Mycoses
Conditions
Keywords
Triazoles
Brief summary
The purpose of this study is to evaluate the efficacy and safety of posaconazole in the early treatment of fungal infections in participants who are refractory to, intolerant to, or medically precluded from first-line monotherapy or first-line combination antifungal therapy.
Detailed description
In the past two decades, invasive fungal infections (IFI) have become increasingly common among immunocompromised people, including solid-organ or hematopoietic stem-cell transplant recipients, those with HIV infection, those with hematological malignancies, and individuals on immunosuppressive drug regimens. There is a high rate of morbidity and mortality associated with IFI. Over the past decade, there has been an increase in resistance to commonly used antifungal agents and an epidemiological shift to more drug-resistant strains. This has demonstrated the need for the development of a new generation of azoles.
Interventions
DRUGPosaconazole
Posaconazole oral suspension was administered as 400 mg twice daily (bis in die, BID) with food or 200 mg four times daily (quater in die, QID) without food for a minimum of 1 month.
Sponsors
JSS Medical Research Inc.
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Proven or probable invasive fungal infection (IFI) including breakthrough infection while on antifungal treatment for at least 7 days. * Refractory or intolerant to prior antifungal therapy, or medically unable to receive standard antifungal therapy. * Age ≥13 years old. * Expected to survive \>1 month. * Negative pregnancy test (serum or urine) at baseline for women of childbearing potential.
Exclusion criteria
* Serum bilirubin \>10 times upper limit of normal (ULN). * Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>10 times ULN. * Documented allergy to azoles. * Unable to take oral suspension medications or enteral feeding. * Pregnant or breastfeeding. * Participants who have received an investigational drug are allowed to be enrolled if the investigational drug was given 30 days prior to study registration, unless approved by the Sponsor. * Requires surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) by 12 Weeks or End of Treatment | Up to 6 months | Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a CR or PR by 12 Weeks | Up to 12 Weeks | Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. |
| Percentage of Participants With CR or PR by 4 Weeks and by 26 Weeks | Up to 26 weeks | Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. |
| Percentage of Participants With Infection-free Survival After the Last Dose of Study Drug | Up to 6 months | Infection-free survival was the proportion of evaluable participants included in the efficacy analysis who are infection-free and alive at 6 months post last dose visit. Infection-free is defined as the resolution of signs and symptoms of infection. |
| Number of Participants With ≥50% Decrease in Lesion Size or Number | Up to 6 months | Reduction in lesion size was analyzed by computed tomography (CT) scan. An imaging response was defined as \>=50% reduction in lesion size for pulmonary and cerebral disease or \>=50% reduction in the number of lesions for liver disease. |
| Number of Participants With Response to Posaconazole in Combination Therapy | Up to 6 months | Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. |
| Number of Participants Experiencing Adverse Events (AEs) | Up to 12 months | An adverse event (AE) is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration whether or not considered related to the use of the study drug. |
| Overall Survival at 3 Months | 3 months | Total number of participant survivors was assessed at 3 months. |
Participant flow
Recruitment details
The study was conducted in 8 medical centers across Canada.
Participants by arm
| Arm | Count |
|---|---|
| Posaconazole Posaconazole oral suspension was administered as 400 mg twice daily (bis in die, BID) with food or 200 mg four times daily (quater in die, QID) without food for a minimum of 1 month. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 4 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Palliative care | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Posaconazole |
|---|---|
| Age, Customized | 48 Years |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 35 / 40 |
| serious Total, serious adverse events | 16 / 40 |
Outcome results
Primary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) by 12 Weeks or End of Treatment
Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline.
Time frame: Up to 6 months
Population: The Efficacy Population included those participants with both a baseline and at least 1 post-baseline assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Percentage of Participants With Complete Response (CR) or Partial Response (PR) by 12 Weeks or End of Treatment | Complete Response | 26 Percentage of participants |
| Posaconazole | Percentage of Participants With Complete Response (CR) or Partial Response (PR) by 12 Weeks or End of Treatment | Partial Response | 46 Percentage of participants |
Secondary
Number of Participants Experiencing Adverse Events (AEs)
An adverse event (AE) is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration whether or not considered related to the use of the study drug.
Time frame: Up to 12 months
Population: All enrolled participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Number of Participants Experiencing Adverse Events (AEs) | 39 Number of participants |
Secondary
Number of Participants With ≥50% Decrease in Lesion Size or Number
Reduction in lesion size was analyzed by computed tomography (CT) scan. An imaging response was defined as \>=50% reduction in lesion size for pulmonary and cerebral disease or \>=50% reduction in the number of lesions for liver disease.
Time frame: Up to 6 months
Population: This outcome measure was not reported as the Safety and Steering Committee (SSC) no longer considered it relevant based on revised Mycoses Study Group and European Organization for Research and Treatment of Cancer (MSG/EORTC) Consensus Criteria.
Secondary
Number of Participants With Response to Posaconazole in Combination Therapy
Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline.
Time frame: Up to 6 months
Population: The proportion of participants with response to posaconzole who received a prior combination antifungal regimen is not reported as per recommendation from the Safety and Steering Committee since only 1 participant was evaluable for this outcome measure.
Secondary
Overall Survival at 3 Months
Total number of participant survivors was assessed at 3 months.
Time frame: 3 months
Population: All enrolled participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Overall Survival at 3 Months | 85 Percentage of Participants |
Secondary
Percentage of Participants With a CR or PR by 12 Weeks
Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline.
Time frame: Up to 12 Weeks
Population: The Efficacy Population included those participants with both a baseline and at least 1 post-baseline assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Percentage of Participants With a CR or PR by 12 Weeks | 75 Percentage of participants |
Secondary
Percentage of Participants With CR or PR by 4 Weeks and by 26 Weeks
Complete Response was defined as resolution of all attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline. Partial Response was defined as clinically meaningful improvement in attributable clinical signs and symptoms and radiologic and mycologic abnormalities, if present at baseline.
Time frame: Up to 26 weeks
Population: The Efficacy Population included those participants with both a baseline and at least 1 post-baseline assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Posaconazole | Percentage of Participants With CR or PR by 4 Weeks and by 26 Weeks | Week 4, CR | 6 Percentage of Participants |
| Posaconazole | Percentage of Participants With CR or PR by 4 Weeks and by 26 Weeks | Week 26, CR | 26 Percentage of Participants |
| Posaconazole | Percentage of Participants With CR or PR by 4 Weeks and by 26 Weeks | Week 4, PR | 28 Percentage of Participants |
| Posaconazole | Percentage of Participants With CR or PR by 4 Weeks and by 26 Weeks | Week 26, PR | 48 Percentage of Participants |
Secondary
Percentage of Participants With Infection-free Survival After the Last Dose of Study Drug
Infection-free survival was the proportion of evaluable participants included in the efficacy analysis who are infection-free and alive at 6 months post last dose visit. Infection-free is defined as the resolution of signs and symptoms of infection.
Time frame: Up to 6 months
Population: The Efficacy Population included those participants with a visit 6 months after the last dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Posaconazole | Percentage of Participants With Infection-free Survival After the Last Dose of Study Drug | 56 Percentage of participants |