Healthy
Conditions
Keywords
ceftriaxone, cephalosporins, pharmacokinetics, subcutaneous, hyaluronoglucosaminidase, hyaluronidase, hyaluronan, rHuPH20
Brief summary
The objectives of this study are: * to establish the safety of subcutaneous administration of ceftriaxone at different concentrations, with and without HYLENEX recombinant, and to determine the maximum tolerated concentration; * and to establish the pharmacokinetic comparability of subcutaneous administration of ceftriaxone with HYLENEX recombinant to subcutaneous administration without HYLENEX recombinant and to IV administration.
Interventions
DRUGSC HYLENEX and Ceftriaxone
single, subcutaneous, 150 U dose of HYLENEX; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)
DRUGSC Placebo and Ceftriaxone
single, subcutaneous injection of 1 mL 0.9% sodium chloride solution; followed by single, subcutaneous, 1 gm dose of ceftriaxone (350 mg/mL solution administered at 2.5 mL/min over 1.14 minutes)
DRUGIV Ceftriaxone
single, intravenous infusion of 1 gm ceftriaxone (40 mg/mL solution administered at 0.83 mL/min over 30 minutes)
Sponsors
Halozyme Therapeutics
Baxter Healthcare Corporation
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female, 18-65 years of age * If female: non-lactating; non-pregnant; and incapable of becoming pregnant, or taking specific precautions to avoid becoming pregnant before and during study * Normal clinical laboratory parameters * Adequate venous access in both upper extremities * Agreeing to refrain from smoking and from ingesting any alcohol or caffeine-containing products before and during the study * Good health based on medical history, physical examination and laboratory tests * Non-smoking; or smoking less than 10 cigarettes per day and willing to refrain from use of nicotine products before and during study
Exclusion criteria
* Received a cephalosporin within the 21 days prior to study or anticipated to receive non-study cephalosporin during study * Pregnant or breast-feeding. * Previously exposed to a hyaluronidase drug product * Medical condition presenting unacceptable safety risk or likely to prevent completion of study * Known hypersensitivity to hyaluronidase or any other ingredient in HYLENEX recombinant * Contraindication to ceftriaxone, including known allergy to beta-lactam antibiotics * Local condition precluding subcutaneous injection or injection site evaluation * History of gastrointestinal disease (in particular colitis) * Consumption of caffeine- or other methylxanthine-containing beverage within 24 hours before and/or during the PK sampling period * Participation in study of any investigational drug or device within 30 days before this study * Serum hemoglobin \<12 g/dL. * Blood donation or significant loss of blood within 56 days, or plasma donation within 7 days, prior to study * Medical history/condition, screening physical examination finding or clinical laboratory result precluding safe participation in study, or which might adversely effect interpretation of study results * History of drug or alcohol abuse within 2 years prior to study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t | Start of ceftriaxone administration through time of last measureable plasma ceftriaxone concentration | Area under the drug concentration-time curve from time zero to the time of the last measurable concentration (calculated by the linear trapezoidal method) |
| AUC0-inf | from the start of ceftriaxone administration to infinity | Area under the drug concentration-time curve from time zero to infinity, calculated as AUC0-t + Ct/kel (Ct = time of last measurable concentration; kel = terminal elimination rate constant) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | at the time of the highest measured plasma ceftriaxone concentration | Maximum measured plasma ceftriaxone concentration |
| Tmax | from start of ceftriaxone administration until time of maximum measured plasma ceftriaxone concentration | Time to maximum measured plasma ceftriaxone concentration |
Participant flow
Recruitment details
Healthy volunteers recruited via subject-initiated telephone or internet contacts or visits to Phase I unit. Those considered potentially eligible were, after obtaining consent, screened in detail to determine eligibility against protocol eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| HYLENEX SC, Placebo SC, IV subcutaneous HYLENEX and ceftriaxone as first intervention, subcutaneous placebo and ceftriaxone as second intervention, intravenous ceftriaxone as third intervention | 5 |
| HYLENEX SC, IV, Placebo SC subcutaneous HYLENEX and ceftriaxone as first intervention, intravenous ceftriaxone as second intervention, subcutaneous placebo and ceftriaxone as third intervention | 5 |
