A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MEDI2452 (PB2452) With and Without Ticagrelor Pretreatment in Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- PB2452 Infusion
- Conditions
- Healthy
- Sponsor
- SFJ Pharmaceuticals, Inc.
- Enrollment
- 64
- Locations
- 1
- Primary Endpoint
- Number of Participants With Adverse Events (AEs)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This is a Phase 1, first-in-human, randomized, double-blind, placebo-controlled, single ascending dose, sequential group study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PB2452 with and without ticagrelor pretreatment when administered to healthy male and female subjects.
Up to 6 dose levels will be evaluated. This study will have up to 10 cohorts and up to a total of approximately 76 subjects with either 4 or 8 healthy young subjects in Cohorts 1 through 9 or approximately 16 older subjects in Cohort 10. The starting dose of PB2452 will be 100 mg and the planned doses for subsequent cohorts are 300, 1000, 3000, 9000, and 18000 mg.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The subject is male or female between 18 and 50 years of age, inclusive.
- •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.
- •Specific inclusionary laboratory values at screening and check-in require the following:
- •Aspartate transaminase (AST), alanine transaminase (ALT), total serum bilirubin and alkaline phosphatase levels within the normal range as defined by the clinical laboratory
- •White blood cell (WBC) count, platelet count and hemoglobin level within the normal range as defined by the clinical laboratory
- •Thyroid stimulating hormone (TSH) level within the normal range as defined by the clinical laboratory at screening
- •Prothrombin time (PT) and partial thromboplastin time (PTT) level within the normal range as defined by the clinical laboratory
- •Female subjects of childbearing potential must not be pregnant, lactating, or planning to become pregnant before 3 months after the last dose of study drug, and have a negative serum pregnancy test at screening and check-in. Female subjects of childbearing potential must use 2 effective methods of birth control (ie, oral, implantable, patch, or injectable contraceptives in combination with a condom, hormone-containing intrauterine device that has been in place for at least 2 months prior to screening in combination with a condom, double-barrier method \[ie, condoms, sponge, diaphragm, or cervical cap with spermicidal gels or cream\], or vasectomy for male subjects or male partners of female subjects) from 30 days before study drug administration through the end of the study. Women are considered not to be of childbearing potential if they have fulfilled one of the following criteria: documentation of irreversible surgical sterilization (ie, hysterectomy, or bilateral oophorectomy \[not tubal ligation\]), or postmenopausal (defined as amenorrhea for 12 consecutive months following cessation of all exogenous hormonal treatments, and documented plasma follicle-stimulating hormone level \>40 IU/mL or amenorrhea for 24 consecutive months). Male subjects with partners of childbearing potential must agree to use appropriate and effective measures of contraception (eg, condom plus diaphragm with spermicide; condom plus spermicide) during the study and for 30 days after the last dose of study drug, and to refrain from donating sperm for at least 7 days prior to the first dose of study drug until at least 90 days following the last dose of study drug.
- •The subject agrees to comply with all protocol requirements.
Exclusion Criteria
- •History of any clinically significant acute or chronic disease or medical disorder.
- •History or presence of gastrointestinal, hepatic (with the exception of Gilbert's syndrome), or renal disease or renal insufficiency (ie, estimated glomerular filtration rate \<60 ml/min/1.73m2), or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- •Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study drug or any planned surgical procedure that will occur during the study (from screening through the Day 28 follow up visit).
- •Any clinically significant abnormal findings in physical examination, vital signs, laboratory assessments, and ECG parameters identified during screening or check-in.
- •Any history of arterial or venous thrombosis, including any of the following:
- •History of transient ischemic attack, cardiovascular accident, stroke (ischemic or hemorrhagic), unstable angina, myocardial infarction, or peripheral arterial disease
- •History of deep venous thrombosis, pulmonary embolus, thrombophlebitis, or cavernous malformations
- •Any increased risk of bleeding, including the following:
- •Recent history (within 30 days preceding the first dose of study drug) of gastrointestinal bleeding
- •Any history of severe head trauma, intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, aneurysm, or proliferative retinopathy
Arms & Interventions
1: 100 mg PB2452 or Placebo (no Ticagrelor)
PB2452 Infusion or Placebo - Sodium Chloride
Intervention: PB2452 Infusion
1: 100 mg PB2452 or Placebo (no Ticagrelor)
PB2452 Infusion or Placebo - Sodium Chloride
Intervention: Placebo - Sodium Chloride
2: 300 mg PB2452 or Placebo (no Ticagrelor)
PB2452 Infusion or Placebo - Sodium Chloride
Intervention: PB2452 Infusion
2: 300 mg PB2452 or Placebo (no Ticagrelor)
PB2452 Infusion or Placebo - Sodium Chloride
Intervention: Placebo - Sodium Chloride
3: 1000 mg PB2452 or Placebo (no Ticagrelor)
PB2452 Infusion or Placebo - Sodium Chloride
Intervention: PB2452 Infusion
3: 1000 mg PB2452 or Placebo (no Ticagrelor)
PB2452 Infusion or Placebo - Sodium Chloride
Intervention: Placebo - Sodium Chloride
4: 1000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride With Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: PB2452 Infusion
4: 1000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride With Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: Placebo - Sodium Chloride
5: 3000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: PB2452 Infusion
5: 3000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: Placebo - Sodium Chloride
5: 3000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: Ticagrelor Oral Tablet - Pre-Treatment
6: 9000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: PB2452 Infusion
6: 9000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: Placebo - Sodium Chloride
6: 9000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: Ticagrelor Oral Tablet - Pre-Treatment
7: 18000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: PB2452 Infusion
7: 18000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: Placebo - Sodium Chloride
7: 18000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
Intervention: Ticagrelor Oral Tablet - Pre-Treatment
8: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses
Intervention: PB2452 Infusion
8: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses
Intervention: Placebo - Sodium Chloride
8: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses
Intervention: Ticagrelor Oral Tablet - Pre-Treatment
9: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre and Post-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses and 180 mg 24 hours post-dose
Intervention: PB2452 Infusion
9: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre and Post-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses and 180 mg 24 hours post-dose
Intervention: Placebo - Sodium Chloride
9: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre and Post-Trx)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses and 180 mg 24 hours post-dose
Intervention: Ticagrelor Oral Tablet - Pre-Treatment and Post-Treatment
10: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Txt)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses
Intervention: PB2452 Infusion
10: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Txt)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses
Intervention: Placebo - Sodium Chloride
10: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Txt)
PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses
Intervention: Ticagrelor Oral Tablet - Pre-Treatment
Outcomes
Primary Outcomes
Number of Participants With Adverse Events (AEs)
Time Frame: Day -3 (Cohorts 4 through 10) or Day -1 (Cohorts 1 through 3) until Day 28
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.
