An Open-label, Randomized, Parallel-Design Study to Characterize the Effect of Heparin on Palifermin Activity in Healthy Adult Subjects
Overview
- Phase
- Phase 1
- Intervention
- Heparin
- Conditions
- Oral Mucositis
- Sponsor
- Swedish Orphan Biovitrum
- Enrollment
- 44
- Locations
- 1
- Primary Endpoint
- Ratio to Baseline of Epithelial Cell Proliferation as Assessed by Ki67 Staining of Buccal Mucosal Tissue.
- Status
- Completed
- Last Updated
- 11 years ago
Overview
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.
Investigators
Eligibility Criteria
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.
Arms & Interventions
Palifermin 40 µg/kg and heparin IV infusion
Treatment A: palifermin 40 µg/kg/day for three consecutive days as IV bolus injections and continuous heparin IV infusion
Intervention: Heparin
Palifermin 40 µg/kg and heparin IV infusion
Treatment A: palifermin 40 µg/kg/day for three consecutive days as IV bolus injections and continuous heparin IV infusion
Intervention: Palifermin
Palifermin 40 µg/kg
Treatment B: palifermin 40 µg/kg/day for three consecutive days as IV bolus injections
Intervention: Palifermin
Outcomes
Primary Outcomes
Ratio to Baseline of Epithelial Cell Proliferation as Assessed by Ki67 Staining of Buccal Mucosal Tissue.
Time Frame: 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.
Time Frame: 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
Time Frame: Day 5
Ratio to baseline amylase at Day 5 was calculated as Day 5 amylase divided by baseline amylase.
Ratio to Baseline of Lipase.
Time Frame: 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
Time Frame: 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 Outcomes
- Palifermin Pharmacokinetic (PK) Parameters: Clearance (CL)(Day 1)
- Palifermin PK Parameters: Estimated Concentration at Time 0 (C0)(Day 1)
- Palifermin PK Parameters: C0(Day 3)
- Palifermin PK Parameters: Apparent Volume of Distribution at Steady State (Vss)(Day 1)
- Palifermin PK Parameters: CL(Day 3)
- Palifermin PK Parameters: Area Under the Serum Curve (AUC) (0-24)(Day 1)
- Palifermin PK Parameters: AUC (0-24)(Day 3)
- Palifermin PK Parameters: Vss(Day 3)
- Subject Incidence of Treatment-emergent Adverse Event(Day 45)
- Subject Incidence of Proteinuria(Day 4)
- Ratio to Baseline of Protein/Creatinine(Day 3)
- Ratio to Baseline of Albumin/Creatinine(Day 4)