Oral Mucositis
Conditions
Brief summary
The purpose of this study is to evaluate the effect of a continuous intravenous infusion of unfractionated heparin on the multiple-dose pharmacodynamics of palifermin in healthy adult subjects.
Detailed description
The planned study is designed to characterize the impact of heparin on the biologic activity of palifermin and assess the impact of the combination of palifermin and heparin on tolerability. Approximately forty-three (43) eligible healthy adult men and oophorectomized or postmenopausal women between 18-45 years of age will be assigned to one of three treatment groups where treatment group A will receive a daily dose of palifermin 40 µg/kg for three consecutive days as intravenous (IV) bolus injections and continuous heparin IV infusion, treatment B will receive a daily dose of palifermin 40 µg/kg for three consecutive days as IV bolus injections and treatment C will be a control group without any treatment administered. The subjects will be randomized in a 20:15:8 ratio (Treatment A:B:C). The study consists of a up to 21-days screening period, a 5-days treatment period and a up to 45-days follow-up period.
Interventions
DRUGPalifermin
40 µg/kg IV bolus injections for three consecutive days
DRUGHeparin
Heparin continuous IV infusion
Sponsors
Swedish Orphan Biovitrum
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy men or postmenopausal or oophorectomized women. * Subjects should have a Body Mass Index between 19 and 30 inclusive. * A negative screen for drug abuse, tobacco use and alcohol breath test. * Subjects should be willing to be resident in the research facility for up to 6 nights and return to the research facility for scheduled study and follow-up procedures. * Men must agree for the duration of the study to use an appropriate method of birth control
Exclusion criteria
* History or evidence of clinically significant disorder, condition or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. * History or evidence of any oral mucosal disease that may affect mucosal keratinocyte proliferation. * Evidence or history of thrombocytopenia, heparin-induced thrombocytopenia or other contraindications to heparin (e.g. recent surgeries). * Known hypersensitivity to heparin or topical or injectable local anesthetic. * Known allergies to Escherichia coli-derived products or allergies to palifermin or its excipients. * Use of medications (except vitamins, hormonal replacement therapy and topical medications) within 10 days of admission to research facility. * Blood donation within 8 weeks prior to dosing of investigational drug. * History of hypertension, clinically significant bleeding, gastrointestinal ulcers, arteriovenous malformation (AVM), aneurysm, or other vascular malformation. * History of coagulopathy, bleeding disorders or abnormal platelet counts. * History of malignancy of any type, other than surgically excised non-melanoma skin cancers or in situ cervical cancer. * For males, past history of epididymitis. * Known alcohol abuse or use of illicit drugs within 12 months prior to admission to the research facility. * History of smoking or using smokeless tobacco within the past year before admission to the research facility. * Any other condition that might reduce the chance of obtaining data (eg, known poor compliance) required by the protocol or that might compromise the ability to give informed consent. * Previous participation in a palifermin study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio to Baseline of Epithelial Cell Proliferation as Assessed by Ki67 Staining of Buccal Mucosal Tissue. | Day 4 | This outcome is a measure of the palifermin effect on the buccal mucosal cells. Ki67 is a measure of proliferation of cells in the buccal mucosa. This measure assess the number of cells per millimeter (mm) before and after palifermin treatment. |
| Incidence of Grade 2 or Higher Specific Skin-related Adverse Events. | Day 45 | Incidence of grade 2 or higher specific skin-related treatment emergent adverse events following palifermin administration was calculated for subjects in treatment groups A and B. Incidence was calculated by treatment as number of subjects with grade 2 or higher specific skin-related AEs divided by the total number of subjects. The Common Terminology Criteria for Adverse Events (CTCAE v3.0) for Dermatology/Skin was used to determine the toxicity grade for a skin-related adverse event. (http://ctep.cancer.gov/protocolDevelopment/electronic\_applications/docs/ctcaev3.pdf) |
| Ratio to Baseline of Amylase | Day 5 | Ratio to baseline amylase at Day 5 was calculated as Day 5 amylase divided by baseline amylase. |
| Ratio to Baseline of Lipase. | Day 5 | Ratio to baseline lipase at Day 5 was calculated as Day 5 lipase divided by baseline lipase. |
