Bacteremia, Skin Diseases, Infectious, Soft Tissue Infections
Conditions
Keywords
methicillin-resistant S. aureus (MRSA) infections, complicated skin and soft tissue infections (cSSTI)
Brief summary
The purpose of this study is to assess the safety, efficacy and pharmacokinetic (PK) parameters of daptomycin for injection in Japanese pediatric participants aged 1 to 17 years with complicated skin and soft tissue infection (cSSTI) or bacteremia caused by gram-positive cocci.
Interventions
Once daily administration of 5, 7, 9, 10, or 12 mg/kg intravenous (IV) daptomycin infused with 25-50 mL saline over 30-60 minutes depending upon infection type and age level.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Requires treatment for cSSTI or bacteremia. * Is male or female Japanese aged ≥ 1 to ≤ 17 years on the day of signing informed consent. * As a male participant, has agreed to use contraception during the treatment period and for at least 14 days after the last dose of study treatment and refrain from donating sperm during this period. * As a female participant, has agreed to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 14 days after the last dose of study treatment. * Has agreed to allow any bacterial isolates obtained from protocol-required specimens related to the current infection to be provided the Central Microbiology Reference Laboratory for study-related microbiological testing, long-term storage, and other future testing. cSSTI Participants * Has cSSTI known or suspected to be caused by gram-positive cocci that requires intravenous antibiotic treatment and diagnosed with either Gram stain or culture. * Has at least 3 of the following clinical signs and symptoms associated with the cSSTI: pain, tenderness to palpation, temperature \>37.0°C axillary or \>37.5°C oral or \>38.0° C rectal, forehead, or aural, white blood count (WBC) \>12,000/mm\^3 or ≥10% bands, swelling and/or induration, erythema (\>1 cm beyond edge of wound or abscess), pus formation, CRP \> upper limited of normal. Bacteremia Participants * Have proven bacteremia with pathogen identification of gram-positive cocci at least one blood culture bottle by conventional culture methods or by a rapid diagnostic test in screening period. * Have probable bacteremia with a blood culture result demonstrating gram-positive cocci by Gram stain in screening period.
Exclusion criteria
* Has received previous systemic antimicrobial therapy that is effective against gram-positive cocci and exceeding 72 hours duration administered at any time during the 96 hours prior to the first dose of study drug. * Has a known infection caused solely by gram-negative pathogen(s), fungus(i) or virus(es). * Has pneumonia (septic emboli in the lung is not an exclusion if clear evidence of source of infection is other than lungs), empyema, meningitis, endocarditis, or osteoarticular infection. * Has a history of or current rhabdomyolysis. * Is anticipated to require non-study systemic antibiotics that may be potentially effective against gram-positive pathogen(s). * Has shock or hypotension unresponsive to fluids or vasopressors for ≥ 4 hours. * Has significant allergy/hypersensitivity or intolerance to daptomycin. * Has renal insufficiency. * Has a history of clinically significant (as assessed by the Investigator) muscular disease, nervous system or seizure disorder, including unexplained muscular weakness, history of peripheral neuropathy, Guillain-Barre or spinal cord injury; previous uncomplicated febrile seizure allowed. * Has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might expose the participant to risk by participating in the trial, confound the results of the trial, or interfere with the participant's participation for the full duration of the trial. * Is a female who is pregnant or is expecting to conceive (or is a male partner of a female who is expecting to conceive), is breastfeeding, or plans to breastfeed prior to completion of the study. * Is currently participating in, or has participated in, any other clinical study involving the administration of investigational or experimental medication (not licensed by regulatory agencies) at the time of the presentation or during the previous 30 days prior to screening or is anticipated to participate in such a clinical study during the course of this trial. * Has previously participated in this study at any time. * Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Adverse Event | Up to 56 days | An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. |
| Percentage of Participants That Discontinued Study Treatment Due to an Adverse Event (AE) | Up to 42 days | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin | Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment | Blood samples were collected at pre-specified time points to determine the AUC0-24 of daptomycin. |
| Maximum Plasma Concentration (Cmax) of Daptomycin | Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment | Blood samples were collected at pre-specified timepoints to determine Cmax of daptomycin. |
