Candidiasis, Fungemia
Conditions
Keywords
Candidiasis; Invasive Candidiasis; Deep Tissue Candidiasis; Candida; Candidemia; Fungal Infection
Brief summary
The purpose of this study is to gather information on the use of anidulafungin for the treatment of serious Candida infection. It is expected that anidulafungin will be at least as safe and as effective as the comparator drug, caspofungin.
Interventions
Subjects in this arm will receive active anidulafungin and placebo caspofungin
Subjects in this arm will receive active caspofungin and placebo anidulafungin
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of deep tissue Candida infection, defined as growth of Candida sp. from a culture specimen obtained from a normally sterile site accompanied by signs and symptoms of infection. * Male or female ≥ 16 years of age. * Expected hospitalization for at least fourteen (14) days.
Exclusion criteria
* Pregnancy or breast feeding or planning to become pregnant during the study. * Recent treatment with one of the study drugs over the last 30 days. * Allergy to either study drug or to this class of drugs. * Significant liver dysfunction. * Suspected Candida osteomyelitis, endocarditis, meningitis or any other infections of the central nervous system.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Global Response at End of Treatment (Day 14 To Day 42) | End of Treatment (Day 14 to Day 42) | Participants had successful global response if there was clinical response of cure/improvement,microbiological eradication/presumed eradication.Clinical cure:resolution of signs/symptoms (s/s) of Candida infection;no additional systemic/oral antifungal treatment needed.Clinical improvement:significant,but incomplete resolution of s/s of Candida infection;no additional systemic/oral antifungal treatment needed.Microbiological eradication/presumed eradication:baseline pathogen not isolated from original site culture,or culture data not available for participant with successful clinical outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response Based on Clinical Cure and Microbiological Success | EOT (Day 14 to 42), 2-week follow-up (2 weeks after EOT), 6-week follow-up (6 weeks after EOT) | A participant had a successful response if there was clinical response of cure and microbiological success (eradication or presumed eradication). Clinical response of cure: resolution of signs and symptoms attributed to Candida infection; no additional systemic or oral antifungal treatment required to complete the course of therapy. Microbiological eradication or presumed eradication: baseline pathogen not isolated from original site culture, or culture data not available for a participant with successful clinical outcome. |
| Percentage of Participants With Clinical Response | Day 10 | A participant had a successful clinical response if there was clinical response of cure or improvement. Clinical response of cure: resolution of signs and symptoms attributed to Candida infection; no additional systemic or oral antifungal treatment required to complete the course of therapy. Clinical response of improvement: significant, but incomplete resolution of signs and symptoms of Candida infection; no additional systemic or oral antifungal treatment required. |
| Percentage of Participants With Relapse | 2-week follow-up (2 weeks after EOT), 6-week follow-up (6 weeks after EOT) | Relapse was defined as any baseline Candida sp. isolated following eradication (documented or presumed) or culture data not available for participants with a clinical response of failure after a previous response of success. Prophylactic treatment with oral antifungal agents was not sufficient to document a relapse. |
| Percentage of Participants With Global Response at 2-week and 6-week Follow-up Visit | 2-week follow-up (2 weeks after end of treatment [EOT]), 6-week follow-up (6 weeks after EOT) | Participants had successful global response if there was clinical response of cure/improvement,microbiological eradication/presumed eradication.Clinical cure:resolution of signs/symptoms (s/s) of Candida infection;no additional systemic/oral antifungal treatment needed.Clinical improvement:significant,but incomplete resolution of s/s of Candida infection;no additional systemic/oral antifungal treatment needed.Microbiological eradication/presumed eradication:baseline pathogen not isolated from original site culture,or culture data not available for participant with successful clinical outcome. |
| Time to Negative Blood Culture | Baseline up to 6-week follow-up (6 weeks after EOT) | Negative blood culture referred to absence of Candida sp. in the blood sample of participants who had a positive blood culture at baseline. Time to negative blood culture (days) was calculated as date of first negative blood culture minus first treatment date plus 1. |
