Fungal Infection
Conditions
Keywords
refractory or first line medication intolerable invasive fungal infection
Brief summary
The purpose of this multicenter, open label study, is to evaluate the safety and efficacy of a 12-week treatment with Posaconazole Oral Suspension in participants with IFI
Interventions
DRUGPosaconazole
400mg BID oral suspension for 12 weeks
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 70 Years
Healthy volunteers
No
Inclusion criteria
* Participants must be 18-70 years male or female * Identified or clinically diagnosed IFI participants or high risk population who are resistant to, or recurrent from, or intolerable to, or may suffer toxic reaction from standard antifungal treatment. * Sign informed consent form
Exclusion criteria
* Female participants who are pregnant or are nursing. * Participants with known or suspected hypersensitivity or idiosyncratic reaction to azole agents or amphotericin B * Participants with progressive nervous system diseases( excluding those IFI caused) * Participants who take the following drugs known with interference with azole antifungal preparations * terfenadine, cisapride, and ebastine within 24 hours before entry * astemizole at entry or within 10 days before entry * cimetidine, rifampin, carbamazepine, phenytoin, rifabutin, barbiturates, isoniazid atharanthine and anthracyclines within 24 hours before entry * The drugs listed above are prohibited during the investigation * Serious organ diseases except hematological disorder such as cardiac or neurologic disorders or impairment expected to be unstable or progressive during the course of this study (eg, seizures or demyelinating syndromes, acute myocardial infarction within 3 months of study entry, myocardial ischemia, congestive heart failure, atrial fibrillation with ventricular rate \<60/min, or history of torsades de pointes, symptomatic ventricular or sustained arrhythmias), unstable electrolyte abnormalities. * Participants having an ECG with a prolonged QTc interval: QTc greater than 450 msec for men and greater than 470 msec for women. * Expected to take during investigation or is taking systemic antifungal treatment * Participants with severe renal insufficiency (estimated creatinine clearance less than 50 mL/minute or likely to require dialysis during the study), ALT,AST AKP or total bilirubin are \>2×ULN. * Participants expected to survive no more than 72hrs * Participants receiving artificial aeration and will not withdraw within 24hrs * Participants who have used any investigational drugs or biologic agents or anticipated other clinical trials within 30 days of study entry. * Prior enrollment in this study. * History of alcohol and/or drug abuse. * Participants cannot be compliant in investigator's opinion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had Clinical Response at 12 Weeks With Posaconazole Treatment | Treatment week 12 | EVALUATION OF PARTICIPANTS' CLINICAL RESPONSE BASED ON CRITERIA: Complete Response: resolution of Invasive Fungal Infection (IFI) attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment. Partial Response: clinically significant improvement in IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment, of which, one still had not achieved complete recession. Stable disease: no progress in IFI attributable symptoms, if present at enrollment. Failure: deterioration in IFI attributable clinical symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had Clinical Response at 8 Weeks With Posaconazole Treatment | Treatment week 8 | EVALUATION OF PARTICIPANTS' CLINICAL RESPONSE BASED ON CRITERIA: Complete Response: resolution of IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment. Partial Response: clinically significant improvement in IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment, of which, one still had not achieved complete recession. Stable disease: no progress in IFI attributable symptoms, if present at enrollment. Failure: deterioration in IFI attributable clinical symptoms. |
| Number of Participants With Pathogenic Fungal Eradication at 4 Weeks With Posaconazole Treatment | Treatment week 4 | EVALUATION OF FUNGAL ERADICATION: Participants' mycological response to therapy was assessed by the following: Eradication: Negative culture or histologically documented absence of infecting fungal pathogen from a primary site previously positive. Presumed Eradication: Resolution of all IFI attributable symptoms, signs and laboratory or radiological abnormalities in which a repeat culture/biopsy was contraindicated. Persistence: Continued isolation of fungal pathogen from a primary site previously positive or cytological documentation of presence of fungal pathogen. |
| Number of Participants Who Had Clinical Response at 4 Weeks With Posaconazole Treatment | Treatment week 4 | EVALUATION OF PARTICIPANTS' CLINICAL RESPONSE BASED ON CRITERIA: Complete Response: resolution of IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment. Partial Response: clinically significant improvement in IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment, of which, one still had not achieved complete recession. Stable disease: no progress in IFI attributable symptoms, if present at enrollment. Failure: deterioration in IFI attributable clinical symptoms. |