| Time to Maximum Plasma Concentration (Tmax) of Daptomycin | Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment | Blood samples were collected at pre-specified time points to determine Tmax of daptomycin |
| Percentage of Participants With Methicillin-Resistant Staphylococcus Aureus (MRSA) Infections Who Experienced Clinical Success | Up to 7 days following end of treatment (up to 49 days) | Clinical success in participants with MRSA infections was defined as either Cure - Resolution of clinically significant signs and symptoms associated with admission infection and no further antibiotic therapy required, OR Improved- partial resolution of clinical signs or symptoms of infection with no further antibiotic therapy required. |
| Volume of Distribution at Steady State (Vss) of Daptomycin | Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment | Blood samples were collected at pre-specified time points to determine Vss (mL) of daptomycin. |
| Apparent Terminal Half-Life (t½) of Daptomycin | Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment | Blood samples were collected at pre-specified time points to determine the t½ of daptomycin. |
| Body Weight Adjusted Clearance (CLss/wt) of Daptomycin | Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment | Blood samples were collected at pre-specified time points to determine CLss/wt of daptomycin at steady state. |
| Percentage of Participants With MRSA Infections Who Experienced a Microbiological Response | Up to 7 days following end of treatment (up to 49 days) | Participant-level microbiological response in participants with MRSA infections at baseline is defined as absence or presumed absence of all baseline infecting pathogens AND no gram-positive superinfection or gram-positive new infection, as assessed by infection site specimen culture or blood culture. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daptomycin Participants aged 1 to 17 years old with cSSTI or bacteremia received daptomycin intravenously every 24 hours for either 5-14 days for cSSTI or for 5-42 days for bacteremia. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 1 |
Baseline characteristics
| Characteristic | Daptomycin |
|---|---|
| Age, Continuous | 6.9 Years STANDARD_DEVIATION 5.1 |
| Age, Customized 85 years and over | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 4 Participants |
| Age, Customized Adults (18-64 years) | 0 Participants |
| Age, Customized Children (2-11 years) | 9 Participants |
| Age, Customized From 65-84 years | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 5 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 18 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 0 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 10 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Percentage of Participants That Discontinued Study Treatment Due to an Adverse Event (AE)
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.
Time frame: Up to 42 days
Population: All enrolled participants who received at least one dose of daptomycin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin | Percentage of Participants That Discontinued Study Treatment Due to an Adverse Event (AE) | 0 Percentage of Participants |
Primary
Percentage of Participants With an Adverse Event
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.
Time frame: Up to 56 days
Population: All enrolled participants who received at least one dose of daptomycin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin | Percentage of Participants With an Adverse Event | 55.6 Percentage of Participants |
Secondary
Apparent Terminal Half-Life (t½) of Daptomycin
Blood samples were collected at pre-specified time points to determine the t½ of daptomycin.
Time frame: Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment
Population: All enrolled participants who received at least 3 consecutive IV infusions of study treatment, had at least 1 PK sample following study drug administration, and did not have any protocol violations affecting the PK profile
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daptomycin | Apparent Terminal Half-Life (t½) of Daptomycin | Age Category 7-11 Years | 5.07 Hours | Standard Deviation 1.09 |
| Daptomycin | Apparent Terminal Half-Life (t½) of Daptomycin | Age Category 2-6 Years | 3.87 Hours | Standard Deviation 0.514 |
| Daptomycin | Apparent Terminal Half-Life (t½) of Daptomycin | Age Category 1-<2 Years | 4.94 Hours | Standard Deviation 0.46 |
| Daptomycin | Apparent Terminal Half-Life (t½) of Daptomycin | Age Category 12-17 Years | 5.71 Hours | Standard Deviation 0.942 |
| Daptomycin (MRSA With Bacteremia) | Apparent Terminal Half-Life (t½) of Daptomycin | Age Category 1-<2 Years | 4.46 Hours | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Apparent Terminal Half-Life (t½) of Daptomycin | Age Category 7-11 Years | 5.85 Hours | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Apparent Terminal Half-Life (t½) of Daptomycin | Age Category 12-17 Years | 3.98 Hours | Standard Deviation 0 |
Secondary
Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin
Blood samples were collected at pre-specified time points to determine the AUC0-24 of daptomycin.
