Study to Evaluate the Safety, Tolerability, PK and PD of PB2452 in Healthy Younger, Older and Elderly Subjects

A Phase 2A, Randomized, Double-blind, Placebo-controlled, Single Dose, Sequential Group Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PB2452 With Ticagrelor Pretreatment in Older and Elderly Subjects and With High-Dose Ticagrelor Pretreatment in Healthy Younger Subjects

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03928353

Enrollment

Registered

2019-04-26

Start date

2019-04-16

Completion date

2019-10-09

Last updated

2024-05-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy

Brief summary

This is a Phase 2A, randomized, double-blind, placebo-controlled, single dose, sequential group study to evaluate the safety, tolerability, PK, and PD of PB2452 vs matching placebo with ticagrelor (with or without acetylsalicylic acid (ASA)) pretreatment when various dose levels and administration regimens are administered to healthy younger (ages 18 to 50), older (ages 50 to 64 years) and elderly (ages 65 to 80 years) male and female subjects. Up to 5 dose levels and/or administration regimens will be evaluated in up to 5 cohorts. Each cohort will include approximately 8 to 12 subjects randomized in a 3:1 ratio (PB2452:placebo).

Detailed description

The study will consist of a Screening period, a Check-in day and Pretreatment Period, an on-site Randomization/Treatment day, 3 days on-site for treatment and safety monitoring, a Follow-up Visit (Day 7), and a Final Follow-up visit (Day 28). Seven days prior to Randomization, subjects in Cohorts 1 and 2 will be administered acetylsalicylic acid (ASA) 81 mg orally once daily (QD) until the final dose on the morning of Day 1 before receiving study drug. A ticagrelor 180 mg oral dose will be administered on the morning of Day -2 followed by either 90 mg or 180 mg every 12 hours (BID) until the 5th dose has been administered on the morning of Day 1. On Day 1, subjects who meet all the inclusion criteria and none of the exclusion criteria will be randomized in a ratio 3:1 (PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 hours following the 5th ticagrelor dose. Subjects may be discharged from the clinical site between Days 3 and 7 inclusive and will return for a Follow-up visit on Day 7, if already discharged, and on Day 28 (±2 days).

Interventions

DRUGPB2452 Infusion

30 minute - 24 hour infusion

DRUGPlacebo - Sodium Chloride

30 minute - 24 hour infusion

DRUGTicagrelor Oral Tablet - Pre-Treatment

Ticagrelor 180 mg + 90 mg BID for 5 doses prior to PB2452 or Placebo

DRUGTicagrelor Oral Tablet - Pre-Treatment and Post-Treatment

Ticagrelor 180 mg + 90 mg BID for 5 doses prior to PB2452 or Placebo and Ticagrelor 180 mg 24 hours following PB2452 or Placebo

Study design

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Yes

Inclusion criteria

1. The subject provides written informed consent and agrees to comply with all protocol requirements. 2. The subject is male or female between 18 and 80 years of age, inclusive (50 to 80 years for Cohorts 1-2, 18 to 50 years for Cohorts 3-5). 3. The subject has a body mass index (BMI) between 18 and 35 kg/m2 and a weight of ≥50 kg but ≤120 kg, inclusive, at Screening. 4. 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. Older and elderly subjects with chronic, stable, and well-controlled medical conditions are eligible provided they meet all other inclusion/

Exclusion criteria

. Some examples of stable and well-controlled medical conditions include but are not limited to: * Hypertension (HTN) controlled with ≤2 antihypertensive drugs * Diabetes controlled with diet/exercise or treated with up to 2 oral diabetes medications * Subjects with diabetes must have a glycated hemoglobin HbA1c ≤8 mg/dL at Screening. * Mild hepatic enzyme elevation (aspartate aminotransferase (AST) or alanine transaminase (ALT) \<1.5 x ULN or total bilirubin \<1.2 x ULN) * Controlled hyperlipidemia (defined with a Screening low density lipoprotein LDL \<160 mg/dL) 5. Specific inclusionary laboratory values at Screening and Check-in require: * White blood cell (WBC) count, platelet count, hemoglobin (Hgb) level within normal range, as defined by the clinical laboratory * Thyroid stimulating hormone (TSH) level within normal range, as defined by the clinical laboratory at Screening * Prothrombin time (PT) and partial thromboplastin time (PTT) level within normal range, as defined by the clinical laboratory 6. Subjects taking medications for well-controlled medical conditions must have been on a stable dose (meaning no changes in dose) for at least 30 days prior to Screening visit. 7. Older and elderly subjects entering the study who are not already taking daily ASA must be willing to start an 81 mg daily dose of ASA on Day -7 and continue daily dosing until the final dose is administered on the morning of Day 1. Subjects entering the study who are already taking ASA daily will be administered 81 mg ASA daily between Day -7 and Day 1 and must suspend further ASA dosing until discharge from the clinical facility. 8. 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, 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 from 30 days before study drug administration through to the end of the study. * Effective birth control methods include oral, implantable, patch, or injectable contraceptive hormone treatment, hormone-containing intrauterine device that has been in place ≥2 months prior to Screening, sponge, diaphragm, or cervical cap with spermicidal gel or cream for female subjects or condom or vasectomy for male subjects. * Women are considered to not be of childbearing potential if they have fulfilled one of these criteria: documentation of irreversible surgical sterilization (i.e., hysterectomy or bilateral oophorectomy \[not tubal ligation\]) or are postmenopausal (defined as amenorrhea for 12 consecutive months following cessation of all exogenous hormonal treatments, and documented plasma follicle-stimulating hormone (FSH) 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 (e.g., condom plus diaphragm with spermicide, condom plus spermicide) during the study and for 30 days after the last dose of study drug, and refrain from donating sperm for ≥90 days following the last dose of study drug.

