Healthy
Conditions
Brief summary
The main purpose of this study is to assess the effect of Pirtobrutinib (LOXO-305) on the heart rate-corrected QT (QTc) interval and to conduct blood tests to measure how much pirtobrutinib (LOXO-305) is in the bloodstream and how the body handles and eliminates pirtobrutinib. The study will also evaluate the safety and tolerability of pirtobrutinib. The study will last up to 71 days, including screening.
Interventions
DRUGPirtobrutinib
Administered orally
DRUGPlacebo
Administered orally
DRUGMoxifloxacin
Administered orally
Sponsors
Loxo Oncology, Inc.
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
This is a partially double-blind study (for LOXO-305 only, not moxifloxacin).
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Must have Body mass index (BMI) within the range of 18.0 to 32.0 kilograms per square meter (kg/m²), inclusive at Screening * Male and female participants in good health, determined by no clinically significant findings from medical history, 12-lead Electrocardiogram (ECG), vital sign measurements, or clinical laboratory evaluations as assessed by the investigator * Female participants of non-childbearing potential and male participants who follow standard contraceptive methods * Must have comply with all study procedures, including the 15-night stay at the Clinical Research Unit (CRU) and follow-up phone call
Exclusion criteria
* History or presence of any diseases or conditions of clinical significance by the Investigator (or designee) and/or Sponsor * Positive serologic test for hepatitis B surface antigen (HBsAg), hepatitis B virus immunoglobulin M (HBV IgM) core antibody, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody at Screening. * Positive polymerase chain reaction (PCR) test for COVID-19 at Screening * Known ongoing alcohol and/or drug abuse within 2 years prior to Screening * History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee) * Have previously received pirtobrutinib (LOXO-305) in any other study investigating pirtobrutinib (LOXO-305), within 30 days prior to Day 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF) | Baseline (Predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | The cardiodynamic assessment was performed through 12-lead electrocardiogram (ECG) extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Placebo-corrected change from baseline in QTcF (ΔΔQTcF) was calculated based on model-predicted effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Heart Rate (ΔHR) | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | Heart rate is the number of times the ventricles of the heart contract and relax per minute. Change from baseline in heart rate (ΔHR) was calculated using linear mixed-effects model analysis. |
| Change From Baseline in Pulse Rate (ΔPR) | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | Pulse rate is number of times heart beats per minute. Pulse rate measurements were performed using the same arm for each reading and measurements were taken after the participant had been resting in the supine position for at least 5 minutes. Change from baseline in pulse rate (ΔPR) was calculated using linear mixed-effects model analysis. |
| Change From Baseline in QRS Intervals (Δ QRS) | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | QRS interval in an ECG measured the total time of ventricular depolarization. It begins with Q or R wave and ends at the end of the S wave. Change from baseline in QRS intervals (Δ QRS) was calculated using linear mixed-effects model analysis. |
| Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔQTcS), If a Substantial Heart Rate Effect Was Observed | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcS. |
| Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔQTcI), If a Substantial Heart Rate Effect Was Observed | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcI. |
| Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | Heart rate is the number of times the ventricles of the heart contract and relax per minute. Placebo-corrected change from baseline in heart rate (ΔΔHR) was calculated using linear mixed-effects model analysis. |
| Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | Pulse rate is number of times heart beats per minute. Pulse rate measurements were performed using the same arm for each reading and measurements were taken after the participant had been resting in the supine position for at least 5 minutes. Placebo-corrected change from baseline in pulse rate (ΔPR) was calculated using linear mixed-effects model analysis. |
| Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | QRS interval in an ECG measured the total time of ventricular depolarization. It begins with Q or R wave and ends at the end of the S wave. Placebo-corrected change from baseline in QRS intervals (ΔΔQRS) was calculated using linear mixed-effects model analysis. |
| Placebo-corrected Change From Baseline in ΔQTcF (ΔΔQTcF), If a Substantial Heart Rate Effect Was Observed | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. |
| Placebo-corrected Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔΔQTcS), If a Substantial Heart Rate Effect Was Observed | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcS. |
| Placebo-corrected Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔΔQTcI), If a Substantial Heart Rate Effect Was Observed | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcI. |
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Changes | Baseline up to Day 33 | The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. Number of participants with potentially clinically significant ECG changes were reported. |
| Change From Baseline in (Δ) QTcF | Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose | The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Change from baseline in (Δ) QTcF was calculated using linear mixed-effects model analysis. |
| Pharmacokinetic (PK): Percentage of AUC0-inf Extrapolated (AUC%Extrap) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: %AUCextrap was defined as percentage extrapolation for AUC0-inf. |