Time frame: Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment
Population: All enrolled participants who received at least 3 consecutive intravenous (IV) infusions of study treatment, had at least 1 pharmacokinetic (PK) sample following study drug administration, and did not have any protocol violations affecting the PK profile
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daptomycin | Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin | Age Category 7-11 years | 409 µg·hr/mL | Standard Deviation 143 |
| Daptomycin | Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin | Age Category 2-6 years | 431 µg·hr/mL | Standard Deviation 53.6 |
| Daptomycin | Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin | Age Category 1-<2 years | 574 µg·hr/mL | Standard Deviation 99.1 |
| Daptomycin | Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin | Age Category 12-17 years | 316 µg·hr/mL | Standard Deviation 18.2 |
| Daptomycin (MRSA With Bacteremia) | Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin | Age Category 1-<2 years | 502 µg·hr/mL | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin | Age Category 7-11 years | 599 µg·hr/mL | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Area Under the Concentration Time Curve From 0 to 24 Hours (AUC0-24hr) of Daptomycin | Age Category 12-17 years | 422 µg·hr/mL | Standard Deviation 0 |
Secondary
Body Weight Adjusted Clearance (CLss/wt) of Daptomycin
Blood samples were collected at pre-specified time points to determine CLss/wt of daptomycin at steady state.
Time frame: Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment
Population: All enrolled participants who received at least 3 consecutive IV infusions of study treatment, had at least 1 PK sample following study drug administration, and did not have any protocol violations affecting the PK profile
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daptomycin | Body Weight Adjusted Clearance (CLss/wt) of Daptomycin | Age Category 7-11 Years | 19.4 mL/hr/kg | Standard Deviation 8.27 |
| Daptomycin | Body Weight Adjusted Clearance (CLss/wt) of Daptomycin | Age Category 2-6 Years | 21.1 mL/hr/kg | Standard Deviation 2.69 |
| Daptomycin | Body Weight Adjusted Clearance (CLss/wt) of Daptomycin | Age Category 1-<2 Years | 17.8 mL/hr/kg | Standard Deviation 2.86 |
| Daptomycin | Body Weight Adjusted Clearance (CLss/wt) of Daptomycin | Age Category 12-17 Years | 15.8 mL/hr/kg | Standard Deviation 0.917 |
| Daptomycin (MRSA With Bacteremia) | Body Weight Adjusted Clearance (CLss/wt) of Daptomycin | Age Category 1-<2 Years | 23.9 mL/hr/kg | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Body Weight Adjusted Clearance (CLss/wt) of Daptomycin | Age Category 7-11 Years | 15.0 mL/hr/kg | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Body Weight Adjusted Clearance (CLss/wt) of Daptomycin | Age Category 12-17 Years | 16.6 mL/hr/kg | Standard Deviation 0 |
Secondary
Maximum Plasma Concentration (Cmax) of Daptomycin
Blood samples were collected at pre-specified timepoints to determine Cmax of daptomycin.
Time frame: Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment
Population: All enrolled participants who received at least 3 consecutive IV infusions of study treatment, had at least 1 PK sample following study drug administration, and did not have any protocol violations affecting the PK profile
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daptomycin | Maximum Plasma Concentration (Cmax) of Daptomycin | Age Category 7-11 years | 64.4 μg/mL | Standard Deviation 15.1 |
| Daptomycin | Maximum Plasma Concentration (Cmax) of Daptomycin | Age Category 2-6 years | 80.3 μg/mL | Standard Deviation 4.48 |
| Daptomycin | Maximum Plasma Concentration (Cmax) of Daptomycin | Age Category 1-<2 years | 91.7 μg/mL | Standard Deviation 6.66 |
| Daptomycin | Maximum Plasma Concentration (Cmax) of Daptomycin | Age Category 12-17 years | 49.3 μg/mL | Standard Deviation 1.33 |
| Daptomycin (MRSA With Bacteremia) | Maximum Plasma Concentration (Cmax) of Daptomycin | Age Category 1-<2 years | 104 μg/mL | Standard Deviation 8.7 |
| Daptomycin (MRSA With Bacteremia) | Maximum Plasma Concentration (Cmax) of Daptomycin | Age Category 7-11 years | 73.1 μg/mL | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Maximum Plasma Concentration (Cmax) of Daptomycin | Age Category 12-17 years | 94.0 μg/mL | Standard Deviation 0 |
Secondary
Percentage of Participants With Methicillin-Resistant Staphylococcus Aureus (MRSA) Infections Who Experienced Clinical Success
Clinical success in participants with MRSA infections was defined as either Cure - Resolution of clinically significant signs and symptoms associated with admission infection and no further antibiotic therapy required, OR Improved- partial resolution of clinical signs or symptoms of infection with no further antibiotic therapy required.
