Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Subcutaneous Rivipansel With rHuPH20 in Healthy Subjects

Study Overview
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Brief Summary
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This is a 2 part study designed to provide an initial assessment on the safety, tolerability, and PK of rivipansel, following single ascending (Part 1) and multiple ascending dosing (Part 2) given subcutaneously with rHuPH20, in healthy subjects. Part 1 of the study will be conducted using a cross-over design while Part 2 of the study will be conducted using a parallel design.

Official Title
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A Phase 1, Randomized, Double Blind, Sponsor Open, Placebo Controlled, Single And Multiple Ascending Dose Study To Evaluate The Safety, Tolerability, And Pharmacokinetics Of Rivipansel (pf 06460031) Following Subcutaneous Administration With Rhuph20 (pf 06744547) In Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Rivipansel
* Drug: Placebo
* Drug: Rivipansel
* Drug: Rivipansel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and/or female subjects of non-childbearing potential between the ages of 18 and 55 years, inclusive. Body Mass Index 17.5 - 30.5 kg/m2 and body weight >50 kg at Screening. Normal skin without potentially obscuring features in the area intended for infusion. Subjects willing to defer receiving prophylactic immunizations (eg, influenza or pneumococcal vaccines) during the study. Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative has been informed of all pertinent aspects of the study Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). History of a recent major surgery (within 3 months of screening). Serious infection within 1 month of screening. Subjects with chronic skin condition that may interfere in the assessment of emergent safety data. A positive urine drug screen. Known sensitivity to hyaluronidases. History of hepatitis or positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C antibodies (HCV). Unwilling or unable to comply with the Lifestyle Guidelines described in this protocol. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Single ascending dose in 3 period cross-over design (with optional 4th period) | Drug: Rivipansel<br>* Rivipansel administered as a single dose subcutaneously with rHuPH20 in cross-over fashion. Each subject may receive up to 4 study treatments (placebo and up to 3 doses of rivipansel). The planned dose levels are 350 mg, 1210 mg, and 4200 mg (these are subject to change based on emerging data).<br>Drug: Placebo<br>* Matched Placebo administered as single dose subcutaneously with rHuPH20.<br>|
| Experimental: Cohort 2<br>Multiple ascending dose | Drug: Rivipansel<br>* Rivipansel administered q12h for 7 days (a total of 13 doses) subcutaneously with rHuPH20. Planned doses are 1400 mg loading and 700 mg maintenance for 12 doses (these are subject to change based on emerging data).<br>Drug: Placebo<br>* Matched Placebo administered q12h for 7 days (a total of 13 doses) subcutaneously with rHuPH20.<br>|
| Experimental: Cohort 3<br>Multiple ascending dose | Drug: Rivipansel<br>* Rivipansel administered q12h for 7 days (a total of 13 doses) subcutaneously with rHuPH20. Planned doses are 2800 mg loading and 1400 mg maintenance for 12 doses (these are subject to change based on emerging data).<br>Drug: Placebo<br>* Matched Placebo administered q12h for 7 days (a total of 13 doses) subcutaneously with rHuPH20.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of adverse events (AEs) |  | Baseline up to 7 days of dosing | 
| Assessment of cardiac conduction intervals as assessed via 12-lead electrocardiogram (ECG) |  | Baseline up to 7 days of dosing | 
| Assessment of vital signs (including blood pressure and pulse rate) |  | Baseline up to 7 days of dosing | 
| Assessment of clinical laboratory tests |  | Baseline up to 7 days of dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) for rivipansel following single dose |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for rivipansel following single dose |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for rivipansel following single dose |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) for rivipansel following single dose |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Dose-Normalized Cmax for rivipansel following single dose |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Dose-Normalized AUClast for rivipansel |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Dose-Normalized AUCinf for rivipansel |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Plasma Decay Half-Life (t1/2) for rivipansel following single dose |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Apparent Clearance (CL/F) for rivipansel following single dose |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Apparent Volume of Distribution (Vz/F) for rivipansel following single dose |  | Samples are collected pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72 H following single dose administration | 
| Maximum Observed Plasma Concentration (Cmax) for rivipansel following multiple dose |  | Days 1, 7 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for rivipansel following multiple dose |  | Days 1, 7 | 
| Area Under the Curve from Time Zero to end of dosing interval (AUCtau) for rivipansel following multiple dose administration, where tau is 12 hours |  | Days 1, 7 | 
| Dose-Normalized Cmax for rivipansel following multiple dose administration |  | Days 1, 7 | 
| Dose-Normalized AUCtau for rivipansel following multiple dose administration |  | Days 1, 7 | 
| Plasma Decay Half-Life (t1/2) for rivipansel following multiple dose |  | Day 7 | 
| Minimum Observed Plasma Concentration (Cmin) for rivipansel following multiple dose |  | Day 7 | 
| Apparent Clearance (CL/F) for rivipansel following multiple dose |  | Day 7 | 
| Peak to Trough Ratio (PTR) of plasma concentration for rivipanselmultiple dose administration |  | Day 7 | 
| Accumulation ratio for Area Under the Curve during the dosing interval (Rac) for rivipansel |  | Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy subjects, Randomized, Double-blind, Single ascending dose, Multiple ascending dose