| Number of Participants With Pathogenic Fungal Eradication at 12 Weeks With Posaconazole Treatment | Treatment week 12 | EVALUATION OF FUNGAL ERADICATION: Participants' mycological response to therapy was assessed by the following: Eradication: Negative culture or histologically documented absence of infecting fungal pathogen from a primary site previously positive. Presumed Eradication: Resolution of all IFI attributable symptoms, signs and laboratory or radiological abnormalities in which a repeat culture/biopsy was contraindicated. Persistence: Continued isolation of fungal pathogen from a primary site previously positive or cytological documentation of presence of fungal pathogen. |
| Number of Participant Survivors at Week 14 of Post-Posaconazole Treatment Follow-up | Follow-up week 14 | Total number of participant deaths was assessed at the end of 2 week post-treatment follow-up (14 weeks). The total number of deaths was compared to the number of survivors at baseline. |
| Number of Participants With Pathogenic Fungal Eradication at 8 Weeks With Posaconazole Treatment | Treatment week 8 | EVALUATION OF FUNGAL ERADICATION: Participants' mycological response to therapy was assessed by the following: Eradication: Negative culture or histologically documented absence of infecting fungal pathogen from a primary site previously positive. Presumed Eradication: Resolution of all IFI attributable symptoms, signs and laboratory or radiological abnormalities in which a repeat culture/biopsy was contraindicated. Persistence: Continued isolation of fungal pathogen from a primary site previously positive or cytological documentation of presence of fungal pathogen. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Posaconazole 400 mg twice a day (BID) oral suspension for
12 weeks | 62 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Cumulative use of antifungal agent | 2 |
| Overall Study | Death | 2 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 7 |
Baseline characteristics
| Characteristic | Posaconazole |
|---|---|
| Age, Continuous | 40.41 years STANDARD_DEVIATION 14.752 |
| Region of Enrollment China | 62 participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 40 / 62 |
| serious Total, serious adverse events | 5 / 62 |
Outcome results
Primary
Number of Participants Who Had Clinical Response at 12 Weeks With Posaconazole Treatment
EVALUATION OF PARTICIPANTS' CLINICAL RESPONSE BASED ON CRITERIA: Complete Response: resolution of Invasive Fungal Infection (IFI) attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment. Partial Response: clinically significant improvement in IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment, of which, one still had not achieved complete recession. Stable disease: no progress in IFI attributable symptoms, if present at enrollment. Failure: deterioration in IFI attributable clinical symptoms.
Time frame: Treatment week 12
Population: Pool of participants were from the Full Analysis Set (FAS): included all randomized participants who received at least one dose of study drug and who had valid data of primary efficacy endpoint for at least one follow-up visit after treatment. Did not include the 3 participants from the SS population (n=62) who withdrew from the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Number of Participants Who Had Clinical Response at 12 Weeks With Posaconazole Treatment | Complete response | 6 Participants |
| Posaconazole | Number of Participants Who Had Clinical Response at 12 Weeks With Posaconazole Treatment | Partial response | 32 Participants |
| Posaconazole | Number of Participants Who Had Clinical Response at 12 Weeks With Posaconazole Treatment | Stable | 11 Participants |
| Posaconazole | Number of Participants Who Had Clinical Response at 12 Weeks With Posaconazole Treatment | Failure | 10 Participants |
Secondary
Number of Participant Survivors at Week 14 of Post-Posaconazole Treatment Follow-up
Total number of participant deaths was assessed at the end of 2 week post-treatment follow-up (14 weeks). The total number of deaths was compared to the number of survivors at baseline.
Time frame: Follow-up week 14
Population: Pool of participants were from the FAS: included all randomized participants who received at least one dose of study drug and who had valid data of primary efficacy endpoint for at least one follow-up visit after treatment. Did not include the 3 participants from the SS population (n=62) who withdrew from the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Number of Participant Survivors at Week 14 of Post-Posaconazole Treatment Follow-up | Survival | 57 Participants |
| Posaconazole | Number of Participant Survivors at Week 14 of Post-Posaconazole Treatment Follow-up | Death | 2 Participants |
Secondary
Number of Participants Who Had Clinical Response at 4 Weeks With Posaconazole Treatment
EVALUATION OF PARTICIPANTS' CLINICAL RESPONSE BASED ON CRITERIA: Complete Response: resolution of IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment. Partial Response: clinically significant improvement in IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment, of which, one still had not achieved complete recession. Stable disease: no progress in IFI attributable symptoms, if present at enrollment. Failure: deterioration in IFI attributable clinical symptoms.
