 (32) 21.8%
(10.5%, 33.0%)
p<0.0001
  Survival at Day 84 § 102/144 (71) 77/133 (58) 13.1%
(2.1%, 24.2%)
 
Success by Species
Success n/N (%)
  Overall success 76/144 (53) 42/133 (32)
 
Mycologically confirmed 37/84 (44) 16/67 (24)
 
Aspergillus spp.#
  A. fumigatus 28/63 (44) 12/47 (26)
  A. flavus 3/6 4/9
  A. terreus 2/3 0/3
  A. niger 1/4 0/9
  A. nidulans 1/1 0/0

Study 304 – Primary and Salvage Therapy of Aspergillosis

In this non-comparative study, an overall success rate of 52% (26/50) was seen in patients treated with voriconazole for primary therapy. Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success in patients who received voriconazole as salvage therapy is presented in Table 14.

Study 309/604 – Treatment of Patients with Invasive Aspergillosis who were Refractory to, or Intolerant of, other Antifungal Therapy

Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 16. In this non-comparative study, overall mycological eradication for culture-documented infections due to fumigatus and non-fumigatus species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in voriconazole treated patients. Patients had various underlying diseases and species other than A. fumigatus contributed to mixed infections in some cases.

For patients who were infected with a single pathogen and were refractory to, or intolerant of, other antifungal agents, the satisfactory response rates for voriconazole in studies 304 and 309/604 are presented in Table 14.

Table 14: Combined Response Data in Salvage Patients with Single Aspergillus Species (Studies 304 and 309/604)
Success
n/N
A. fumigatus 43/97 (44%)
A. flavus 5/12
A. nidulans 1/3
A. niger 4/5
A. terreus 3/8
A. versicolor 0/1

Nineteen patients had more than one species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.

14.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open-label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150-608 are presented in Table 15.

Table 15: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen*,
Baseline Pathogen Clinical and Mycological Success (%)
Voriconazole Amphotericin B --> Fluconazole
*
A few patients had more than one pathogen at baseline.
Patients who did not have a 12-week assessment for any reason were considered a treatment failure.
C. albicans 46/107 (43%) 30/63 (48%)
C. tropicalis 17/53 (32%) 1/16 (6%)
C. parapsilosis 24/45 (53%) 10/19 (53%)
C. glabrata 12/36 (33%) 7/21 (33%)
C. krusei 1/4 0/1

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intra-abdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

14.3 Esophageal Candidiasis (EC)

The efficacy of oral voriconazole 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of EC was demonstrated in Study 150-305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven EC. Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent-to-Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline. Voriconazole and fluconazole (200 mg once daily) showed comparable efficacy rates against EC, as presented in Table 16.

Table 16: Success Rates in Patients Treated for Esophageal Candidiasis
Population Voriconazole Fluconazole Difference %
(95% CI)*
*
Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates.
PP (Per Protocol) patients had confirmation of Candida esophagitis by endoscopy, received at least 12 days of treatment, and had a repeat endoscopy at EOT (end of treatment).
ITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.
PP 113/115 (98.2%) 134/141 (95.0%) 3.2 (-1.1, 7.5)
ITT 175/200 (87.5%) 171/191 (89.5%) -2.0 (-8.3, 4.3)

Microbiologic success rates by Candida species are presented in Table 17.

Table 17: Clinical and Mycological Outcome by Baseline Pathogen in Patients with Esophageal Candidiasis (Study-150-305)
Pathogen* Voriconazole Fluconazole
Favorable endoscopic response Mycological eradication Favorable endoscopic response Mycological eradication
Success/Total (%) Eradication/Total (%) Success/Total (%) Eradication/Total (%)
*
Some patients had more than one species isolated at baseline.
Patients with endoscopic and/or mycological assessment at end of therapy.
C. albicans 134/140 (96%) 90/107 (84%) 147/156 (94%) 91/115 (79%)
C. glabrata 8/8 (100%) 4/7 (57%) 4/4 (100%) 1/4 (25%)
C. krusei 1/1 1/1 2/2 (100%) 0/0

14.4 Other Serious Fungal Pathogens

In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:

Scedosporium apiospermum - Successful response to voriconazole therapy was seen in 15 of 24 patients (63%). Three of these patients relapsed within 4 weeks, including 1 patient with pulmonary, skin and eye infections, 1 patient with cerebral disease, and 1 patient with skin infection. Ten patients had evidence of cerebral disease and 6 of these had a successful outcome (1 relapse). In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.

Fusarium spp. - Nine of 21 (43%) patients were successfully treated with voriconazole. Of these 9 patients, 3 had eye infections, 1 had an eye and blood infection, 1 had a skin infection, 1 had a blood infection alone, 2 had sinus infections, and 1 had disseminated infection (pulmonary, skin, hepatosplenic). Three of these patients (1 with disseminated disease, 1 with an eye infection and 1 with a blood infection) had Fusarium solani and were complete successes. Two of these patients relapsed, 1 with a sinus infection and profound neutropenia and 1 post surgical patient with blood and eye infections.

