Phase 2B Study to Evaluate the Efficacy of Bentracimab (PB2452) in Reversal of Ticagrelor in Subjects Aged 50-80 Years Old

Study Overview
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Brief Summary
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This phase 2B study is a multi-center, randomized, double-blind, placebo-controlled study. The study is designed to evaluate the efficacy of bentracimab (PB2452) in reversing the anti-platelet effects of ticagrelor as part of a dual antiplatelet regimen and to evaluate the safety and tolerability of bentracimab (PB2452) in subjects aged 50-80 years old. A total of 205 subjects between 50-80 years old will be enrolled in the US or other countries at the discretion of the Sponsor across 5-15 sites. The subjects will be randomized at a ratio of 3:1 receiving either the bentracimab (PB2452) investigational study drug or placebo. Hence, a total of 154 subjects will be receiving bentracimab (PB2452) and approximately 51 subjects will be receiving placebo.

Detailed Description
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The study will consist of a Screening period, a Check-in day, an on-site Randomization/Treatment day, a 2-day on-site Follow-up period (Days 2 through 3), a Follow-up visit (Day 7), and a Final Follow-up visit (Day 35±3). If needed and at the discretion of the Investigator, a subject may remain in the study facility beyond the scheduled Day 3 discharge to accommodate Day 7 and Day 35±3 follow-up visits. Seven days prior to enrollment, subjects will be administered ASA 81 mg orally once daily (QD) until the final dose on Day 1. Beginning in the morning on Day -2, a single dose of oral ticagrelor 180 mg will be given, followed by oral ticagrelor 90 mg every 12 hours for 4 additional doses through to Day 1 (2 hours before study drug is initiated; this will be 5 total doses of ticagrelor). On Day 1, subjects who meet all the inclusion criteria and none of the exclusion criteria will be randomized with 3:1 allocation ratio (active:placebo), to receive an IV dose of bentracimab (PB2452) or placebo 2 hours following the 5th ticagrelor dose. Subjects may be discharged from the clinical site on Day 3 and will return for a Follow-up visit on Day 7, if already discharged, and on Day 35 (±3 days). A subject may remain in the study facility beyond the scheduled Day 3 discharge to accommodate Day 7 and Day 35±3 follow-up visits. If a subject is taking a moderate or strong CYP3A inhibitor, a 36 g alternative regimen of bentracimab (PB2452) will be administered consisting of 12 g infused over 10 minutes followed by a 12 g loading dose infused over 6 hours, then a maintenance dose of 12 g infused over the next 18 hours immediately following completion of the loading period for a total infusion time of approximately 24 hours.

Official Title
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A Phase 2B, Randomized, Double-blind, Multicenter, Placebo-controlled Study to Evaluate the Efficacy of Bentracimab (PB2452) in Reversing Ticagrelor in Subjects Aged 50 to 80 Years Old

Conditions
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Healthy

Intervention / Treatment
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* Drug: Ticagrelor Oral Tablet - Pre-Treatment
* Drug: Aspirin (ASA) Oral Tablet - Pre-Treatment
* Drug: Bentracimab (PB2452) Infusion
* Drug: Placebo (0.9% Sodium chloride) infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject provides written or verbal informed consent (in-person or remotely) and agrees to comply with all protocol requirements throughout study participation. The subject is male or female between ≥50 and ≤80 years of age. The subject has a body mass index between 18 and 35 kg/m2 and a weight of ≥ 50 kg but ≤ 120 kg, inclusive, at screening. The subject is considered by the Investigator to be in good general health as determined by medical history, clinical laboratory test results, vital sign measurements, 12 lead ECG results, and physical examination findings at screening and Check-in. Subjects with chronic, stable, and well-controlled medical conditions, are eligible provided they meet all other inclusion/exclusion criteria. The subject has specific inclusionary laboratory values at screening and check-in: white blood cell (WBC) count, platelet count, haemoglobin level, thyroid-stimulating hormone (TSH) level, and prothrombin time (PT) and partial thromboplastin time (PTT) levels within the normal range. Subjects taking medications for well-controlled medical conditions must have been on a stable dose for at least 30 days prior to screening visit. Subjects entering the study must be willing to start and/or document an 81 mg daily dose of aspirin on Day -7 and must document daily dosing until the final dose is administered on the morning of Day 1. Subjects already taking daily aspirin must suspend aspirin dosing after Day 1 until discharge from the clinical facility. Female subjects of childbearing potential must not be pregnant, lactating, or planning to become pregnant for 3 months after the last dose of study drug. Female subjects of childbearing potential must use two effective methods of birth control from screening and before study drug administration through to the end of the study. Exclusion Criteria: In the opinion of the Investigator there are concern(s) regarding the inability of the subject to comply with study procedures and/or follow up, or, if the subject is not suitable for entry into the study. History of any acute or chronic medical disorder expected to decrease the life expectancy of the subject to an extent where the subject's study participation is affected. Any clinically significant acute illness, medical/surgical procedure, or trauma within 4 weeks of the administration of study drug or any planned surgical procedure that will occur during the study. Any clinically significant abnormal findings in physical examination, vital signs, laboratory assessments, and ECG parameters identified during screening or check-in. Any specific contraindication to ticagrelor as described in the ticagrelor prescribing information. Receiving chronic treatment with nonsteroidal anti-inflammatory drugs [including aspirin (>100 mg daily), anticoagulants, or other antiplatelet agents that cannot be discontinued 14 days prior to screening including clopidogrel, prasugrel, ticlopidine, dipyridamole, or cilostazol]. First positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at screening. Has received another investigational drug within 30 days of the administration of study drug in this study or within 5 half-lives of the experimental medication, whichever is longer. History of severe or ongoing allergy/hypersensitivity to any biologic therapeutic agent. Involvement with any PhaseBio or study site employee or their close relatives (e.g., spouse, parents, siblings, or children whether biological or legally adopted). Previously received Bentracimab (PB2452) or had been randomized to receive study drug in an earlier cohort for this study