Time frame: Up to 7 days following end of treatment (up to 49 days)
Population: All enrolled participants with cSSTI or bacteremia who had a positive culture of MRSA at baseline and received at least one dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin | Percentage of Participants With Methicillin-Resistant Staphylococcus Aureus (MRSA) Infections Who Experienced Clinical Success | 85.7 Percentage of Participants |
| Daptomycin (MRSA With Bacteremia) | Percentage of Participants With Methicillin-Resistant Staphylococcus Aureus (MRSA) Infections Who Experienced Clinical Success | 100 Percentage of Participants |
Secondary
Percentage of Participants With MRSA Infections Who Experienced a Microbiological Response
Participant-level microbiological response in participants with MRSA infections at baseline is defined as absence or presumed absence of all baseline infecting pathogens AND no gram-positive superinfection or gram-positive new infection, as assessed by infection site specimen culture or blood culture.
Time frame: Up to 7 days following end of treatment (up to 49 days)
Population: All enrolled participants with cSSTI or bacteremia who had a positive culture of MRSA at baseline and received at least one dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin | Percentage of Participants With MRSA Infections Who Experienced a Microbiological Response | 71.4 Percentage of Participants |
| Daptomycin (MRSA With Bacteremia) | Percentage of Participants With MRSA Infections Who Experienced a Microbiological Response | 100 Percentage of Participants |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Daptomycin
Blood samples were collected at pre-specified time points to determine Tmax of daptomycin
Time frame: Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment
Population: All enrolled participants who received at least 3 consecutive IV infusions of study treatment, had at least 1 PK sample following study drug administration, and did not have any protocol violations affecting the PK profile
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Daptomycin | Time to Maximum Plasma Concentration (Tmax) of Daptomycin | Age Category 7-11 Years | 0.833 Hours |
| Daptomycin | Time to Maximum Plasma Concentration (Tmax) of Daptomycin | Age Category 2-6 Years | 1.23 Hours |
| Daptomycin | Time to Maximum Plasma Concentration (Tmax) of Daptomycin | Age Category 1-<2 Years | 1.33 Hours |
| Daptomycin | Time to Maximum Plasma Concentration (Tmax) of Daptomycin | Age Category 12-17 Years | 0.750 Hours |
| Daptomycin (MRSA With Bacteremia) | Time to Maximum Plasma Concentration (Tmax) of Daptomycin | Age Category 1-<2 Years | 1.27 Hours |
| Daptomycin (MRSA With Bacteremia) | Time to Maximum Plasma Concentration (Tmax) of Daptomycin | Age Category 7-11 Years | 0.800 Hours |
| Daptomycin (MRSA With Bacteremia) | Time to Maximum Plasma Concentration (Tmax) of Daptomycin | Age Category 12-17 Years | 0.733 Hours |
Secondary
Volume of Distribution at Steady State (Vss) of Daptomycin
Blood samples were collected at pre-specified time points to determine Vss (mL) of daptomycin.
Time frame: Pre-dose and at 15 minutes, 1 hour, 4 hours, and 12 hours post-dose on Day 3 of daptomycin treatment
Population: All enrolled participants who received at least 3 consecutive IV infusions of study treatment, had at least 1 PK sample following study drug administration, and did not have any protocol violations affecting the PK profile
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daptomycin | Volume of Distribution at Steady State (Vss) of Daptomycin | Age Category 7-11 Years | 3929 mL | Standard Deviation 2032 |
| Daptomycin | Volume of Distribution at Steady State (Vss) of Daptomycin | Age Category 2-6 Years | 1753 mL | Standard Deviation 486 |
| Daptomycin | Volume of Distribution at Steady State (Vss) of Daptomycin | Age Category 1-<2 Years | 1146 mL | Standard Deviation 299 |
| Daptomycin | Volume of Distribution at Steady State (Vss) of Daptomycin | Age Category 12-17 Years | 6414 mL | Standard Deviation 1086 |
| Daptomycin (MRSA With Bacteremia) | Volume of Distribution at Steady State (Vss) of Daptomycin | Age Category 1-<2 Years | 1918 mL | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Volume of Distribution at Steady State (Vss) of Daptomycin | Age Category 7-11 Years | 4013 mL | Standard Deviation 0 |
| Daptomycin (MRSA With Bacteremia) | Volume of Distribution at Steady State (Vss) of Daptomycin | Age Category 12-17 Years | 5106 mL | Standard Deviation 0 |