| Placebo SC, HYLENEX SC, IV subcutaneous placebo and ceftriaxone as first intervention, subcutaneous HYLENEX and ceftriaxone as second intervention, intravenous ceftriaxone as third intervention | 5 |
| Placebo SC, IV, HYLENEX SC subcutaneous placebo and ceftriaxone as first intervention, intravenous ceftriaxone as second intervention, subcutaneous HYLENEX and ceftriaxone as third intervention | 5 |
| IV, HYLENEX SC, Placebo SC intravenous ceftriaxone as first intervention, subcutaneous HYLENEX and ceftriaxone as second intervention, subcutaneous placebo and ceftriaxone as third intervention | 5 |
| IV, Placebo SC, HYLENEX SC intravenous ceftriaxone as first intervention, subcutaneous placebo and ceftriaxone as second intervention, subcutaneous HYLENEX and ceftriaxone as third intervention | 5 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Third Intervention | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | HYLENEX SC, IV, Placebo SC | Placebo SC, HYLENEX SC, IV | Placebo SC, IV, HYLENEX SC | HYLENEX SC, Placebo SC, IV | IV, HYLENEX SC, Placebo SC | IV, Placebo SC, HYLENEX SC | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 30 Participants |
| Age Continuous | 37.6 years STANDARD_DEVIATION 4 | 34.2 years STANDARD_DEVIATION 11.5 | 34.8 years STANDARD_DEVIATION 17.5 | 32.2 years STANDARD_DEVIATION 10.6 | 34.8 years STANDARD_DEVIATION 11 | 33.2 years STANDARD_DEVIATION 8 | 34.5 years STANDARD_DEVIATION 10.3 |
| Region of Enrollment United States | 5 participants | 5 participants | 5 participants | 5 participants | 5 participants | 5 participants | 30 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 3 Participants | 5 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 30 / 30 | 30 / 30 | 22 / 29 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 | 0 / 29 |
Outcome results
Primary
AUC0-inf
Area under the drug concentration-time curve from time zero to infinity, calculated as AUC0-t + Ct/kel (Ct = time of last measurable concentration; kel = terminal elimination rate constant)
Time frame: from the start of ceftriaxone administration to infinity
Population: Per protocol (excludes one participant that did not receive intravenous ceftriaxone intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYLENEX SC | AUC0-inf | 1162.6 µg*hr/mL | Standard Deviation 210.36 |
| Placebo SC | AUC0-inf | 1141.3 µg*hr/mL | Standard Deviation 192.86 |
| Intravenous | AUC0-inf | 1085.8 µg*hr/mL | Standard Deviation 187.5 |
90% CI: [98.64, 104.98]Schuirmann two one-sided tests procedure
90% CI: [103.67, 110.33]Schuirmann two one-sided tests procedure
90% CI: [101.87, 108.42]Schuirmann two one-sided tests procedure
Primary
AUC0-t
Area under the drug concentration-time curve from time zero to the time of the last measurable concentration (calculated by the linear trapezoidal method)
Time frame: Start of ceftriaxone administration through time of last measureable plasma ceftriaxone concentration
Population: Per protocol (excludes one participant that did not receive intravenous ceftriaxone intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYLENEX SC | AUC0-t | 1139.3 μg*hr/mL | Standard Deviation 200.3 |
| Placebo SC | AUC0-t | 1115.6 μg*hr/mL | Standard Deviation 180.55 |
| Intravenous | AUC0-t | 1065.3 μg*hr/mL | Standard Deviation 176.07 |
90% CI: [98.95, 105.12]Schuirmann two one-sided tests procedure
90% CI: [103.61, 110.07]Schuirmann two one-sided tests procedure
90% CI: [101.59, 107.92]Schuirmann two one-sided tests procedure
Secondary
Cmax
Maximum measured plasma ceftriaxone concentration
Time frame: at the time of the highest measured plasma ceftriaxone concentration
Population: Per protocol (excludes one participant that did not receive intravenous ceftriaxone intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYLENEX SC | Cmax | 92.0 µg/mL | Standard Deviation 15.1 |
| Placebo SC | Cmax | 82.2 µg/mL | Standard Deviation 13.5 |
| Intravenous | Cmax | 150 µg/mL | Standard Deviation 19.9 |
90% CI: [108.57, 115.12]Schuirmann two one-sided tests procedure
90% CI: [59.06, 62.62]Schuirmann two one-sided tests procedure
90% CI: [52.82, 56.01]Schuirmann two one-sided tests procedure
Secondary
Tmax
Time to maximum measured plasma ceftriaxone concentration
Time frame: from start of ceftriaxone administration until time of maximum measured plasma ceftriaxone concentration
Population: Per protocol (excludes one participant that did not receive intravenous ceftriaxone intervention)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HYLENEX SC | Tmax | 2.02 hr |
| Placebo SC | Tmax | 3.02 hr |
| Intravenous | Tmax | 0.502 hr |
p-value: <0.0190% CI: [-1.25, -0.75]Wilcoxon signed-rank test
p-value: <0.0190% CI: [1.27, 1.71]Wilcoxon signed-rank test
p-value: <0.0190% CI: [2.26, 2.76]Wilcoxon signed-rank test