| Ratio to Baseline of Protein/Creatinine | Day 4 | Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Palifermin PK Parameters: C0 | Day 3 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin C0 was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. |
| Palifermin PK Parameters: Apparent Volume of Distribution at Steady State (Vss) | Day 1 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin (Treatment A and Treatment B only). Descriptive pharmacokinetic parameters for palifermin Vss was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. |
| Palifermin PK Parameters: Vss | Day 3 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin (Treatment A and Treatment B only). Descriptive pharmacokinetic parameters for palifermin Vss was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. |
| Palifermin Pharmacokinetic (PK) Parameters: Clearance (CL) | Day 1 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive PK parameters for palifermin CL for subjects assigned to Treatment A and Treatment B was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. |
| Subject Incidence of Proteinuria | Day 4 | Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result at the specified time point. Incidence of proteinuria defined as urinary protein/creatinine ratio exceeding 200 mg/g was calculated at Day 4 and overall at any time point. Incidence was calculated by treatment as number of subjects with proteinuria divided by the total number of subjects. |
| Ratio to Baseline of Protein/Creatinine | Day 1 | Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio. |
| Ratio to Baseline of Albumin/Creatinine | Day 1 | The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio. |
| Subject Incidence of Treatment-emergent Adverse Event | Day 45 | Adverse events (AE) was considered treatment emergent if the AE started after the time of heparin titration (Treatment A), palifermin dosing on Day 1 (Treatment B), or set zero point (Treatment C). |
| Palifermin PK Parameters: CL | Day 3 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive PK parameters for palifermin CL for subjects assigned to Treatment A and Treatment B was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. |
| Palifermin PK Parameters: Area Under the Serum Curve (AUC) (0-24) | Day 1 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin AUC(0-24) was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was deleted from calculation. |
| Palifermin PK Parameters: AUC (0-24) | Day 3 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin AUC(0-24) was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was deleted from calculation. |
| Palifermin PK Parameters: Estimated Concentration at Time 0 (C0) | Day 1 | Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin C0 was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero. |
Countries
United States
Participant flow
Recruitment details
This open-label, randomized, parallel-design, Phase I study in healthy adult subjects was performed in 1 center (New Orleans Center for Clinical Research, Knoxville, TN, USA) between July and December 2010.
Pre-assignment details
Subjects randomized to receive palifermin in combination with heparin did first enter a titration period where they received titrated heparin doses to achieve an aPTT of 1.5 to 2.0 × baseline. Subjects who could not be successfully titrated within the heparin titration period were discontinued, and did not enter the palifermin treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Palifermin - Heparin Treatment A: palifermin 40 µg/kg/day for three consecutive days as IV bolus injections and continuous heparin IV infusion | 15 |
| Palifermin Alone Treatment B: palifermin 40 µg/kg/day for three consecutive days as IV bolus injections | 16 |
| Untreated Control Treatment C: control group without any treatment administered | 8 |
| Total | 39 |
Baseline characteristics
| Characteristic | Palifermin - Heparin | Palifermin Alone | Untreated Control | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 16 Participants | 8 Participants | 39 Participants |
| Age, Continuous | 25.9 years STANDARD_DEVIATION 5.29 | 32.9 years STANDARD_DEVIATION 7.82 | 22.8 years STANDARD_DEVIATION 3.62 | 28.1 years STANDARD_DEVIATION 7 |
| Body Mass Index | 24.95 kg/m2 STANDARD_DEVIATION 2.144 | 26.08 kg/m2 STANDARD_DEVIATION 2.111 | 25.98 kg/m2 STANDARD_DEVIATION 3.185 | 25.62 kg/m2 STANDARD_DEVIATION 2.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 16 Participants | 8 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 14 Participants | 7 Participants | 33 Participants |
| Region of Enrollment United States | 15 participants | 16 participants | 8 participants | 39 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 15 Participants | 16 Participants | 8 Participants | 39 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 | 9 / 20 | 9 / 16 | 3 / 8 |
| serious Total, serious adverse events | 0 / 20 | 0 / 16 | 0 / 8 |
Outcome results
Primary
Incidence of Grade 2 or Higher Specific Skin-related Adverse Events.