Design outcomes

Primary

Measure	Time frame	Description
Number Of Participants With Treatment-emergent Adverse Events (TEAEs) And Serious Adverse Events (SAEs)	Day -3 up to Day 28	An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug-related. A TEAE is defined as any AE not present before exposure to study drug or any AE already present that worsens in intensity or frequency after exposure to study drug. An SAE/suspected unexpected serious adverse reaction if, in the view of either the investigator or Sponsor, it results in any of the following outcomes: death, life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or congenital anomaly or birth defect. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Number of Participants With Clinical Laboratory Abnormalities	Day -45 up to Day 28	Number of participants with clinically significant abnormal laboratory findings for hematology, coagulation, serum chemistry, and urinalysis.
Mean Diastolic Blood Pressure at Baseline	Baseline	—
Percent Change In Diastolic Blood Pressure From Baseline To Day 28	Day 1 (10, 20, 30, 45, and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Diastolic blood pressure measurements were measured at specific time points.
Mean Systolic Blood Pressure at Baseline	Baseline	—
Percent Change In Systolic Blood Pressure From Baseline To Day 28	Day 1 (10, 20, 30, 45, and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Systolic blood pressure measurements were measured at specific time points.
Mean Oral Body Temperature at Baseline	Baseline	—
Percent Change In Oral Body Temperature From Baseline To Day 28	Day 1 (45 and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Body temperature measurements were measured at specific time points.
Mean Respiratory Rate at Baseline	Baseline	—
Percent Change In Respiratory Rate From Baseline To Day 28	Day 1 (45 and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Respiratory rate measurements were measured at specific time points.
Mean Heart Rate at Baseline	Baseline	—
Percent Change In Heart Rate From Baseline To Day 28	Baseline, Day 1 (10, 20, 30, 45, and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Heart rate measurements were measured at specific time points.
Incidence Of Clinically Significant 12-Lead Electrocardiogram (ECG) Findings	Up to Day 28	Number of participants per cohort with clinically significant ECG findings.
Participants Experiencing Anti-drug Antibodies (ADAs)	Day -3, Day 1, Day 7, and Day 28	Number of participants who developed ADAs to PB2452.
Number of Participants With Adverse Events During Physical Examination	Baseline through Day 28	Participants with adverse events noted during physical exam between baseline and end of study.

Countries

United States

Participant flow

Recruitment details

Healthy, younger, older, and elderly male and female participants were enrolled and randomized in a single center.

Participants by arm

Arm	Count
Part A - Cohort 1 Older and elderly participants pretreated with ticagrelor + ASA received 18 g of PB2452 IV during the treatment period.	6
Part A - Cohort 2 Older and elderly participants pretreated with ticagrelor + ASA received 18 g of PB2452 IV during the treatment period.	5
Part A - Placebo Older and elderly participants pretreated with ticagrelor + ASA received 0.9% sodium chloride IV during the treatment period.	4
Part B - Cohort 3 Healthy and younger participants pretreated with a high dose of ticagrelor (180 mg BID) received 36 g of PB252 IV during the treatment period.	6
Part B - Placebo Healthy and younger participants pretreated with a high dose of ticagrelor (180 mg BID) received 0.9% sodium chloride IV during the treatment period.	2
Total	23

Baseline characteristics

Characteristic	Part A - Cohort 1	Part A - Cohort 2	Part A - Placebo	Part B - Cohort 3	Part B - Placebo	Total
Age, Continuous	59.0 years STANDARD_DEVIATION 7.24	63.8 years STANDARD_DEVIATION 9.31	60.5 years STANDARD_DEVIATION 4.65	34.7 years STANDARD_DEVIATION 8.14	30.5 years STANDARD_DEVIATION 2.12	51.48 years STANDARD_DEVIATION 14.76
Race/Ethnicity, Customized Black or African American	2 Participants	2 Participants	0 Participants	3 Participants	0 Participants	7 Participants
Race/Ethnicity, Customized Hispanic or Latino	3 Participants	0 Participants	1 Participants	1 Participants	1 Participants	6 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	3 Participants	5 Participants	3 Participants	5 Participants	1 Participants	17 Participants
Race/Ethnicity, Customized White	4 Participants	3 Participants	4 Participants	3 Participants	2 Participants	16 Participants
Renal Function Mild (Mild decrease in kidney function)	3 Participants	5 Participants	2 Participants	2 Participants	1 Participants	13 Participants
Renal Function Normal (Normal kidney function)	3 Participants	0 Participants	2 Participants	4 Participants	1 Participants	10 Participants
Sex: Female, Male Female	4 Participants	3 Participants	2 Participants	1 Participants	1 Participants	11 Participants
Sex: Female, Male Male	2 Participants	2 Participants	2 Participants	5 Participants	1 Participants	12 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 5	0 / 4	0 / 6	0 / 2
other Total, other adverse events	1 / 6	2 / 5	3 / 4	4 / 6	1 / 2
serious Total, serious adverse events	0 / 6	1 / 5	0 / 4	0 / 6	0 / 2

Outcome results

Primary