| Percentage of Participants With All-cause Mortality | Baseline to EOT (Day 14 to 42), After EOT to 2-week follow-up (2 weeks after EOT), After 2-week follow-up to 6-week follow-up (6 weeks after EOT) | All-cause mortality during study therapy and at follow-up visits reported as unique death at EOT, 2 week follow-up and 6 week follow-up. |
| Time to Death | Baseline up to 6-week follow-up (6 weeks after EOT) | Time to death (days) was assessed as date of death minus first treatment date plus 1. |
| Percentage of Participants With New Infection | 2-week follow-up (2 weeks after EOT), 6-week follow-up (6 weeks after EOT) | New Infection: participant presenting with clinical failure with the emergence of new Candida sp. at the original site of infection or at a distant site of infection. Clinical failure: no significant improvement in signs and symptoms, or death due to Candida infection. Participants must have had received at least 3 doses of study drug to be classified as a failure. |
Countries
Belgium, Bulgaria, Canada, Netherlands, Portugal, Romania, Russia, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Anidulafungin Anidulafungin at a loading dose 200 milligram (mg) as two 100 mg consecutive infusions intravenously over 1.5 hours each, administered prior to or following placebo matched to caspofungin 70 mg infusion intravenously over 1 hour on Day 1. Anidulafungin 100 mg infusion intravenously over 1.5 hours once daily, administered prior to or following placebo matched to caspofungin 50 mg infusion intravenously over 1 hour once daily starting from Day 2 to end of treatment (Day 14 to Day 42). | 26 |
| Caspofungin Caspofungin at a loading dose 70 mg infusion intravenously over 1 hour, administered prior to or following 2 placebo infusions, each matched to anidulafungin 100 mg infusion, intravenously over 1.5 hours each on Day 1. Caspofungin 50 mg infusion intravenously over 1 hour once daily, administered prior to or following placebo matched to anidulafungin 100 mg infusion intravenously over 1.5 hours once daily starting from Day 2 to end of treatment (Day 14 to Day 42). | 13 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 7 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Randomized, but not treated | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Anidulafungin | Caspofungin | Total |
|---|---|---|---|
| Age Continuous | 56.3 years STANDARD_DEVIATION 16.2 | 63.4 years STANDARD_DEVIATION 16.3 | 58.6 years STANDARD_DEVIATION 16.4 |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 14 Participants |
| Sex: Female, Male Male | 17 Participants | 8 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 26 | 11 / 13 |
| serious Total, serious adverse events | 12 / 26 | 7 / 13 |
Outcome results
Primary
Percentage of Participants With Global Response at End of Treatment (Day 14 To Day 42)
Participants had successful global response if there was clinical response of cure/improvement,microbiological eradication/presumed eradication.Clinical cure:resolution of signs/symptoms (s/s) of Candida infection;no additional systemic/oral antifungal treatment needed.Clinical improvement:significant,but incomplete resolution of s/s of Candida infection;no additional systemic/oral antifungal treatment needed.Microbiological eradication/presumed eradication:baseline pathogen not isolated from original site culture,or culture data not available for participant with successful clinical outcome.
Time frame: End of Treatment (Day 14 to Day 42)
Population: Modified Intent-To-Treat (MITT) population included all participants who received at least 1 dose of study drug and had a positive culture for Candida species (sp.).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anidulafungin | Percentage of Participants With Global Response at End of Treatment (Day 14 To Day 42) | 83.3 percentage of participants |
| Caspofungin | Percentage of Participants With Global Response at End of Treatment (Day 14 To Day 42) | 61.5 percentage of participants |
Comparison: The 95 percent (%) confidence interval (CI) was calculated using method of exact unconditional confidence limits for the difference. Global response (rates of success) by using a 2-sided 95% CI for the true difference in efficacy (Anidulafungin minus Caspofungin) was calculated. Statistical testing was done at 2.5% alpha.95% CI: [-12.3, 53.3]
Secondary
Percentage of Participants With All-cause Mortality
All-cause mortality during study therapy and at follow-up visits reported as unique death at EOT, 2 week follow-up and 6 week follow-up.
