Healthy Volunteers
Conditions
Brief summary
The purpose of this study to evaluate the safety, tolerability and pharmacokinetics (PK) of lanadelumab administered by Intravenous (IV) infusion in healthy adult volunteers.
Detailed description
A Randomized, Double-blind, Placebo-Controlled, Repeat-dose, Single-center Phase 1a Study to Determine the Safety, Tolerability, and Pharmacokinetics of Lanadelumab Administered Intravenously in Healthy Adult Volunteer Subjects
Interventions
DRUGLanadelumab
Participants will receive lanadelumab 300 mg IV infusion on Day 1 followed by Day 4.
OTHERPlacebo
Participants will receive placebo matching to lanadelumab IV infusion on Day 1 followed by Day 4.
Sponsors
Takeda Development Center Americas, Inc.
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy, adult, male or female, 19-55 years of age, inclusive, at screening. * Continuous non-smoker who has not used nicotine-containing products for at least 30 days prior to the first dosing and throughout the study, based on participant self-reporting. * Body mass index (BMI) greater than or equal to (\>=) 18.0 and less than or equal to (\<=) 32.0 kilogram per square meter (kg/m\^2) at screening. * Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or electrocardiograms (ECGs), per the investigator. * Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive requirements of the protocol or females of non-childbearing potential. * Understands the study procedures in the informed consent form (ICF) and be willing and able to comply with the protocol.
Exclusion criteria
* Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study. * History or presence of clinically significant medical or psychiatric condition or disease per the investigator. * History of any illness that might confound the results of the study or poses an additional risk to the participant by their participation in the study, per the investigator. * History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing per the investigator. * History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or related compounds. * History or presence of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or psychiatric disease, gall bladder removal, or current or recurrent disease that could affect the action, absorption, or disposition of the investigational product, or clinically significant clinical or laboratory assessments per the investigator. * Female participants with a positive pregnancy test or lactating. * Positive urine drug or alcohol results at screening. * Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV). * Supine blood pressure is less than 90/40 millimetre of mercury (mmHg) or greater than 140/90 mmHg at screening. * Supine heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening. * Orthostatic vital sign results with a decrease in systolic greater than (\>) 20 mmHg or decrease in diastolic \> 10 mmHg and increase in pulse of \> 20 beats per minute. * QTcF interval is \> 450 milliseconds (msec) (males) or \> 470 msec (females) or ECG findings are deemed abnormal with clinical significance at screening per the investigator. * Estimated creatinine clearance less than (\<) 80 milliliters per minute (mL/min) at screening. * Unable to refrain from or anticipates the use of any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements within 14 days prior to the first dosing and throughout the study. Medication listed as part of acceptable birth control methods will be allowed. Thyroid hormone replacement medication may be permitted if the participant has been on the same stable dose for the immediate 3 months prior to first study drug administration. After randomization/dosing, a nonsteroidal anti-inflammatory drug may be administered at the discretion of the investigator. Hormone replacement therapy will also be allowed if the participant has been on the same stable dose for the immediate 3 months prior to first study drug administration. * Has been on a diet incompatible with the on-study diet, per the investigator, within the 30 days prior to the first dosing and throughout the study. * Donation of blood or significant blood loss within 56 days prior to the first dosing. * Plasma donation within 7 days prior to the first dosing. * Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. The 30-day window or 5 half-lives will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of the current study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | From the first dose of study treatment up to the end of study (Day 112) | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant who has signed informed consent to participate in a study that did not necessarily have a causal relationship with the treatment. TEAEs were events that occurred on or after the date and time of administration of the first dose of study medication. TEAEs included both serious TEAEs and non-serious TEAEs. Number of participants with TEAEs were reported. |
| Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters | From the first dose of study treatment up to the end of study (Day 112) | Clinical laboratory assessment included hematology, clinical chemistry, coagulation, and urinalysis. Any changes in clinical laboratory results that were deemed clinically significant were judged by the investigator. The number of participants with clinically significant change from baseline in laboratory values were reported. |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | From the first dose of study treatment up to the end of study (Day 112) | Vital signs included blood pressure (systolic and diastolic), heart rate, and body temperature (oral). Any changes in vital signs that were deemed clinically significant were judged by the investigator. The number of participants with clinically significant change from baseline in vital signs were reported. |
| Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings | From the first dose of study treatment up to the end of study (Day 112) | 12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. Any changes in ECG parameters that were deemed clinically significant were judged by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported. |
| AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration for Lanadelumab | Pre-dose (Day 1) up to 2664 hours post-dose | AUC0-last for lanadelumab was reported. |
| AUC0-inf: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity for Lanadelumab | Pre-dose (Day 1) up to 2664 hours post-dose | AUC0-inf for lanadelumab was reported. |
| Cmax1: Maximum Observed Plasma Concentration Following the First IV Dose for Lanadelumab | Pre-dose (Day 1) up to 2664 hours post-dose | Cmax1 following the first IV dose for lanadelumab was reported. |
| Cmax2: Maximum Observed Plasma Concentration Following the Second IV Dose for Lanadelumab | Pre-dose (Day 4) up to 2592 hours post-dose | Cmax2 following the second IV dose for lanadelumab was reported. |
| Tmax1: Minimum Observed Time to Reach the First Cmax1 for Lanadelumab | Pre-dose (Day 1) up to 2664 hours post-dose | Tmax1 following the first IV dose for lanadelumab was reported. |
| Tmax2: Minimum Observed Time to Reach the Second Cmax2 for Lanadelumab | Pre-dose (Day 4) up to 2592 hours post-dose | Tmax2 following the second IV dose for lanadelumab was reported. |
| Terminal Half-Life (T1/2) of Lanadelumab in Plasma | Pre-dose (Day 1) up to 2664 hours post-dose | T1/2 is defined as the time required for the concentration of the drug to reach half of its original value. T1/2 for lanadelumab was reported. |
| Clearance (CL) of Lanadelumab in Plasma | Pre-dose (Day 1) up to 2664 hours post-dose | Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL for lanadelumab was reported. |
| Vss: Volume of Distribution at Steady State in Plasma for Lanadelumab | Pre-dose (Day 1) up to 2664 hours post-dose | Volume of distribution is 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. Vss for lanadelumab was reported. |
| First Order Elimination Rate Constant Associated With the Terminal (Log-linear) Portion of the Curve (Lambda z) of Lanadelumab | Pre-dose (Day 1) up to 2664 hours post-dose | Lambda z of Lanadelumab was reported. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 1 investigative site in the United States between 10 August 2020 (first participant first visit) and 23 December 2020 (last participant last visit).
Pre-assignment details
A total of 12 healthy participants were enrolled and randomized to receive lanadelumab 300 milligrams (mg) or matching placebo in this study.
Participants by arm
| Arm | Count |
|---|---|
| Lanadelumab 300 mg Participants received a single dose of lanadelumab 300 mg IV infusion on Day 1 followed by a second dose on Day 4. | 9 |
| Placebo Participants received a single dose of placebo (normal saline) IV infusion on Day 1 followed by a second dose on Day 4. | 3 |
| Total | 12 |
Baseline characteristics
| Characteristic | Placebo | Total | Lanadelumab 300 mg |
|---|---|---|---|
| Age, Continuous | 42.0 years STANDARD_DEVIATION 10.44 | 36.3 years STANDARD_DEVIATION 11.48 | 34.3 years STANDARD_DEVIATION 11.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 11 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 3 |
| other Total, other adverse events | 7 / 9 | 2 / 3 |
| serious Total, serious adverse events | 0 / 9 | 0 / 3 |
Outcome results
Primary
AUC0-inf: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity for Lanadelumab
AUC0-inf for lanadelumab was reported.
Time frame: Pre-dose (Day 1) up to 2664 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lanadelumab 300 mg | AUC0-inf: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity for Lanadelumab | 33305 h*mcg/mL | Geometric Coefficient of Variation 10.5 |
Primary
AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration for Lanadelumab
AUC0-last for lanadelumab was reported.
Time frame: Pre-dose (Day 1) up to 2664 hours post-dose
Population: The pharmacokinetic (PK) analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lanadelumab 300 mg | AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration for Lanadelumab | 32955 hour*microgram per milliliter (h*mcg/mL) | Geometric Coefficient of Variation 10.5 |
Primary
Clearance (CL) of Lanadelumab in Plasma
Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL for lanadelumab was reported.
Time frame: Pre-dose (Day 1) up to 2664 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lanadelumab 300 mg | Clearance (CL) of Lanadelumab in Plasma | 18.1 milliliter per hour (mL/h) | Geometric Coefficient of Variation 10.4 |
Primary
Cmax1: Maximum Observed Plasma Concentration Following the First IV Dose for Lanadelumab
Cmax1 following the first IV dose for lanadelumab was reported.