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bentracimab (PB2452)<br>PB2452 18 g Intravenous Infusion over a 16 hour duration. | Drug: Ticagrelor Oral Tablet - Pre-Treatment<br>* Ticagrelor 90 mg oral tablet; administered as 180 mg (2 × 90 mg tablet) loading dose plus 90 mg every 12 hours for 4 additional doses.<br>Drug: Aspirin (ASA) Oral Tablet - Pre-Treatment<br>* Aspirin 81 mg oral tablet; administered daily between Day -7 to the morning before receiving study medication on Day 1, for a total of 8 tablets only.<br>Drug: Bentracimab (PB2452) Infusion<br>* Bentracimab (PB2452) 18 g Intravenous Infusion over a 16 hour duration In subjects with potential drug interaction from concomitant use of moderate or strong CYP3A inhibitors with ticagrelor, the active treatment period may be 24 hours and 10 min if receiving the 36 g infusion.<br>|
| Placebo Comparator: Placebo<br>Placebo (0.9% Sodium chloride) intravenous Infusion over a 16 hour duration. | Drug: Ticagrelor Oral Tablet - Pre-Treatment<br>* Ticagrelor 90 mg oral tablet; administered as 180 mg (2 × 90 mg tablet) loading dose plus 90 mg every 12 hours for 4 additional doses.<br>Drug: Aspirin (ASA) Oral Tablet - Pre-Treatment<br>* Aspirin 81 mg oral tablet; administered daily between Day -7 to the morning before receiving study medication on Day 1, for a total of 8 tablets only.<br>Drug: Placebo (0.9% Sodium chloride) infusion<br>* 0.9% Sodium chloride Intravenous Infusion over a 16 hour duration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reversal effect of intravenous infusion of bentracimab (PB2452) compared to baseline - Minimum % inhibition of PRU (VerifyNow) | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Four hours after the start of infusion (compared against pre-dose sample) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Incidence and severity of AEs |  | 83 days - Starting up to 45 days prior to dosing | 
| Safety - Incidence and severity of adverse events based on physical examination |  | 83 days - Starting up to 45 days prior to dosing and collected pre-dose and Days 3, 7, and 35±3 | 
| Safety - Incidence of Clinical Laboratory Testing Abnormalities |  | 83 days - Starting up to 45 days prior to dosing, pre-dose and Day 2, 7 and 35±3 | 
| Safety - Changes in Systolic Blood Pressure |  | 83 days - Starting up to 45 days prior to dosing and collected pre-dose and Days 1, 2, 3, 7, and 35±3 | 
| Safety - Changes in Diastolic Blood Pressure |  | 83 days - Starting up to 45 days prior to dosing and collected pre-dose and Days 1, 2, 3, 7, and 35±3 | 
| Safety - Changes in Oral Body Temperature |  | 83 days - Starting up to 45 days prior to dosing and collected pre-dose and Days 1, 2, 3, 7, and 35±3 | 
| Safety - Changes in Respiratory Rate |  | 83 days - Starting up to 45 days prior to dosing and collected pre-dose and Days 1, 2, 3, 7, and 35±3 | 
| Safety - Changes in Heart Rate |  | 83 days - Starting up to 45 days prior to dosing and collected pre-dose and Days 1, 2, 3, 7, and 35±3 | 
| Safety - Incidence of clinically significant findings as measured by 12-Lead ECG |  | 83 days - Starting up to 45 days prior to dosing and collected pre-dose and Days 1, 2, 7, and 35±3 | 
| Safety - Incidence of positive testing for Anti-Drug Antibodies |  | 41 days - Starting 3 days prior to dosing and collected post-dose at Day 1, 7 and Day 35±3. May be extended in the event that result does not return to baseline in time allotted. | 
| Cmax Bentracimab (PB2452) | Maximum concentration | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion (exact sample times may be adjusted) | 
| AUC (0-t) Bentracimab (PB2452) | Area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| Tmax Bentracimab (PB2452) | Time to maximum concentration | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| AUC0-24 Bentracimab (PB2452) | Area under the plasma concentration versus time curve 0-24 hours | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24 hours after the start of infusion | 
| AUC0-48 Bentracimab (PB2452) | Area under the plasma concentration versus time curve 0-48 hours | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| AUC0-tau Bentracimab (PB2452) | Area under the plasma concentration versus time curve from time zero to the time of the end of the dosing period | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| AUC0-inf Bentracimab (PB2452) | Area under the plasma concentration versus time curve at time 0 extrapolated to infinity | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| t½ Bentracimab (PB2452) | Terminal elimination half-life | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| CL Bentracimab (PB2452) | Clearance | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| Vd Bentracimab (PB2452) | Volume of distribution | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| Cmax (Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Maximum concentration | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| AUC0-last (Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, and 12 hours after the start of infusion | 
| Tmax (Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Time to maximum concentration | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| AUC(0-24) (Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Area under the plasma concentration versus time curve 0-24 hours | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, and 24 hours after the start of infusion | 