Incidence of grade 2 or higher specific skin-related treatment emergent adverse events following palifermin administration was calculated for subjects in treatment groups A and B. Incidence was calculated by treatment as number of subjects with grade 2 or higher specific skin-related AEs divided by the total number of subjects. The Common Terminology Criteria for Adverse Events (CTCAE v3.0) for Dermatology/Skin was used to determine the toxicity grade for a skin-related adverse event. (http://ctep.cancer.gov/protocolDevelopment/electronic\_applications/docs/ctcaev3.pdf)
Time frame: Day 45
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B), or who had a set zero point (Treatment C). This outcome was assessed for Treatment A and B only as per study plan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palifermin - Heparin | Incidence of Grade 2 or Higher Specific Skin-related Adverse Events. | 0 proportion of participants |
| Palifermin Alone | Incidence of Grade 2 or Higher Specific Skin-related Adverse Events. | 0.0625 proportion of participants |
Primary
Ratio to Baseline of Amylase
Ratio to baseline amylase at Day 5 was calculated as Day 5 amylase divided by baseline amylase.
Time frame: Day 5
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment A and B only as per study plan.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Amylase | 0.242 ratio |
| Palifermin Alone | Ratio to Baseline of Amylase | 0.547 ratio |
Comparison: 80% power achieved for detecting a 20% increase (or 17% reduction) when Treatment A was compared to Treatment B; assuming that the coefficient of variation of amylase would be 14% (as observed in other study)95% CI: [0.614, 0.885]ANCOVA
Primary
Ratio to Baseline of Epithelial Cell Proliferation as Assessed by Ki67 Staining of Buccal Mucosal Tissue.
This outcome is a measure of the palifermin effect on the buccal mucosal cells. Ki67 is a measure of proliferation of cells in the buccal mucosa. This measure assess the number of cells per millimeter (mm) before and after palifermin treatment.
Time frame: Day 4
Population: The pharmacodynamic population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B), or who had a set zero point (Treatment C) and had both baseline and Day 4 buccal biopsy samples collected. This analysis was only performed for Treatment A relative to Treatment B as per study plan.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Epithelial Cell Proliferation as Assessed by Ki67 Staining of Buccal Mucosal Tissue. | 0.267 ratio |
| Palifermin Alone | Ratio to Baseline of Epithelial Cell Proliferation as Assessed by Ki67 Staining of Buccal Mucosal Tissue. | 0.414 ratio |
Comparison: H0: mean ratio\<0.7 or mean ratio\>1.43; H1: 0.7\< mean ratio \<1.43 Sample size calculation assumed change in Ki67 expression following palifermin administration would not be affected by co-administration of heparin. With n=26 (13 + 13), an approx. 80% probability that the 90% CI of the ratio of geometric means of Ki67 for palifermin when co-administered with heparin compared to palifermin alone would fall in the interval (0.7, 1.43). This assumed a Coefficient of Variation (CV) for Ki67 of 31%.90% CI: [0.759, 0.982]ANCOVA
Primary
Ratio to Baseline of Lipase.
Ratio to baseline lipase at Day 5 was calculated as Day 5 lipase divided by baseline lipase.
Time frame: Day 5
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment A and B only as per study plan.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Lipase. | -0.487 ratio |
| Palifermin Alone | Ratio to Baseline of Lipase. | 0.499 ratio |
Comparison: 80% power achieved for detecting a 70% increase (or 41% reduction) when Treatment A was compared to Treatment B; assuming that the coefficient of variation of lipase would be 49% (as observed in other study)95% CI: [0.216, 0.645]ANCOVA
Primary
Ratio to Baseline of Protein/Creatinine
Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio.
Time frame: Day 4
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Protein/Creatinine | 0.076 ratio |
| Palifermin Alone | Ratio to Baseline of Protein/Creatinine | 0.104 ratio |
Comparison: 80% power achieved for detecting a 140% increase with 13 and 6 subjects (respectively) when Treatment B was compared to Treatment C; assuming that the coefficient of variation of the protein/creatinine ratio would be 67% (Ginsberg et al 1983)95% CI: [0.768, 1.231]ANCOVA
Secondary
Palifermin Pharmacokinetic (PK) Parameters: Clearance (CL)
Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive PK parameters for palifermin CL for subjects assigned to Treatment A and Treatment B was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero.
Time frame: Day 1
Population: The pharmacokinetics (PK) population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) and at least one post dose PK serum sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Palifermin Pharmacokinetic (PK) Parameters: Clearance (CL) | 121.1 (mL/hr/kg) | Geometric Coefficient of Variation 29.1 |
| Palifermin Alone | Palifermin Pharmacokinetic (PK) Parameters: Clearance (CL) | 527.8 (mL/hr/kg) | Geometric Coefficient of Variation 33.5 |
p-value: <0.0001ANOVA
Secondary
Palifermin PK Parameters: Apparent Volume of Distribution at Steady State (Vss)
Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin (Treatment A and Treatment B only). Descriptive pharmacokinetic parameters for palifermin Vss was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero.