| PK: Mean Residence Time (MRT) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: MRT was calculated by the area under the first moment curve divided by the area under the concentration time curve. |
| PK: Apparent Volume of Distribution at the Terminal Phase (Vz/F) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was calculated as (CL/F)/Lambda Z. Where, CL/F is the apparent total clearance and lambda Z is the apparent terminal elimination rate constant. |
| PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: Tmax was defined as the time to reach maximum observed plasma concentration (Cmax) for pirtobrutinib. |
| PK: Apparent Plasma Terminal Elimination Half-life (t1/2) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: t1/2 was defined as the terminal elimination phase half-life for pirtobrutinib. |
| PK: Maximum Observed Concentration (Cmax) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: Cmax was defined as the maximum plasma concentration for pirtobrutinib. |
| PK: Area Under the Concentration-time Curve, From Time 0 to 24 Hours Post-dose (AUC0-24) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24 hours post-dose | PK: AUC(0-24) was defined as the area under the plasma concentration-time curve from 0 time to 24 hours post-dose. |
| PK: Area Under the Concentration-time Curve, From Time 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 time to last measurable point for pirtobrutinib. |
| PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as (Dose/AUC(0-inf))/F. Where AUC(0-inf) is the area under the plasma concentration-time curve from zero to infinity and F is the bioavailability of the drug. |
| PK: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: AUC(0-inf) was defined as the area under the plasma concentration-time curve from 0 to infinity for pirtobrutinib. |
| PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose | PK: Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase. |
| Number of Participants With Treatment Emergent Changes in T-wave Morphology and U-wave Presence | Baseline up to Day 33 | The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. Number of participants with treatment emergent changes in T-wave morphology and U-wave presence were reported. |
Countries
United States
Participant flow
Pre-assignment details
A total of 31 participants were enrolled in this study. Participants were randomly assigned to 1 of 6 treatment sequences (ABC, BCA, CAB, ACB, CBA and BAC) where Treatment A was single oral dose of 900 milligrams (mg) pirtobrutinib, Treatment B was single oral dose of 900 mg pirtobrutinib matched placebo and Treatment C was single oral dose of 400 mg moxifloxacin.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence: ABC Participants received a single oral dose of 900 mg pirtobrutinib (Treatment A) on Day 1, followed by a single oral dose of 900 mg pirtobrutinib matched placebo (Treatment B) on Day 12 and a single oral dose of 400 mg moxifloxacin (Treatment C) on Day 23, under fasted conditions | 5 |
| Treatment Sequence: BCA Participants received a single oral dose of 900 mg pirtobrutinib matched placebo (Treatment B) on Day 1, followed by a single oral dose of 400 mg moxifloxacin (Treatment C) on Day 12 and a single oral dose of 900 mg pirtobrutinib (Treatment A) on Day 23, under fasted conditions. | 6 |
| Treatment Sequence: CAB Participants received a single oral dose of 400 mg moxifloxacin (Treatment C) on Day 1, followed by a single oral dose of 900 mg pirtobrutinib (Treatment A) on Day 12 and a single oral dose of 900 mg pirtobrutinib matched placebo (Treatment B) on Day 23, under fasted conditions. | 5 |
| Treatment Sequence: ACB Participants received a single oral dose of 900 mg pirtobrutinib (Treatment A) on Day 1, followed by a single oral dose of 400 mg moxifloxacin (Treatment C) on Day 12 and a single oral dose of 900 mg pirtobrutinib matched placebo (Treatment B) on Day 23, under fasted conditions. | 5 |
| Treatment Sequence: CBA Participants received a single oral dose of 400 mg moxifloxacin (Treatment C) on Day 1, followed by a single oral dose of 900 mg pirtobrutinib matched placebo (Treatment B) on Day 12 and a single oral dose of 900 mg pirtobrutinib (Treatment A) on Day 23, under fasted conditions. | 5 |
| Treatment Sequence: BAC Participants received a single oral dose of 900 mg pirtobrutinib matched placebo (Treatment B) on Day 1, followed by a single oral dose of 900 mg pirtobrutinib (Treatment A) on Day 12 and a single oral dose of 400 mg moxifloxacin (Treatment C) on Day 23, under fasted conditions. | 5 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (Day 1) | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment Sequence: BCA | Treatment Sequence: ABC | Treatment Sequence: CAB | Treatment Sequence: ACB | Treatment Sequence: CBA | Treatment Sequence: BAC | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 39.0 years STANDARD_DEVIATION 8.81 | 35.0 years STANDARD_DEVIATION 9.87 | 37.8 years STANDARD_DEVIATION 7.95 | 35.6 years STANDARD_DEVIATION 7.86 | 34.4 years STANDARD_DEVIATION 6.77 | 38.2 years STANDARD_DEVIATION 10.01 | 36.7 years STANDARD_DEVIATION 8.08 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 4 Participants | 4 Participants | 3 Participants | 4 Participants | 2 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 0 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 14 Participants |
| Region of Enrollment United States | 6 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 31 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 3 Participants | 5 Participants | 5 Participants | 3 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 6 / 30 | 1 / 31 | 1 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 31 | 0 / 30 |
Outcome results
Primary
Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF)
The cardiodynamic assessment was performed through 12-lead electrocardiogram (ECG) extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Placebo-corrected change from baseline in QTcF (ΔΔQTcF) was calculated based on model-predicted effect.