Time frame: Pre-dose (Day 1) up to 2664 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lanadelumab 300 mg | Cmax1: Maximum Observed Plasma Concentration Following the First IV Dose for Lanadelumab | 75.6 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 16.1 |
Primary
Cmax2: Maximum Observed Plasma Concentration Following the Second IV Dose for Lanadelumab
Cmax2 following the second IV dose for lanadelumab was reported.
Time frame: Pre-dose (Day 4) up to 2592 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lanadelumab 300 mg | Cmax2: Maximum Observed Plasma Concentration Following the Second IV Dose for Lanadelumab | 120 mcg/mL | Geometric Coefficient of Variation 20.7 |
Primary
First Order Elimination Rate Constant Associated With the Terminal (Log-linear) Portion of the Curve (Lambda z) of Lanadelumab
Lambda z of Lanadelumab was reported.
Time frame: Pre-dose (Day 1) up to 2664 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lanadelumab 300 mg | First Order Elimination Rate Constant Associated With the Terminal (Log-linear) Portion of the Curve (Lambda z) of Lanadelumab | 9.90 Per hour (/h) | Geometric Coefficient of Variation 31 |
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant who has signed informed consent to participate in a study that did not necessarily have a causal relationship with the treatment. TEAEs were events that occurred on or after the date and time of administration of the first dose of study medication. TEAEs included both serious TEAEs and non-serious TEAEs. Number of participants with TEAEs were reported.
Time frame: From the first dose of study treatment up to the end of study (Day 112)
Population: The safety analysis set consisted of all participants who had started at least 1 dose of lanadelumab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lanadelumab 300 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 7 Participants |
| Placebo | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
Primary
Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings
12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, and QT interval. Any changes in ECG parameters that were deemed clinically significant were judged by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported.
Time frame: From the first dose of study treatment up to the end of study (Day 112)
Population: The safety analysis set consisted of all participants who had started at least 1 dose of lanadelumab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lanadelumab 300 mg | Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
Primary
Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters
Clinical laboratory assessment included hematology, clinical chemistry, coagulation, and urinalysis. Any changes in clinical laboratory results that were deemed clinically significant were judged by the investigator. The number of participants with clinically significant change from baseline in laboratory values were reported.
Time frame: From the first dose of study treatment up to the end of study (Day 112)
Population: The safety analysis set consisted of all participants who had started at least 1 dose of lanadelumab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lanadelumab 300 mg | Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in Laboratory Parameters | 0 Participants |
Primary
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Vital signs included blood pressure (systolic and diastolic), heart rate, and body temperature (oral). Any changes in vital signs that were deemed clinically significant were judged by the investigator. The number of participants with clinically significant change from baseline in vital signs were reported.
Time frame: From the first dose of study treatment up to the end of study (Day 112)
Population: The safety analysis set consisted of all participants who had started at least 1 dose of lanadelumab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lanadelumab 300 mg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 Participants |
Primary
Terminal Half-Life (T1/2) of Lanadelumab in Plasma
T1/2 is defined as the time required for the concentration of the drug to reach half of its original value. T1/2 for lanadelumab was reported.
Time frame: Pre-dose (Day 1) up to 2664 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lanadelumab 300 mg | Terminal Half-Life (T1/2) of Lanadelumab in Plasma | 19.3 days |
Primary
Tmax1: Minimum Observed Time to Reach the First Cmax1 for Lanadelumab
Tmax1 following the first IV dose for lanadelumab was reported.
Time frame: Pre-dose (Day 1) up to 2664 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lanadelumab 300 mg | Tmax1: Minimum Observed Time to Reach the First Cmax1 for Lanadelumab | 2.01 hours |
Primary
Tmax2: Minimum Observed Time to Reach the Second Cmax2 for Lanadelumab
Tmax2 following the second IV dose for lanadelumab was reported.
Time frame: Pre-dose (Day 4) up to 2592 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lanadelumab 300 mg | Tmax2: Minimum Observed Time to Reach the Second Cmax2 for Lanadelumab | 74.03 hours |
Primary
Vss: Volume of Distribution at Steady State in Plasma for Lanadelumab
Volume of distribution is 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. Vss for lanadelumab was reported.
Time frame: Pre-dose (Day 1) up to 2664 hours post-dose
Population: The PK analysis set consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK concentration post-dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lanadelumab 300 mg | Vss: Volume of Distribution at Steady State in Plasma for Lanadelumab | 8070 milliliter (mL) | Geometric Coefficient of Variation 19.5 |