Time frame: Day 1
Population: The pharmacokinetics population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) and at least one post dose PK serum sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Palifermin PK Parameters: Apparent Volume of Distribution at Steady State (Vss) | 411.5 mL/kg | Geometric Coefficient of Variation 42.4 |
| Palifermin Alone | Palifermin PK Parameters: Apparent Volume of Distribution at Steady State (Vss) | 1586 mL/kg | Geometric Coefficient of Variation 48.1 |
p-value: <0.0001ANOVA
Secondary
Palifermin PK Parameters: Area Under the Serum Curve (AUC) (0-24)
Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin AUC(0-24) was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was deleted from calculation.
Time frame: Day 1
Population: The pharmacokinetics population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) and at least one post dose PK serum sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Palifermin PK Parameters: Area Under the Serum Curve (AUC) (0-24) | 330.1 ng*hr/mL | Geometric Coefficient of Variation 26.9 |
| Palifermin Alone | Palifermin PK Parameters: Area Under the Serum Curve (AUC) (0-24) | 75.80 ng*hr/mL | Geometric Coefficient of Variation 37.1 |
p-value: <0.0001ANOVA
Secondary
Palifermin PK Parameters: AUC (0-24)
Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin AUC(0-24) was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was deleted from calculation.
Time frame: Day 3
Population: The pharmacokinetics population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) and at least one post dose PK serum sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Palifermin PK Parameters: AUC (0-24) | 328.1 ng*hr/mL | Geometric Coefficient of Variation 20.4 |
| Palifermin Alone | Palifermin PK Parameters: AUC (0-24) | 76.26 ng*hr/mL | Geometric Coefficient of Variation 36.3 |
p-value: <0.0001ANOVA
Secondary
Palifermin PK Parameters: C0
Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin C0 was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero.
Time frame: Day 3
Population: The pharmacokinetics population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) and at least one post dose PK serum sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Palifermin PK Parameters: C0 | 361.0 ng/mL | Geometric Coefficient of Variation 92.3 |
| Palifermin Alone | Palifermin PK Parameters: C0 | 563.2 ng/mL | Geometric Coefficient of Variation 105.7 |
p-value: 0.9944ANOVA
Secondary
Palifermin PK Parameters: CL
Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive PK parameters for palifermin CL for subjects assigned to Treatment A and Treatment B was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero.
Time frame: Day 3
Population: The pharmacokinetics population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) and at least one post dose PK serum sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Palifermin PK Parameters: CL | 121.9 (mL/hr/kg) | Geometric Coefficient of Variation 20.4 |
| Palifermin Alone | Palifermin PK Parameters: CL | 524.3 (mL/hr/kg) | Geometric Coefficient of Variation 59.4 |
p-value: <0.0001ANOVA
Secondary
Palifermin PK Parameters: Estimated Concentration at Time 0 (C0)
Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin. Descriptive pharmacokinetic parameters for palifermin C0 was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero.
Time frame: Day 1
Population: The pharmacokinetics population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) and at least one post dose PK serum sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Palifermin PK Parameters: Estimated Concentration at Time 0 (C0) | 229.1 ng/mL | Geometric Coefficient of Variation 116.6 |
| Palifermin Alone | Palifermin PK Parameters: Estimated Concentration at Time 0 (C0) | 584.7 ng/mL | Geometric Coefficient of Variation 111.9 |
p-value: 0.4123ANOVA
Secondary
Palifermin PK Parameters: Vss
Blood samples for palifermin PK was collected pre-dose on Days 1 and 3 of the treatment period; 2, 5, 15 and 30 minutes; and 1, 2, 4, 6, 12, 18 and 24 hours after the Day 1 and Day 3 dose of palifermin (Treatment A and Treatment B only). Descriptive pharmacokinetic parameters for palifermin Vss was determined by linear/log trapezoidal method. Parameters was calculated from individual subject serum concentration-time data using actual subject blood collection times. Serum concentrations reported below the lower limit of quantification (LLOQ) was treated as zero.