Time frame: Baseline (Predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: Pharmacokinetic/Corrected QT interval (PK/QTc) population included all participants who were in both the PK and QT/QTc populations with at least 1 pair of post-dose PK and ΔQTc data from the same time point in at least 1 period as well as participants in the QT/QTc population who received placebo. As per planned analysis, data was planned to be reported only for Treatment A (900 mg pirtobrutinib) concentration for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF) | 0.73 milliseconds (msec) |
Secondary
Change From Baseline in Heart Rate (ΔHR)
Heart rate is the number of times the ventricles of the heart contract and relax per minute. Change from baseline in heart rate (ΔHR) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. Here, 'Number Analyzed' signifies participants who were evaluable at specific timepoints. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 0.75 hour post-dose | 0.0 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 3 hours post-dose | 1.3 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 1.5 hours post-dose | 0.9 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 4 hours post-dose | 1.4 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 0.5 hour post-dose | -0.5 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 6 hours post-dose | 2.0 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 2 hours post-dose | 0.5 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 8.5 hours post-dose | 4.0 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 1 hour post-dose | 1.0 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 12 hours post-dose | 2.0 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 2.5 hours post-dose | 2.2 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 24 hours post-dose | 1.2 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Heart Rate (ΔHR) | Change at 0.25 hour post-dose | 0.1 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 24 hours post-dose | 0.8 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 0.25 hour post-dose | -0.9 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 0.5 hour post-dose | -1.2 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 0.75 hour post-dose | -0.4 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 1 hour post-dose | -0.1 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 1.5 hours post-dose | -1.7 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 2 hours post-dose | -0.8 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 2.5 hours post-dose | -0.1 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 3 hours post-dose | 0.4 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 4 hours post-dose | 0.4 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 6 hours post-dose | 0.5 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 8.5 hours post-dose | 3.4 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Heart Rate (ΔHR) | Change at 12 hours post-dose | 0.4 beats per minute (beats/min) |
Secondary
Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔQTcS), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcS.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔQTcS), If a Substantial Heart Rate Effect Was Observed | NA msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔQTcS), If a Substantial Heart Rate Effect Was Observed | NA msec |
Secondary
Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔQTcI), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcI.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔQTcI), If a Substantial Heart Rate Effect Was Observed | NA msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔQTcI), If a Substantial Heart Rate Effect Was Observed | NA msec |
Secondary
Change From Baseline in Pulse Rate (ΔPR)
Pulse rate is number of times heart beats per minute. Pulse rate measurements were performed using the same arm for each reading and measurements were taken after the participant had been resting in the supine position for at least 5 minutes. Change from baseline in pulse rate (ΔPR) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. Here, 'Number Analyzed' signifies participants evaluable for specific timepoints. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 0.75 hour post-dose | 0.3 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 3 hours post-dose | -0.9 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 1.5 hours post-dose | -0.9 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 4 hours post-dose | -1.6 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 0.5 hour post-dose | 0.3 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 6 hours post-dose | -4.4 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 2 hours post-dose | -0.5 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 8.5 hours post-dose | -6.2 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 1 hour post-dose | -0.1 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 12 hours post-dose | -4.9 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 2.5 hours post-dose | -3.9 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 24 hours post-dose | -4.2 beats per minute (beats/min) |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in Pulse Rate (ΔPR) | Change at 0.25 hour post-dose | -2.6 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 24 hours post-dose | -0.6 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 0.25 hour post-dose | -0.8 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 0.5 hour post-dose | 1.5 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 0.75 hour post-dose | 1.0 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 1 hour post-dose | 0.7 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 1.5 hours post-dose | -1.2 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 2 hours post-dose | -0.5 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 2.5 hours post-dose | -0.8 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 3 hours post-dose | -1.3 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 4 hours post-dose | -2.3 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 6 hours post-dose | -2.7 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 8.5 hours post-dose | -5.1 beats per minute (beats/min) |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in Pulse Rate (ΔPR) | Change at 12 hours post-dose | -2.8 beats per minute (beats/min) |