14.5 Pediatric Studies

A total of 22 patients aged 12 to 18 years with IA were included in the adult therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg every 12 hours.

Fifty-three pediatric patients aged 2 to less than 18 years old were treated with voriconazole in two prospective, open-label, non-comparative, multicenter clinical studies.

One study was designed to enroll pediatric patients with IA or infections with rare molds (such as Scedosporium or Fusarium). Patients aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous VFEND loading dose of 9 mg/kg every 12 hours for the first 24-hours followed by an 8 mg/kg intravenous maintenance dose every 12 hours. After completing 7 days of intravenous therapy patients had an option to switch to oral VFEND. The oral maintenance dose was 9 mg/kg every 12 hours (maximum dose of 350 mg). All other pediatric patients aged 12 to less than 18 years received the adult VFEND dosage regimen. Patients received VFEND for at least 6 weeks and up to a maximum of 12 weeks.

The study enrolled 31 patients with possible, proven, or probable IA. Fourteen of 31 patients, 5 of whom were 2 to less than 12 years old and 9 of whom were 12 to less than 18 years old, had proven or probable IA and were included in the modified intent-to-treat (MITT) efficacy analyses. No patients with rare mold were enrolled. A successful global response was defined as resolution or improvement in clinical signs and symptoms and at least 50% resolution of radiological lesions attributed to IA. The overall rate of successful global response at 6 weeks in the MITT population is presented in Table 18 below.

Table 18: Global Response* in Patients with Invasive Aspergillosis, Modified Intent-to-Treat (MITT) Population
Parameter Global Response at Week 6
Ages 2–<12 years
N=5
Ages 12–<18 years
N=9
Overall
N=14
*
Global response rate was defined as the number of subjects with a successful response (complete or partial) as a percentage of all subjects (including subjects with an indeterminate or missing response) at 6 weeks in the MITT population.
The Modified Intent-to-Treat (MITT) population was defined as all subjects who received at least 1 dose of study drug and who were diagnosed with proven or probable IA as defined by the modified EORTC/MSG criteria.
Number of successes, n (%) 2 (40%) 7 (78%) 9 (64%)

The second study enrolled 22 patients with invasive candidiasis including candidemia (ICC) and EC requiring either primary or salvage therapy. Patients with ICC aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous VFEND loading dose of 9 mg/kg every 12 hours for the first 24 hours followed by an 8 mg/kg intravenous maintenance dose every 12-hours. After completing 5 days of intravenous therapy patients had an option to switch to oral VFEND. The oral maintenance dose was 9 mg/kg every 12 hours (maximum dose of 350 mg). All other pediatric patients aged 12 to less than 18 years received the adult VFEND dosage regimen. VFEND was administered for at least 14 days after the last positive culture. A maximum of 42 days of treatment was permitted.

Patients with primary or salvage EC aged 2 to less than 12 years and 12 to 14 years with body weight less than 50 kg received an intravenous VFEND dose of 4 mg/kg every 12 hours followed by an oral VFEND dose of 9 mg/kg every 12 hours (maximum dose of 350 mg) when criteria for oral switch were met. All other pediatric patients aged 12 to less than 18 years received the adult VFEND dosage regimen. VFEND was administered for at least 7 days after the resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted.

For EC, study treatment was initiated without a loading dose of intravenous voriconazole. Seventeen of these patients had confirmed Candida infection and were included in the MITT efficacy analyses. Of the 17 patients included in the MITT analyses, 9 were 2 to less than 12 years old (7 with ICC and 2 with EC) and 8 were 12 to less than18 years old (all with EC). For ICC and EC, a successful global response was defined as clinical cure or improvement with microbiological eradication or presumed eradication. The overall rate of successful global response at EOT in the MITT population is presented in Table 19 below.

Table 19: Global Response* at the End of Treatment in the Treatment of Invasive Candidiasis with Candidemia and Esophageal Candidiasis Modified Intent-to-Treat (MITT) Population
Parameter Global Response at End of Treatment
EC
N=10
ICC
N=7
Ages 2–<12
N=2
Ages 12–<18
N=8
Overall
N=10
Overall
N=7
*
Global response was determined based on the investigator's assessment of clinical and microbiological response in the Modified Intent-to-Treat (MITT) analysis population at end of treatment. Subjects with missing data or whose response was deemed indeterminate were considered failures.
The MITT population was defined as all subjects who received at least 1 dose of study drug and who had microbiologically confirmed invasive candidiasis with candidemia (ICC) and EC, or subjects with EC who had at least confirmation of oropharyngeal candidiasis without confirmation on esophagoscopy.
All subjects with ICC were aged 2 to less than 12.
Number of successes, n (%) 2 (100%) 5 (63%) 7 (70%) 6 (86%)

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