Candida Infection, Candidemia, Invasive Candidiases
Conditions
Brief summary
This is a multicenter, open-label, single arm study to evaluate the efficacy and safety of APX001 for the treatment of candidemia and/or invasive candidiasis caused by C. auris in patients aged 18 years and over with limited antifungal treatment options.
Detailed description
This is a multicenter, open-label, non-comparative, single arm study to evaluate the efficacy and safety of APX001 for the treatment of candidemia and/or invasive candidiasis caused by C. auris in patients aged 18 years and over with limited antifungal treatment options. The Study Drug Treatment Period will be up to a maximum of 42 days (inclusive of the loading dose \[Study Day 1\]). There will be a Follow up Period of 4 weeks (+4 days) after EOST. The total duration of participation in the study is up to approximately 10.5 weeks (inclusive of the Screening Period \[168 hours prior to Baseline\]).
Interventions
DRUGAPX001
Day 1: APX001 1000 mg IV BID over a 3-hour infusion Days 2-3: APX001 600 mg IV QD over a 3-hour infusion Days 4 - 42: APX001 600 mg IV QD over a 3-hour infusion or APX001 800 mg QD oral.
Sponsors
Basilea Pharmaceutica
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, single arm intervention. All patients will receive APX001. On Days 1-3, APX001 will be administered intravenously. Thereafter, if the patient is able to take oral medication, APX001 tablets will be taken orally.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Limited or no treatment options due to resistance, contraindication, intolerance or lack of clinical response to standard of care antifungal therapy, as advocated by the relevant regional/country treatment guidelines * Established mycological and clinical diagnosis of candidemia and/or invasive candidiasis caused by Candida auris * Able to have pre-existing intravascular catheters removed and replaced (if necessary) * Females of childbearing potential with male partners, and males with female partner(s) of childbearing potential, must agree to use 2 forms of highly effective contraception throughout the duration of the study and for 90 days following the last study drug administration. Females of childbearing potential must have a negative urine pregnancy test within 96 hours prior study entry. * Wiling to participate in the study, willing to give written informed consent, and willing to comply with the study restrictions; where permitted by local regulations, written informed consent from a legal authorized representative (LAR) will be obtained for patients who are unable to give consent
Exclusion criteria
* Life expectancy of less than 7 days in the opinion of the Investigator * Human immunodeficiency virus-infected patients who are receiving antiretroviral therapy that are moderate to strong inducers of CYP3A4, or who have detectable viremia, or who have had an active opportunistic infection within 6 months prior * Alanine aminotransferase or aspartate aminotransferase greater than or equal to 5 times the upper limit of normal * Total bilirubin greater than 3 time the upper limit of normal, unless isolated hyperbilirubinemia or due to documented Gilbert's disease * Pregnant or lactating female patient * Inappropriate fungal infection source control * Investigational drug administered within 30 days prior to dosing or five half-lives whichever is longer * Diagnosis of deep-seated Candida-related infections causing hardware associated septic arthritis, osteomyelitis, endocarditis, myocarditis, hepatosplenic candidiasis, or a central nervous system infection or site of infection that would require antifungal therapy to exceed the maximal duration of study drug treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment Success at End of Study Treatment (EOST) as Determined by Data Review Committee (DRC) | EOST: any day from Day 1 up to maximum of Day 42 | Treatment success was defined as meeting all of the following criteria: 1\) Two consecutive blood cultures negative for Candida species, and/or for participants with a deep-seated site of infection, at least 1 negative tissue culture or aspirate/fluid culture. For participants with a deep-seated site of infection involving visceral organs from which a tissue culture was not obtainable, resolution of the attributable clinical signs of infection recorded at Baseline, and as applicable, radiological improvement associated with the site of infection. 2) Alive at EOST and 3) No concomitant use of any other systemic antifungal therapies through EOST. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Mycological Outcomes at EOST and 2 and 4 Weeks After EOST | EOST: any day from Day 1 up to maximum of Day 42, 2 and 4 weeks after EOST | Mycological outcomes were determined based on eradication and presumed eradication. Eradication was defined as a negative blood (and/or other infection site) culture(s) for Candida species. Presumed eradication (applicable to invasive candidiasis) was defined as clinical resolution of invasive Candida species infection where tissue samples were unavailable. These would be applicable only if there were no concomitant or additional systemic antifungal usage. |
| Percentage of Participants With Treatment Success at EOST Determined by Investigator | EOST: any day from Day 1 up to maximum of Day 42 | Treatment success was defined as meeting all of the following criteria: 1\) Two consecutive blood cultures negative for Candida species, and/or for participants with a deep-seated site of infection, at least 1 negative tissue culture or aspirate/fluid culture. For participants with a deep-seated site of infection involving visceral organs from which a tissue culture was not obtainable, resolution of the attributable clinical signs of infection recorded at Baseline, and as applicable, radiological improvement associated with the site of infection. 2) Alive at EOST and 3) No concomitant use of any other systemic antifungal therapies through EOST. |