Secondary
Change From Baseline in QRS Intervals (Δ QRS)
QRS interval in an ECG measured the total time of ventricular depolarization. It begins with Q or R wave and ends at the end of the S wave. Change from baseline in QRS intervals (Δ QRS) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. Here, 'Number Analyzed' signifies participants evaluable for specific timepoints. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 0.75 hour post-dose | 0.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 3 hours post-dose | 0.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 1.5 hours post-dose | -0.1 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 4 hours post-dose | 0.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 0.5 hour post-dose | 0.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 6 hours post-dose | 0.7 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 2 hours post-dose | 0.0 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 8.5 hours post-dose | -0.6 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 1 hour post-dose | 0.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 12 hours post-dose | 0.4 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 2.5 hours post-dose | -0.1 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 24 hours post-dose | 0.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in QRS Intervals (Δ QRS) | Change at 0.25 hour post-dose | 0.0 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 24 hours post-dose | -1.0 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 0.25 hour post-dose | 0.0 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 0.5 hour post-dose | -0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 0.75 hour post-dose | 0.0 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 1 hour post-dose | -0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 1.5 hours post-dose | -0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 2 hours post-dose | -0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 2.5 hours post-dose | -0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 3 hours post-dose | -0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 4 hours post-dose | 0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 6 hours post-dose | 0.2 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 8.5 hours post-dose | 0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in QRS Intervals (Δ QRS) | Change at 12 hours post-dose | 0.3 msec |
Secondary
Change From Baseline in (Δ) QTcF
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Change from baseline in (Δ) QTcF was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. Here, 'Number Analyzed' signifies participants who were evaluable at specific timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 12 hours post-dose | 1.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 4 hours post-dose | 2.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 2 hours post-dose | -2.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 0.75 hour post-dose | -3.8 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 3 hours post-dose | 0.3 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 2.5 hours post-dose | -0.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 0.25 hour post-dose | -0.4 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 0.5 hour post-dose | -4.5 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 8.5 hours post-dose | -5.1 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 1 hour post-dose | -2.8 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 24 hours post-dose | 0.0 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 6 hours post-dose | 3.5 msec |
| Treatment A: 900 mg Pirtobrutinib | Change From Baseline in (Δ) QTcF | Change at 1.5 hours post-dose | -0.6 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 2.5 hours post-dose | 0.2 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 0.25 hour post-dose | 0.0 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 0.5 hour post-dose | -2.8 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 0.75 hour post-dose | -2.0 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 1 hour post-dose | -1.2 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 1.5 hours post-dose | -1.0 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 2 hours post-dose | -1.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 3 hours post-dose | 0.5 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 4 hours post-dose | 0.3 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 6 hours post-dose | 0.9 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 8.5 hours post-dose | -5.2 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 12 hours post-dose | 0.6 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Change From Baseline in (Δ) QTcF | Change at 24 hours post-dose | 0.6 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 4 hours post-dose | 9.8 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 1 hour post-dose | 8.3 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 12 hours post-dose | 6.8 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 6 hours post-dose | 9.3 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 0.75 hour post-dose | 7.6 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 0.25 hour post-dose | -0.1 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 8.5 hours post-dose | 2.8 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 2.5 hours post-dose | 10.1 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 2 hours post-dose | 9.4 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 0.5 hour post-dose | 4.2 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 3 hours post-dose | 9.9 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 1.5 hours post-dose | 9.8 msec |
| Treatment C: 400 mg Moxifloxacin | Change From Baseline in (Δ) QTcF | Change at 24 hours post-dose | 5.0 msec |
Secondary
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Changes
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. Number of participants with potentially clinically significant ECG changes were reported.
