Fungal Infection
Conditions
Brief summary
To evaluate the safety, tolerability, and efficacy of caspofungin for the treatment of esophageal candidiasis and invasive candidiasis to support the registration of caspofungin for these indications in China.
Interventions
Intravenous (IV) caspofungin acetate 50 mg/day. Participants with esophageal candidiasis will be treated for at least 7 days and for at least 72 hours after symptoms resolve for a maximum of 28 days; participants with invasive candidiasis will have a 70 mg loading dose on study day 1 and will be treated for at least 14 days after the last positive culture of Candida from the blood or other normally sterile body site for a maximum of 60 days; these participants should also have improvement in clinical and radiographic signs of disease for at least 48 hours before completion of the study therapy.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant has a confirmed diagnosis of esophageal candidiasis or invasive candidiasis for whom IV antifungal therapy is appropriate * FOR ESOPHAGEAL CANDIDIASIS * Participant has endoscopic evidence of esophageal candidiasis * Participant has disease documented by symptoms consistent with esophageal candidiasis and positive stain or wetmount KOH of brushing or biopsy from endoscopy followed by positive culture for Candida or positive histopathologic evidence of Candida infection * FOR INVASIVE CANDIDIASIS * Participant has at least 1 positive culture of a Candida species from blood or other normally sterile body site obtained within 96 hours of study entry * Participant has clinical evidence of infection within 96 hours before study entry * Temperature \>100\^◦F (37.8\^◦F) on 2 occasions at least 4 hours apart or 1 determination of \>101\^◦F (38.3\^◦F) or clinically significant hypothermia \<96.8\^◦F (36.0\^◦C) * Systolic blood pressure \<90 or ≥30 mm Hg decrease in systolic blood pressure from the participant's normal baseline * Signs of inflammation at a site infected with Candida
Exclusion criteria
* Participant has any of the following abnormal laboratory values: International Normalization Ratio (INR) \>1.6 or, if participant is receiving anticoagulants, INR \>4.0; bilirubin \>5 times the upper limit of normal range; aspartate aminotransferase (AST, or serum glutamic oxaloacetic transaminase \[SGOT\]) or alanine aminotransferase (ALT, or serum glutamic pyruvic transaminase \[SGPT\]) \>5 times the upper limit of normal range * FOR ESOPHAGEAL CANDIDIASIS * Participant has Candida disease limited to the oropharynx * Participant has another cause of esophagitis or has clearly defined ulcers on endoscopy with high likelihood of another non-Candida pathogen * Participant has other esophageal pathology on endoscopy that is unrelated to acute esophageal candidiasis * FOR INVASIVE CANDIDIASIS * Participant has evidence of infection limited to a positive culture for Candida from urine, sputum, catheter tip, indwelling drain, or mucosal or superficial skin surface * Participant has suspected Candida endocarditis, osteomyelitis, or meningitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Drug-related Serious Adverse Events | First dose of study drug through 14 days post therapy (maximum 28 days of study drug for esophageal candidiasis, 60 days for invasive candidiasis; mean treatment duration of 14 days) | A serious adverse event is one that results in death, disability/incapacity, or hospitalization or is life threatening, a congenital anomaly or birth defect, cancer, an overdose, or otherwise jeopardizes the patient and may require medical intervention. A drug-related adverse event is a determination by the investigator physician that the study drug caused the event based on exposure, time course, likely cause, dechallenge (event resolved/improved when drug was discontinued), rechallenge (event resolved/improved when drug was re-introduced), and consistency with the drug profile. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Drug-related Adverse Events | First dose of study drug through 14 days post therapy (maximum 28 days of study drug for esophageal candidiasis, 60 days for invasive candidiasis; mean treatment duration of 14 days) | A drug-related adverse event is a determination by the investigator physician that the study drug caused the event based on exposure, time course, likely cause, dechallenge (event resolved/improved when drug was discontinued), rechallenge (event resolved/improved when drug was re-introduced), and consistency with the drug profile. |
| Number of Participants Who Discontinued Due to a Drug-related Adverse Event | First dose of study drug through 14 days post therapy (maximum 28 days of study drug for esophageal candidiasis, 60 days for invasive candidiasis; mean treatment duration of 14 days) | A drug-related adverse event is a determination by the investigator physician that the study drug caused the event based on exposure, time course, likely cause, dechallenge (event resolved/improved when drug was discontinued), rechallenge (event resolved/improved when drug was re-introduced), and consistency with the drug profile. |
| Number of Participants With Favorable Overall Response for Esophageal Candidiasis or Invasive Candidiasis | First dose of study drug through up to 60 days of therapy (maximum 28 days of study drug for esophageal candidiasis, 60 days for invasive candidiasis; mean treatment duration of 14 days) | Efficacy response for esophageal candidiasis was based on clinical and endoscopic criteria; favorable responses included complete and partial improvement in symptoms and endoscopic lesions. Efficacy response for invasive candidiasis was based on microbiological and clinical assessments; favorable responses required both favorable microbiological response (i.e., eradication or presumptive eradication based on symptoms, physical exam, and non-invasive tests) and complete or partial clinical response. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Caspofungin 50 mg q.d. Intravenous (IV) Three participants with esophageal candidiasis were treated with IV caspofungin 50 mg daily (q.d.) for at least 7 days and for at least 72 hours past the resolution of symptoms for a maximum treatment duration of 28 days.