| Time to First Negative Blood Culture | Day 1 up to maximum of Day 42 | Time to first negative blood culture was defined as the number of days from date of first dose of study drug to the date of first negative blood culture plus 1. Participants without a negative blood culture at post-baseline visits were censored at the last assessment date. Kaplan-Meier method was used for analysis. |
| All-Cause Mortality Through Study Day 30 | Day 1 through Day 30 | Percentage of participants who died through study Day 30 is reported in this outcome measure. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Day 1 up to maximum of 32 days of follow up post last dose of study drug, where maximum treatment duration was 42 days (maximum up to 74 days) | An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were events between first dose of study drug and up to Week 4 (+4 days) post last dose of study drug that were absent before treatment or that worsened relative to pretreatment state. |
| Percentage of Participants With Treatment Success at 2 and 4 Weeks After EOST Determined by Investigator and by the DRC | 2 and 4 weeks after EOST (where EOST is any day from Day 1 up to maximum of Day 42) | Treatment success was defined as meeting all of the following criteria: 1\) Two consecutive blood cultures negative for Candida species, and/or for participants with a deep-seated site of infection, at least 1 negative tissue culture or aspirate/fluid culture. For participants with a deep-seated site of infection involving visceral organs from which a tissue culture was not obtainable, resolution of the attributable clinical signs of infection recorded at Baseline, and as applicable, radiological improvement associated with the site of infection. 2) Alive at EOST and 3) No concomitant use of any other systemic antifungal therapies through EOST. |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| APX001 (Fosmanogepix) Participants with candidemia and/or invasive candidiasis caused by Candida auris and with limited antifungal treatment options were administered APX001. On Day 1, participants received APX001 1000 mg as a loading dose over 3 hours by IV infusion BID. On Days 2 and 3, participants received APX001 600 mg as maintenance dose over 3 hours by IV infusion QD. On Day 4 and onwards, maintenance dose was administered as either APX001 600 mg IV infusion QD over 3 hours or APX001 800 mg orally QD. Participants who were clinically stable after 3 days of IV administration and could swallow tablets, could switch from IV to oral dosing from Day 4 and onwards. Maximum treatment duration was of 42 days. Participants were followed up for 4 weeks (+ 4 days) post last dose of study drug. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | APX001 (Fosmanogepix) |
|---|---|
| Age, Continuous | 49.8 Years STANDARD_DEVIATION 17.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 2 / 9 |
Outcome results
Primary
Percentage of Participants With Treatment Success at End of Study Treatment (EOST) as Determined by Data Review Committee (DRC)
Treatment success was defined as meeting all of the following criteria: 1\) Two consecutive blood cultures negative for Candida species, and/or for participants with a deep-seated site of infection, at least 1 negative tissue culture or aspirate/fluid culture. For participants with a deep-seated site of infection involving visceral organs from which a tissue culture was not obtainable, resolution of the attributable clinical signs of infection recorded at Baseline, and as applicable, radiological improvement associated with the site of infection. 2) Alive at EOST and 3) No concomitant use of any other systemic antifungal therapies through EOST.
Time frame: EOST: any day from Day 1 up to maximum of Day 42
Population: The modified intent-to-treat (mITT) population included all participants who received at least 1 dose of study drug and had a confirmed diagnosis of candidemia and/or invasive candidiasis caused by Candida auris within 120 hours (for candidemia) or 168 hours (for invasive candidiasis without candidemia) of study qualification (as determined by the DRC).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| APX001 (Fosmanogepix) | Percentage of Participants With Treatment Success at End of Study Treatment (EOST) as Determined by Data Review Committee (DRC) | 88.9 Percentage of participants |
Secondary
All-Cause Mortality Through Study Day 30
Percentage of participants who died through study Day 30 is reported in this outcome measure.
Time frame: Day 1 through Day 30
Population: The mITT population included all participants who received at least 1 dose of study drug and had a confirmed diagnosis of candidemia and/or invasive candidiasis caused by Candida auris within 120 hours (for candidemia) or 168 hours (for invasive candidiasis without candidemia) of study qualification (as determined by the DRC).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| APX001 (Fosmanogepix) | All-Cause Mortality Through Study Day 30 | 11.1 Percentage of participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were events between first dose of study drug and up to Week 4 (+4 days) post last dose of study drug that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Day 1 up to maximum of 32 days of follow up post last dose of study drug, where maximum treatment duration was 42 days (maximum up to 74 days)
Population: Safety population included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APX001 (Fosmanogepix) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 9 Participants |
Secondary
Percentage of Participants With Mycological Outcomes at EOST and 2 and 4 Weeks After EOST
Mycological outcomes were determined based on eradication and presumed eradication. Eradication was defined as a negative blood (and/or other infection site) culture(s) for Candida species. Presumed eradication (applicable to invasive candidiasis) was defined as clinical resolution of invasive Candida species infection where tissue samples were unavailable. These would be applicable only if there were no concomitant or additional systemic antifungal usage.