Time frame: Baseline up to Day 33
Population: The safety population included all participants who received 1 dose of study drug. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Changes | 0 Participants |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Changes | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Changes in T-wave Morphology and U-wave Presence
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. Number of participants with treatment emergent changes in T-wave morphology and U-wave presence were reported.
Time frame: Baseline up to Day 33
Population: The safety population included all participants who received 1 dose of study drug. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Number of Participants With Treatment Emergent Changes in T-wave Morphology and U-wave Presence | Treatment Emergent Changes in T-wave Morphology | 0 Participants |
| Treatment A: 900 mg Pirtobrutinib | Number of Participants With Treatment Emergent Changes in T-wave Morphology and U-wave Presence | Treatment Emergent Changes in U-wave Presence | 0 Participants |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Number of Participants With Treatment Emergent Changes in T-wave Morphology and U-wave Presence | Treatment Emergent Changes in T-wave Morphology | 0 Participants |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Number of Participants With Treatment Emergent Changes in T-wave Morphology and U-wave Presence | Treatment Emergent Changes in U-wave Presence | 0 Participants |
Secondary
Pharmacokinetic (PK): Percentage of AUC0-inf Extrapolated (AUC%Extrap) of Pirtobrutinib
PK: %AUCextrap was defined as percentage extrapolation for AUC0-inf.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Pharmacokinetic (PK): Percentage of AUC0-inf Extrapolated (AUC%Extrap) of Pirtobrutinib | 5.41 percentage of AUC | Geometric Coefficient of Variation 42 |
Secondary
PK: Apparent Plasma Terminal Elimination Half-life (t1/2) of Pirtobrutinib
PK: t1/2 was defined as the terminal elimination phase half-life for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Plasma Terminal Elimination Half-life (t1/2) of Pirtobrutinib | 23.0 hours | Geometric Coefficient of Variation 14.5 |
Secondary
PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib
PK: Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as (Dose/AUC(0-inf))/F. Where AUC(0-inf) is the area under the plasma concentration-time curve from zero to infinity and F is the bioavailability of the drug.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib | 1.88 liter per hour (L/h) | Geometric Coefficient of Variation 21.4 |
Secondary
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib
PK: Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. Here, 'Overall Number of participants analyzed' signifies individual participants who were evaluable for rate constant evaluation. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 11 | 0.0271 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 12 | 0.0213 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 13 | 0.0337 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 26 | 0.0306 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 27 | 0.0364 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 28 | 0.0299 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 29 | 0.0304 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 1 | 0.0320 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 2 | 0.0270 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 3 | 0.0356 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 4 | 0.0259 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 5 | 0.0270 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 6 | 0.0330 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 7 | 0.0310 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 8 | 0.0331 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 9 | 0.0353 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 10 | 0.0322 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 14 | 0.0273 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 15 | 0.0229 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 16 | 0.0314 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 17 | 0.0364 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 18 | 0.0289 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 19 | 0.0309 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 20 | 0.0271 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 21 | 0.0269 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 22 | 0.0422 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 23 | 0.0346 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 24 | 0.0273 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 25 | 0.0288 one per hour (1/h) |
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib | Participant 30 | 0.0283 one per hour (1/h) |
Secondary
PK: Apparent Volume of Distribution at the Terminal Phase (Vz/F) of Pirtobrutinib
PK: Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was calculated as (CL/F)/Lambda Z. Where, CL/F is the apparent total clearance and lambda Z is the apparent terminal elimination rate constant.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Apparent Volume of Distribution at the Terminal Phase (Vz/F) of Pirtobrutinib | 62.1 liter | Geometric Coefficient of Variation 22.5 |
Secondary
PK: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Pirtobrutinib
PK: AUC(0-inf) was defined as the area under the plasma concentration-time curve from 0 to infinity for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Pirtobrutinib | 480000 h*ng/mL | Geometric Coefficient of Variation 21.4 |
Secondary
PK: Area Under the Concentration-time Curve, From Time 0 to 24 Hours Post-dose (AUC0-24) of Pirtobrutinib