Time frame: Treatment week 4
Population: Pool of participants were from the FAS: included all randomized participants who received at least one dose of study drug and who had valid data of primary efficacy endpoint for at least one follow-up visit after treatment. Did not include the 3 participants from the SS population (n=62) who withdrew from the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Number of Participants Who Had Clinical Response at 4 Weeks With Posaconazole Treatment | Complete response | 2 Particpants |
| Posaconazole | Number of Participants Who Had Clinical Response at 4 Weeks With Posaconazole Treatment | Partial response | 39 Particpants |
| Posaconazole | Number of Participants Who Had Clinical Response at 4 Weeks With Posaconazole Treatment | Stable disease | 11 Particpants |
| Posaconazole | Number of Participants Who Had Clinical Response at 4 Weeks With Posaconazole Treatment | Failure | 7 Particpants |
Secondary
Number of Participants Who Had Clinical Response at 8 Weeks With Posaconazole Treatment
EVALUATION OF PARTICIPANTS' CLINICAL RESPONSE BASED ON CRITERIA: Complete Response: resolution of IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment. Partial Response: clinically significant improvement in IFI attributable symptoms, signs and laboratory or etiological abnormalities, if present at enrollment, of which, one still had not achieved complete recession. Stable disease: no progress in IFI attributable symptoms, if present at enrollment. Failure: deterioration in IFI attributable clinical symptoms.
Time frame: Treatment week 8
Population: Pool of participants were from the FAS: included all randomized participants who received at least one dose of study drug and who had valid data of primary efficacy endpoint for at least one follow-up visit after treatment. Did not include the 3 participants from the SS population (n=62) who withdrew from the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Number of Participants Who Had Clinical Response at 8 Weeks With Posaconazole Treatment | Complete response | 3 Participants |
| Posaconazole | Number of Participants Who Had Clinical Response at 8 Weeks With Posaconazole Treatment | Partial response | 34 Participants |
| Posaconazole | Number of Participants Who Had Clinical Response at 8 Weeks With Posaconazole Treatment | Stable disease | 11 Participants |
| Posaconazole | Number of Participants Who Had Clinical Response at 8 Weeks With Posaconazole Treatment | Failure | 11 Participants |
Secondary
Number of Participants With Pathogenic Fungal Eradication at 12 Weeks With Posaconazole Treatment
EVALUATION OF FUNGAL ERADICATION: Participants' mycological response to therapy was assessed by the following: Eradication: Negative culture or histologically documented absence of infecting fungal pathogen from a primary site previously positive. Presumed Eradication: Resolution of all IFI attributable symptoms, signs and laboratory or radiological abnormalities in which a repeat culture/biopsy was contraindicated. Persistence: Continued isolation of fungal pathogen from a primary site previously positive or cytological documentation of presence of fungal pathogen.
Time frame: Treatment week 12
Population: Only FAS participants with positive fungal culture (of suspected site or blood) were evaluated. LOCF was used for missing data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 12 Weeks With Posaconazole Treatment | Eradication | 2 Participants |
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 12 Weeks With Posaconazole Treatment | Presumable eradication | 7 Participants |
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 12 Weeks With Posaconazole Treatment | Disease persistent | 8 Participants |
Secondary
Number of Participants With Pathogenic Fungal Eradication at 4 Weeks With Posaconazole Treatment
EVALUATION OF FUNGAL ERADICATION: Participants' mycological response to therapy was assessed by the following: Eradication: Negative culture or histologically documented absence of infecting fungal pathogen from a primary site previously positive. Presumed Eradication: Resolution of all IFI attributable symptoms, signs and laboratory or radiological abnormalities in which a repeat culture/biopsy was contraindicated. Persistence: Continued isolation of fungal pathogen from a primary site previously positive or cytological documentation of presence of fungal pathogen.
Time frame: Treatment week 4
Population: Only FAS participants with positive fungal culture (of suspected site or blood) were evaluated. Last Observation Carried Forward (LOCF) was used for missing data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 4 Weeks With Posaconazole Treatment | Eradication | 2 Participants |
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 4 Weeks With Posaconazole Treatment | Presumed eradication | 6 Participants |
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 4 Weeks With Posaconazole Treatment | Disease persistence | 9 Participants |
Secondary
Number of Participants With Pathogenic Fungal Eradication at 8 Weeks With Posaconazole Treatment
EVALUATION OF FUNGAL ERADICATION: Participants' mycological response to therapy was assessed by the following: Eradication: Negative culture or histologically documented absence of infecting fungal pathogen from a primary site previously positive. Presumed Eradication: Resolution of all IFI attributable symptoms, signs and laboratory or radiological abnormalities in which a repeat culture/biopsy was contraindicated. Persistence: Continued isolation of fungal pathogen from a primary site previously positive or cytological documentation of presence of fungal pathogen.
Time frame: Treatment week 8
Population: Only FAS participants with positive fungal culture (of suspected site or blood) were evaluated. LOCF was used for missing data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 8 Weeks With Posaconazole Treatment | Eradication | 2 Participants |
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 8 Weeks With Posaconazole Treatment | Presumable eradication | 6 Participants |
| Posaconazole | Number of Participants With Pathogenic Fungal Eradication at 8 Weeks With Posaconazole Treatment | Disease persistence | 9 Participants |