Time frame: Day 3
Population: The pharmacokinetics population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) and at least one post dose PK serum sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Palifermin PK Parameters: Vss | 361.7 mL/Kg | Geometric Coefficient of Variation 28 |
| Palifermin Alone | Palifermin PK Parameters: Vss | 1318 mL/Kg | Geometric Coefficient of Variation 64.4 |
p-value: <0.0001ANOVA
Secondary
Ratio to Baseline of Albumin/Creatinine
The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio.
Time frame: Day 4
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Albumin/Creatinine | 1.56 ratio | Standard Deviation 1.61 |
| Palifermin Alone | Ratio to Baseline of Albumin/Creatinine | 1.25 ratio | Standard Deviation 0.484 |
Secondary
Ratio to Baseline of Albumin/Creatinine
The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio.
Time frame: Day 1
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Albumin/Creatinine | 1.00 ratio | Standard Deviation 0 |
| Palifermin Alone | Ratio to Baseline of Albumin/Creatinine | 1.00 ratio | Standard Deviation 0 |
Secondary
Ratio to Baseline of Albumin/Creatinine
The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio.
Time frame: Day 2
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Albumin/Creatinine | 1.05 ratio | Standard Deviation 0.373 |
| Palifermin Alone | Ratio to Baseline of Albumin/Creatinine | 0.95 ratio | Standard Deviation 0.23 |
Secondary
Ratio to Baseline of Albumin/Creatinine
The albumin/creatinine ratio is the urinary albumin (mg) divided by the urinary creatinine (g) result at the specified time point. Ratio to baseline was calculated as albumin/creatinine ratio at specified day divided by baseline albumin/creatinine ratio.
Time frame: Day 3
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Albumin/Creatinine | 1.16 ratio | Standard Deviation 0.391 |
| Palifermin Alone | Ratio to Baseline of Albumin/Creatinine | 0.99 ratio | Standard Deviation 0.268 |
Secondary
Ratio to Baseline of Protein/Creatinine
Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio.
Time frame: Day 3
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Protein/Creatinine | 1.1 ratio | Standard Deviation 0.51 |
| Palifermin Alone | Ratio to Baseline of Protein/Creatinine | 1.1 ratio | Standard Deviation 0.33 |
Secondary
Ratio to Baseline of Protein/Creatinine
Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio.
Time frame: Day 1
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Protein/Creatinine | 1.00 ratio | Standard Deviation 0 |
| Palifermin Alone | Ratio to Baseline of Protein/Creatinine | 1.00 ratio | Standard Deviation 0 |
Secondary
Ratio to Baseline of Protein/Creatinine
Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result. Ratio to baseline protein/creatinine ratio was calculated as protein/creatinine ratio at specified day divided by baseline protein/creatinine ratio.
Time frame: Day 2
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Palifermin - Heparin | Ratio to Baseline of Protein/Creatinine | 1.0 ratio | Standard Deviation 0.42 |
| Palifermin Alone | Ratio to Baseline of Protein/Creatinine | 1.0 ratio | Standard Deviation 0.13 |
Secondary
Subject Incidence of Proteinuria
Protein/creatinine ratio is the urinary protein (mg) divided by the urinary creatinine (g) result at the specified time point. Incidence of proteinuria defined as urinary protein/creatinine ratio exceeding 200 mg/g was calculated at Day 4 and overall at any time point. Incidence was calculated by treatment as number of subjects with proteinuria divided by the total number of subjects.
Time frame: Day 4
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C). This outcome was assessed for Treatment B and C only as per study plan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palifermin - Heparin | Subject Incidence of Proteinuria | 0 participants |
| Palifermin Alone | Subject Incidence of Proteinuria | 0 participants |
Secondary
Subject Incidence of Treatment-emergent Adverse Event
Adverse events (AE) was considered treatment emergent if the AE started after the time of heparin titration (Treatment A), palifermin dosing on Day 1 (Treatment B), or set zero point (Treatment C).
Time frame: Day 45
Population: The safety population consist of all randomized subjects who received at least one dose of palifermin (Treatment A or B) or who had a set zero point (Treatment C)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palifermin - Heparin | Subject Incidence of Treatment-emergent Adverse Event | 9 participants |
| Palifermin Alone | Subject Incidence of Treatment-emergent Adverse Event | 8 participants |
| Untreated Control | Subject Incidence of Treatment-emergent Adverse Event | 3 participants |