PK: AUC(0-24) was defined as the area under the plasma concentration-time curve from 0 time to 24 hours post-dose.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Area Under the Concentration-time Curve, From Time 0 to 24 Hours Post-dose (AUC0-24) of Pirtobrutinib | 229000 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 17.5 |
Secondary
PK: Area Under the Concentration-time Curve, From Time 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib
PK: AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 time to last measurable point for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Area Under the Concentration-time Curve, From Time 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | 452000 h*ng/mL | Geometric Coefficient of Variation 20.7 |
Secondary
PK: Maximum Observed Concentration (Cmax) of Pirtobrutinib
PK: Cmax was defined as the maximum plasma concentration for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Maximum Observed Concentration (Cmax) of Pirtobrutinib | 14300 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 23.1 |
Secondary
PK: Mean Residence Time (MRT) of Pirtobrutinib
PK: MRT was calculated by the area under the first moment curve divided by the area under the concentration time curve.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Mean Residence Time (MRT) of Pirtobrutinib | 33.6 hours | Geometric Coefficient of Variation 14.6 |
Secondary
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib
PK: Tmax was defined as the time to reach maximum observed plasma concentration (Cmax) for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
Population: PK population included participants who received 1 dose of pirtobrutinib and have at least 1 quantifiable plasma concentration of pirtobrutinib and have evaluable PK data. As per planned analysis, data was planned to be reported only for Treatment A for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | 4.01 hours |
Secondary
Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR)
Heart rate is the number of times the ventricles of the heart contract and relax per minute. Placebo-corrected change from baseline in heart rate (ΔΔHR) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. As per planned analysis, data was planned to be reported only for Treatment A and C for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 0.5 hours post-dose | 0.6 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 2.5 hours post-dose | 2.3 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 1 hour post-dose | 1.2 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 3 hours post-dose | 0.9 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 0.25 hours post-dose | 0.9 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 4 hours post-dose | 1.0 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 1.5 hours post-dose | 2.6 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 6 hours post-dose | 1.6 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 0.75 hours post-dose | 0.4 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 12 hours post-dose | 1.6 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 2 hours post-dose | 1.3 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 24 hours post-dose | 0.4 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 8.5 hours post-dose | 0.6 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 24 hours post-dose | 1.0 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 8.5 hours post-dose | 1.5 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 0.25 hours post-dose | 0.1 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 0.5 hours post-dose | 3.0 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 0.75 hours post-dose | 3.8 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 1 hour post-dose | 4.2 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 1.5 hours post-dose | 2.8 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 2 hours post-dose | 2.5 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 2.5 hours post-dose | 2.9 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 3 hours post-dose | 1.1 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 4 hours post-dose | 1.9 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 6 hours post-dose | 2.6 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR) | Change at 12 hours post-dose | 4.5 beats/min |
Secondary
Placebo-corrected Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔΔQTcS), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcS.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants w.ho received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔΔQTcS), If a Substantial Heart Rate Effect Was Observed | NA msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔΔQTcS), If a Substantial Heart Rate Effect Was Observed | NA msec |
Secondary
Placebo-corrected Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔΔQTcI), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcI.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔΔQTcI), If a Substantial Heart Rate Effect Was Observed | NA msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔΔQTcI), If a Substantial Heart Rate Effect Was Observed | NA msec |
Secondary
Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR)