| AUC(0-48) (Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Area under the plasma concentration versus time curve 0-48 hours | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| AUC0-tau (Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Area under the plasma concentration versus time curve from time zero to the time of the end of the dosing period | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| AUC0-inf (Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Area under the plasma concentration versus time curve at time 0 extrapolated to infinity | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| t½ (Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Terminal elimination half-life | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36, 48 hours, 7 and 35±3 days after the start of infusion | 
| Ae24 (Urine - Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Total amount of drug excreted in urine at 24 hours | Before dosing and 0 to 6, 6 to 12, and 12 to 24 hours after the initiation of the bentracimab (PB2452) infusion. | 
| Ae48 (Urine - Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Total amount of drug excreted in urine at 48 hours | Before dosing and 0 to 6, 6 to 12, 12 to 24 and 24 to 48 hours after the initiation of the bentracimab (PB2452) infusion | 
| Aet1-t2 (Urine - Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Total amount of drug excreted in urine from time t1 to t2 hours | Before dosing and 0 to 6, 6 to 12, 12 to 24 and 24 to 48 hours after the initiation of the bentracimab (PB2452) infusion | 
| Fe24 (Urine - Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Fraction excreted in urine from 1 to 24 hours | Before dosing and 0 to 6, 6 to 12, and 12 to 24 hours after the initiation of the bentracimab (PB2452) infusion and 5th ticagrelor dose. | 
| Fe48 (Urine - Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Fraction excreted in urine from 1 to 48 hours | Before dosing and 0 to 6, 6 to 12, 12 to 24 and 24 to 48 hours after the initiation of the bentracimab (PB2452) infusion and 5th ticagrelor dose | 
| CLr (Urine - Ticagrelor and Ticagrelor Active Metabolite (TAM)) | Renal clearance | Before dosing and 0 to 6, 6 to 12, and 12 to 24 hours after the initiation of the bentracimab (PB2452) infusion and 5th ticagrelor dose | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) compared to baseline - Minimum % inhibition of PRI (VASP) | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 4 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) compared to baseline - PRU (Verify Now) AUC | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 4 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % of subjects to ≥ 180 PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and 4 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % of subjects to ≥ 60% of reversal in PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % of subjects to ≥ 80% of reversal in PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % of subjects to ≥ 100% of reversal in PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Time to ≥ 60% of reversal by PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Time to ≥ 80% of reversal by PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Time to ≥ 100% of reversal by PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Duration of 80% response rate by PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Duration of 100% response rate by PRU | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - PRI AUC | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 4 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % of subjects with ≥ 60% PRI response rate within 4 hours | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 4 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % of subjects with ≥ 80% PRI response rate within 4 hours | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 4 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % of subjects with ≥ 100% PRI response rate within 4 hours | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 4 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Time to ≥ 60% of reversal by PRI | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Time to ≥ 80% of reversal by PRI | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Time to ≥ 100% of reversal by PRI | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Duration of 80% response rate by PRI | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - Duration of 100% response rate by PRI | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and at 5, 10 and 30 minutes, 1, 2, 4, 8, 12, 20, 24, 36 and 48 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % Reversal of PRU within 4 hours | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and 4 hours after the start of infusion | 
| Reversal effects of intravenous infusion of bentracimab (PB2452) - % Reversal of PRI within 4 hours | Reversal of anti-platelet effects of ticagrelor with intravenous infusion of bentracimab (PB2452) or placebo | Before dosing and 4 hours after the start of infusion |