Number of Participants With Clinically Significant Laboratory Abnormalities
Time Frame: 30 Day - Starting day of dosing
Number of participants with clinically significant abnormal laboratory findings for hematology, coagulation, serum chemistry, urinalysis and drug tests.
Change in Diastolic Blood Pressure
Time Frame: Days 1, 2, 3, 4, 7 and 28
Diastolic blood pressure measurements were measured at specific time points.
Change in Systolic Blood Pressure
Time Frame: Days 1, 2, 3, 4, 7 and 28
Systolic blood pressure measurements were measured at specific time points.
Change In Oral Body Temperature
Time Frame: Days 1, 2, 3, 4, 7 and 28
Body temperature measurements were measured at specific time points.
Change In Respiratory Rate
Time Frame: Days 1, 2, 3, 4, 7 and 28
Respiratory rate measurements were measured at specific time points.
Change In Heart Rate
Time Frame: Days 1, 2, 3, 4, 7 and 28
Heart rate measurements were measured at specific time points.
Incidence of Clinically Significant 12-Lead Electrocardiogram (ECG) Findings
Time Frame: 60 days - Starting up to 28 days prior to dosing
Number of participants per cohort with clinically significant ECG findings.
Incidence of Clinically Significant Cardiac Telemetry Findings
Time Frame: 3 Days - Starting 1 day prior to dosing up to 2 days after dosing
Number of participants per cohort with clinically significant cardiac telemetry findings.
Participants Experiencing Anti-drug Antibodies (ADAs)
Time Frame: Day -3, Day -1, Day 7, and Day 28
Incidence of Immunogenicity.
Maximal Percent of Baseline Platelet Aggregation (PA(Max)) in Cohorts 4-6
Time Frame: Before dosing and at 0.5, 1, 2, 3, 6, 12, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose.
Effectiveness Of Single Ascending Doses Of PB2452. IPA \[maximum (max)\] induced by 20 µM adenosine diphosphate (ADP) at each assessment point.
Final Extent Percent of Baseline Platelet Aggregation in Cohorts 4-6
Time Frame: Before dosing and at 0.5, 1, 2, 3, 6, 12, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose.
Effectiveness Of Single Ascending Doses Of PB2452. IPA \[final extent\] induced by 20 µM adenosine diphosphate (ADP) at each assessment point.
Maximal Actual Platelet Aggregation (APA(Max)) (Cohorts 4-6)
Time Frame: Before dosing and at 0.5, 1, 2, 3, 6, 12, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose (Cohorts 8 and 9 Only).
Effectiveness Of Single Ascending Doses Of PB2452 - Inhibition of maximal platelet aggregation.
Time to Maximum Platelet Aggregation (TPA(Max)) (Cohorts 4-6)
Time Frame: Before dosing and at 0.5, 1, 2, 3, 6, 12, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose.
Effectiveness Of Single Ascending Doses Of PB2452 - Time to IPAmax.
Maximal Percent of Baseline Platelet Aggregation (PA(Max)) (Cohorts 7-10)
Time Frame: Before dosing and at 5 min, 0.25, 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose.
Effectiveness Of Single Ascending Doses Of PB2452 - IPA (max) induced by 20 µM ADP at each assessment point.
Final Extent Percent of Baseline Platelet Aggregation (Cohorts 7-10)
Time Frame: Before dosing and at 5 min, 0.25, 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose.
Effectiveness Of Single Ascending Doses Of PB2452 - IPA (max) induced by 20 µM ADP at each assessment point.
Maximal Actual Platelet Aggregation (APA(Max)) (Cohorts 7-10)
Time Frame: Before dosing and at 5 min, 0.25, 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose
Effectiveness Of Single Ascending Doses Of PB2452 - Inhibition of maximal platelet aggregation.
Time to Maximum Platelet Aggregation (TPA(Max))(Cohorts 7-10)
Time Frame: Before dosing and at 5 min, 0.25, 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose.
Effectiveness Of Single Ascending Doses Of PB2452 - Time to IPAmax