Pulse rate is number of times heart beats per minute. Pulse rate measurements were performed using the same arm for each reading and measurements were taken after the participant had been resting in the supine position for at least 5 minutes. Placebo-corrected change from baseline in pulse rate (ΔPR) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. As per planned analysis, data was planned to be reported only for Treatment A and C for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 0.75 hours post-dose | -0.7 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 3 hours post-dose | 0.4 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 1.5 hours post-dose | 0.3 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 4 hours post-dose | 0.7 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 0.5 hours post-dose | -1.2 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 6 hours post-dose | -1.8 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 2 hours post-dose | 0.0 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 8.5 hours post-dose | -1.1 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 1 hours post-dose | -0.7 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 12 hours post-dose | -2.1 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 2.5 hours post-dose | -3.1 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 24 hours post-dose | -3.6 beats/min |
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 0.25 hours post-dose | -1.9 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 24 hours post-dose | -0.8 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 0.25 hours post-dose | -1.2 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 0.5 hours post-dose | -2.1 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 0.75 hours post-dose | -2.5 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 1 hours post-dose | -3.8 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 1.5 hours post-dose | -3.4 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 2 hours post-dose | -3.6 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 2.5 hours post-dose | -4.6 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 3 hours post-dose | -4.0 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 4 hours post-dose | -4.2 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 6 hours post-dose | -4.3 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 8.5 hours post-dose | -2.1 beats/min |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR) | Change at 12 hours post-dose | -3.5 beats/min |
Secondary
Placebo-Corrected Change From Baseline in QRS (ΔΔQRS)
QRS interval in an ECG measured the total time of ventricular depolarization. It begins with Q or R wave and ends at the end of the S wave. Placebo-corrected change from baseline in QRS intervals (ΔΔQRS) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: QT/QTc population included all participants who received 1 dose of study drug with measurements at baseline as well as on treatment with at least 1 post-dose time point with a valid ΔQTc value. As per planned analysis, data was planned to be reported only for Treatment A and C for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 6 hours post-dose | 0.5 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 0.25 hours post-dose | 0.0 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 0.5 hours post-dose | 0.3 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 0.75 hours post-dose | 0.2 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 1 hours post-dose | 0.3 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 1.5 hours post-dose | 0.0 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 2 hours post-dose | 0.0 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 2.5 hours post-dose | 0.0 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 3 hours post-dose | 0.3 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 4 hours post-dose | 0.1 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 8.5 hours post-dose | -0.8 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 12 hours post-dose | 0.1 msec |
| Treatment A: 900 mg Pirtobrutinib | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 24 hours post-dose | 1.2 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 12 hours post-dose | 0.0 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 2.5 hours post-dose | 0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 0.25 hours post-dose | -0.3 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 8.5 hours post-dose | -0.4 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 0.5 hours post-dose | 0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 3 hours post-dose | -0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 0.75 hours post-dose | 0.3 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 24 hours post-dose | 0.2 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 1 hours post-dose | 0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 4 hours post-dose | -0.3 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 1.5 hours post-dose | 0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 6 hours post-dose | -0.1 msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-Corrected Change From Baseline in QRS (ΔΔQRS) | Change at 2 hours post-dose | 0.1 msec |
Secondary
Placebo-corrected Change From Baseline in ΔQTcF (ΔΔQTcF), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Population: PK/QTc population included all participants who were in both the PK and QT/QTc populations with at least 1 pair of post-dose PK and ΔQTc data from the same time point in at least 1 period as well as participants in the QT/QTc population who received placebo. As per planned analysis, data was planned to be reported only for Treatment A and B for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment A: 900 mg Pirtobrutinib | Placebo-corrected Change From Baseline in ΔQTcF (ΔΔQTcF), If a Substantial Heart Rate Effect Was Observed | NA msec |
| Treatment B: 900 mg Pirtobrutinib Matched Placebo | Placebo-corrected Change From Baseline in ΔQTcF (ΔΔQTcF), If a Substantial Heart Rate Effect Was Observed | NA msec |