Time frame: EOST: any day from Day 1 up to maximum of Day 42, 2 and 4 weeks after EOST
Population: The mITT population included all participants who received at least 1 dose of study drug and had a confirmed diagnosis of candidemia and/or invasive candidiasis caused by Candida auris within 120 hours (for candidemia) or 168 hours (for invasive candidiasis without candidemia) of study qualification (as determined by the DRC).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| APX001 (Fosmanogepix) | Percentage of Participants With Mycological Outcomes at EOST and 2 and 4 Weeks After EOST | EOST | 66.7 Percentage of participants |
| APX001 (Fosmanogepix) | Percentage of Participants With Mycological Outcomes at EOST and 2 and 4 Weeks After EOST | 2 Weeks after EOST | 66.7 Percentage of participants |
| APX001 (Fosmanogepix) | Percentage of Participants With Mycological Outcomes at EOST and 2 and 4 Weeks After EOST | 4 Weeks after EOST | 66.7 Percentage of participants |
Secondary
Percentage of Participants With Treatment Success at 2 and 4 Weeks After EOST Determined by Investigator and by the DRC
Treatment success was defined as meeting all of the following criteria: 1\) Two consecutive blood cultures negative for Candida species, and/or for participants with a deep-seated site of infection, at least 1 negative tissue culture or aspirate/fluid culture. For participants with a deep-seated site of infection involving visceral organs from which a tissue culture was not obtainable, resolution of the attributable clinical signs of infection recorded at Baseline, and as applicable, radiological improvement associated with the site of infection. 2) Alive at EOST and 3) No concomitant use of any other systemic antifungal therapies through EOST.
Time frame: 2 and 4 weeks after EOST (where EOST is any day from Day 1 up to maximum of Day 42)
Population: The mITT population included all participants who received at least 1 dose of study drug and had a confirmed diagnosis of candidemia and/or invasive candidiasis caused by Candida auris within 120 hours (for candidemia) or 168 hours (for invasive candidiasis without candidemia) of study qualification (as determined by the DRC). Here, Overall Number of Participants Analyzed=participants evaluable for this outcome measure and number analyzed= number of participants evaluable for specified rows.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| APX001 (Fosmanogepix) | Percentage of Participants With Treatment Success at 2 and 4 Weeks After EOST Determined by Investigator and by the DRC | 2 Weeks after EOST: DRC | 66.7 Percentage of participants |
| APX001 (Fosmanogepix) | Percentage of Participants With Treatment Success at 2 and 4 Weeks After EOST Determined by Investigator and by the DRC | 4 Weeks after EOST: DRC | 66.7 Percentage of participants |
| APX001 (Fosmanogepix) | Percentage of Participants With Treatment Success at 2 and 4 Weeks After EOST Determined by Investigator and by the DRC | 2 Weeks after EOST: Investigator | 77.8 Percentage of participants |
| APX001 (Fosmanogepix) | Percentage of Participants With Treatment Success at 2 and 4 Weeks After EOST Determined by Investigator and by the DRC | 4 Weeks after EOST: Investigator | 77.8 Percentage of participants |
Secondary
Percentage of Participants With Treatment Success at EOST Determined by Investigator
Treatment success was defined as meeting all of the following criteria: 1\) Two consecutive blood cultures negative for Candida species, and/or for participants with a deep-seated site of infection, at least 1 negative tissue culture or aspirate/fluid culture. For participants with a deep-seated site of infection involving visceral organs from which a tissue culture was not obtainable, resolution of the attributable clinical signs of infection recorded at Baseline, and as applicable, radiological improvement associated with the site of infection. 2) Alive at EOST and 3) No concomitant use of any other systemic antifungal therapies through EOST.
Time frame: EOST: any day from Day 1 up to maximum of Day 42
Population: The mITT population included all participants who received at least 1 dose of study drug and had a confirmed diagnosis of candidemia and/or invasive candidiasis caused by Candida auris within 120 hours (for candidemia) or 168 hours (for invasive candidiasis without candidemia) of study qualification (as determined by the DRC).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| APX001 (Fosmanogepix) | Percentage of Participants With Treatment Success at EOST Determined by Investigator | 88.9 Percentage of participants |
Secondary
Time to First Negative Blood Culture
Time to first negative blood culture was defined as the number of days from date of first dose of study drug to the date of first negative blood culture plus 1. Participants without a negative blood culture at post-baseline visits were censored at the last assessment date. Kaplan-Meier method was used for analysis.
Time frame: Day 1 up to maximum of Day 42
Population: The mITT population included all participants who received at least 1 dose of study drug and had a confirmed diagnosis of candidemia and/or invasive candidiasis caused by Candida auris within 120 hours (for candidemia) or 168 hours (for invasive candidiasis without candidemia) of study qualification (as determined by the DRC). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| APX001 (Fosmanogepix) | Time to First Negative Blood Culture | 6 Days |