This study will assess up to 12 different oral formulations of apremilast to determine how much apremilast is absorbed by the body compared to a reference formulation.
This will be a single-center, open-label, crossover, single modified-release-dose study in adult males to evaluate the pharmacokinetics (PK) of prototype modified-release (MR) formulations compared to the reference immediate-release (IR) apremilast formulation. Within 4 separate groups, participants will be randomly assigned to a treatment sequence. A total of up to 12 test MR formulations may be evaluated. Group 1: A 4-sequence, 4-period design to compare three modified-release prototypes with the reference immediate-release formulation. A total of 16 participants will be enrolled to obtain at least 12 participants who complete all 4 periods. Group 2: A 4-sequence, 4-period design to compare three MR prototypes with the reference IR formulation. Sixteen participants will be enrolled to obtain at least 12 participants who complete all four periods. Group 3: A six-sequence, three-period design to compare two MR prototypes with the reference IR formulation. Eighteen participants will be enrolled to obtain at least 12 participants who complete all three periods. Group 4: A 10-sequence, 5-period design to compare four MR prototypes with the reference IR formulation. Thirty participants will be enrolled to obtain at least 20 participants who complete all five periods.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
80
30 mg immediate release tablets
75 mg oral tablet of prototype modified release (MR) 1
75 mg oral tablet of prototype MR 2
Covance Clinical Research Unit Inc.
Madison, Wisconsin, United States
Group 1: Observed Maximum Plasma Concentration (Cmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Half-life of Apremilast in Terminal Phase (T1/2)
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75 mg oral capsule of prototype MR 3
75 mg oral capsule of prototype MR 4
75 mg oral capsule of prototype MR 5
75 mg oral capsule of prototype MR 6
80 mg oral capsule of prototype MR 8
80 mg oral capsule of prototype MR 9
80 mg oral capsule of prototype MR 11
80 mg oral capsule of prototype MR 12
80 mg oral capsule of prototype MR 13
80 mg oral capsule of prototype MR 14
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Apparent Total Plasma Clearance (CL/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Apparent Total Volume of Distribution (Vz/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Observed Maximum Plasma Concentration (Cmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Half-life of Apremilast in Terminal Phase (T1/2)
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Apparent Total Plasma Clearance (CL/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 3: Observed Maximum Plasma Concentration (Cmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 3: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 3: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 3: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 3: Half-life of Apremilast in Terminal Phase (T1/2)
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 3: Apparent Total Plasma Clearance (CL/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Observed Maximum Plasma Concentration (Cmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Half-life of Apremilast in Terminal Phase (T1/2)
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Apparent Total Plasma Clearance (CL/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Apparent Total Volume of Distribution (Vz/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Group 1: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event.
Time frame: Adverse events were collected for 7 to 10 days after each treatment.
Group 2: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event.
Time frame: Adverse events were collected for 7 to 10 days after each treatment.
Group 3: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event.
Time frame: Adverse events were collected for 7 to 10 days after each treatment.
Group 4: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event.
Time frame: Adverse events were collected for 7 to 10 days after each treatment.