Time frame: Baseline to EOT (Day 14 to 42), After EOT to 2-week follow-up (2 weeks after EOT), After 2-week follow-up to 6-week follow-up (6 weeks after EOT)
Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anidulafungin | Percentage of Participants With All-cause Mortality | Baseline to EOT | 3.8 percentage of participants |
| Anidulafungin | Percentage of Participants With All-cause Mortality | After EOT to 2-week follow-up | 15.4 percentage of participants |
| Anidulafungin | Percentage of Participants With All-cause Mortality | After 2-week follow-up to 6-week follow-up | 7.7 percentage of participants |
| Caspofungin | Percentage of Participants With All-cause Mortality | Baseline to EOT | 15.4 percentage of participants |
| Caspofungin | Percentage of Participants With All-cause Mortality | After EOT to 2-week follow-up | 15.4 percentage of participants |
| Caspofungin | Percentage of Participants With All-cause Mortality | After 2-week follow-up to 6-week follow-up | 0.0 percentage of participants |
Secondary
Percentage of Participants With Clinical Response
A participant had a successful clinical response if there was clinical response of cure or improvement. Clinical response of cure: resolution of signs and symptoms attributed to Candida infection; no additional systemic or oral antifungal treatment required to complete the course of therapy. Clinical response of improvement: significant, but incomplete resolution of signs and symptoms of Candida infection; no additional systemic or oral antifungal treatment required.
Time frame: Day 10
Population: MITT population included all participants who received at least 1 dose of study drug and had a positive culture for Candida species.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anidulafungin | Percentage of Participants With Clinical Response | 70.8 percentage of participants |
| Caspofungin | Percentage of Participants With Clinical Response | 76.9 percentage of participants |
Comparison: The 95% CI was calculated using method of exact unconditional confidence limits for the difference. Global response (rates of success) by using a 2-sided 95% CI for the true difference in efficacy (Anidulafungin minus Caspofungin) was calculated. Statistical testing was done at 2.5% alpha.95% CI: [-39, 27.9]
Secondary
Percentage of Participants With Global Response at 2-week and 6-week Follow-up Visit
Participants had successful global response if there was clinical response of cure/improvement,microbiological eradication/presumed eradication.Clinical cure:resolution of signs/symptoms (s/s) of Candida infection;no additional systemic/oral antifungal treatment needed.Clinical improvement:significant,but incomplete resolution of s/s of Candida infection;no additional systemic/oral antifungal treatment needed.Microbiological eradication/presumed eradication:baseline pathogen not isolated from original site culture,or culture data not available for participant with successful clinical outcome.
Time frame: 2-week follow-up (2 weeks after end of treatment [EOT]), 6-week follow-up (6 weeks after EOT)
Population: MITT population included all participants who received at least 1 dose of study drug and had a positive culture for Candida species. Only participants who completed therapy or who had global response of failure at EOT were evaluable for 2- and 6-week follow-up analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anidulafungin | Percentage of Participants With Global Response at 2-week and 6-week Follow-up Visit | 2-week follow-up | 76.2 percentage of participants |
| Anidulafungin | Percentage of Participants With Global Response at 2-week and 6-week Follow-up Visit | 6-week follow-up | 66.7 percentage of participants |
| Caspofungin | Percentage of Participants With Global Response at 2-week and 6-week Follow-up Visit | 2-week follow-up | 54.5 percentage of participants |
| Caspofungin | Percentage of Participants With Global Response at 2-week and 6-week Follow-up Visit | 6-week follow-up | 54.5 percentage of participants |
Comparison: 2-week follow-up: The 95% CI was calculated using method of exact unconditional confidence limits for the difference. Global response (rates of success) by using a 2-sided 95% CI for the true difference in efficacy (Anidulafungin minus Caspofungin) was calculated. Statistical testing was done at 2.5% alpha.95% CI: [-13.6, 55.6]
Comparison: 6-week follow-up: The 95% CI was calculated using method of exact unconditional confidence limits for the difference. Global response (rates of success) by using a 2-sided 95% CI for the true difference in efficacy (Anidulafungin minus Caspofungin) was calculated. Statistical testing was done at 2.5% alpha.95% CI: [-23.3, 47.3]
Secondary
Percentage of Participants With New Infection
New Infection: participant presenting with clinical failure with the emergence of new Candida sp. at the original site of infection or at a distant site of infection. Clinical failure: no significant improvement in signs and symptoms, or death due to Candida infection. Participants must have had received at least 3 doses of study drug to be classified as a failure.