After a 70 mg loading dose on Study Day 1, 60 participants with invasive candidiasis were treated with IV caspofungin 50 mg q.d. for at least 14 days after the last positive culture of Candida from the blood or other normally sterile body site for a maximum treatment duration of 60 days. | 63 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | No improvement after 7-10 days treatment | 4 |
| Overall Study | Noncompliance with protocol | 1 |
| Overall Study | Other reason | 2 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Rapid progression of baseline disease | 4 |
| Overall Study | Use of other antifungal agent needed | 1 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Caspofungin 50 mg q.d. Intravenous (IV) |
|---|---|
| Age, Continuous | 50.4 years STANDARD_DEVIATION 18.3 |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 43 / 63 |
| serious Total, serious adverse events | 14 / 63 |
Outcome results
Primary
Number of Participants With One or More Drug-related Serious Adverse Events
A serious adverse event is one that results in death, disability/incapacity, or hospitalization or is life threatening, a congenital anomaly or birth defect, cancer, an overdose, or otherwise jeopardizes the patient and may require medical intervention. A drug-related adverse event is a determination by the investigator physician that the study drug caused the event based on exposure, time course, likely cause, dechallenge (event resolved/improved when drug was discontinued), rechallenge (event resolved/improved when drug was re-introduced), and consistency with the drug profile.
Time frame: First dose of study drug through 14 days post therapy (maximum 28 days of study drug for esophageal candidiasis, 60 days for invasive candidiasis; mean treatment duration of 14 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caspofungin 50 mg q.d. IV | Number of Participants With One or More Drug-related Serious Adverse Events | 0 Participants |
Secondary
Number of Participants Who Discontinued Due to a Drug-related Adverse Event
A drug-related adverse event is a determination by the investigator physician that the study drug caused the event based on exposure, time course, likely cause, dechallenge (event resolved/improved when drug was discontinued), rechallenge (event resolved/improved when drug was re-introduced), and consistency with the drug profile.
Time frame: First dose of study drug through 14 days post therapy (maximum 28 days of study drug for esophageal candidiasis, 60 days for invasive candidiasis; mean treatment duration of 14 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caspofungin 50 mg q.d. IV | Number of Participants Who Discontinued Due to a Drug-related Adverse Event | 1 Participants |
Secondary
Number of Participants With Favorable Overall Response for Esophageal Candidiasis or Invasive Candidiasis
Efficacy response for esophageal candidiasis was based on clinical and endoscopic criteria; favorable responses included complete and partial improvement in symptoms and endoscopic lesions. Efficacy response for invasive candidiasis was based on microbiological and clinical assessments; favorable responses required both favorable microbiological response (i.e., eradication or presumptive eradication based on symptoms, physical exam, and non-invasive tests) and complete or partial clinical response.
Time frame: First dose of study drug through up to 60 days of therapy (maximum 28 days of study drug for esophageal candidiasis, 60 days for invasive candidiasis; mean treatment duration of 14 days)
Population: Of the 63 enrolled participants, one participant with invasive candidiasis who withdrew consent before completing the efficacy assessment was not included in the efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caspofungin 50 mg q.d. IV | Number of Participants With Favorable Overall Response for Esophageal Candidiasis or Invasive Candidiasis | 36 Participants |
Secondary
Number of Participants With One or More Drug-related Adverse Events
A drug-related adverse event is a determination by the investigator physician that the study drug caused the event based on exposure, time course, likely cause, dechallenge (event resolved/improved when drug was discontinued), rechallenge (event resolved/improved when drug was re-introduced), and consistency with the drug profile.
Time frame: First dose of study drug through 14 days post therapy (maximum 28 days of study drug for esophageal candidiasis, 60 days for invasive candidiasis; mean treatment duration of 14 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Caspofungin 50 mg q.d. IV | Number of Participants With One or More Drug-related Adverse Events | 31 Participants |