Time frame: 2-week follow-up (2 weeks after EOT), 6-week follow-up (6 weeks after EOT)
Population: MITT population included all participants who received at least 1 dose of study drug and had a positive culture for Candida species.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anidulafungin | Percentage of Participants With New Infection | 2-week follow-up | 0 percentage of participants |
| Anidulafungin | Percentage of Participants With New Infection | 6-week follow-up | 0 percentage of participants |
| Caspofungin | Percentage of Participants With New Infection | 2-week follow-up | 0 percentage of participants |
| Caspofungin | Percentage of Participants With New Infection | 6-week follow-up | 0 percentage of participants |
Secondary
Percentage of Participants With Relapse
Relapse was defined as any baseline Candida sp. isolated following eradication (documented or presumed) or culture data not available for participants with a clinical response of failure after a previous response of success. Prophylactic treatment with oral antifungal agents was not sufficient to document a relapse.
Time frame: 2-week follow-up (2 weeks after EOT), 6-week follow-up (6 weeks after EOT)
Population: MITT population included all participants who received at least 1 dose of study drug and had a positive culture for Candida species.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anidulafungin | Percentage of Participants With Relapse | 2-week follow-up | 0 percentage of participants |
| Anidulafungin | Percentage of Participants With Relapse | 6-week follow-up | 0 percentage of participants |
| Caspofungin | Percentage of Participants With Relapse | 2-week follow-up | 0 percentage of participants |
| Caspofungin | Percentage of Participants With Relapse | 6-week follow-up | 0 percentage of participants |
Secondary
Percentage of Participants With Response Based on Clinical Cure and Microbiological Success
A participant had a successful response if there was clinical response of cure and microbiological success (eradication or presumed eradication). Clinical response of cure: resolution of signs and symptoms attributed to Candida infection; no additional systemic or oral antifungal treatment required to complete the course of therapy. Microbiological eradication or presumed eradication: baseline pathogen not isolated from original site culture, or culture data not available for a participant with successful clinical outcome.
Time frame: EOT (Day 14 to 42), 2-week follow-up (2 weeks after EOT), 6-week follow-up (6 weeks after EOT)
Population: MITT population. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure. Here, 'n' signifies those participants who were evaluable for this measure at given time points for each group respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anidulafungin | Percentage of Participants With Response Based on Clinical Cure and Microbiological Success | EOT (n=21,8) | 81.0 percentage of participants |
| Anidulafungin | Percentage of Participants With Response Based on Clinical Cure and Microbiological Success | 2-week follow-up (n=16,6) | 87.5 percentage of participants |
| Anidulafungin | Percentage of Participants With Response Based on Clinical Cure and Microbiological Success | 6-week follow-up (n=15,6) | 93.3 percentage of participants |
| Caspofungin | Percentage of Participants With Response Based on Clinical Cure and Microbiological Success | EOT (n=21,8) | 62.5 percentage of participants |
| Caspofungin | Percentage of Participants With Response Based on Clinical Cure and Microbiological Success | 2-week follow-up (n=16,6) | 100.0 percentage of participants |
| Caspofungin | Percentage of Participants With Response Based on Clinical Cure and Microbiological Success | 6-week follow-up (n=15,6) | 100.0 percentage of participants |
Secondary
Time to Death
Time to death (days) was assessed as date of death minus first treatment date plus 1.
Time frame: Baseline up to 6-week follow-up (6 weeks after EOT)
Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anidulafungin | Time to Death | 23.0 days |
| Caspofungin | Time to Death | 11.5 days |
Secondary
Time to Negative Blood Culture
Negative blood culture referred to absence of Candida sp. in the blood sample of participants who had a positive blood culture at baseline. Time to negative blood culture (days) was calculated as date of first negative blood culture minus first treatment date plus 1.
Time frame: Baseline up to 6-week follow-up (6 weeks after EOT)
Population: A sub-set of MITT population included only those participants who had a positive blood culture for Candida species at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anidulafungin | Time to Negative Blood Culture | 2.0 days |
| Caspofungin | Time to Negative Blood Culture | 3.5 days |