Healthy Subjects, Pharmacodynamics, Pharmacokinetics
Conditions
Keywords
Pharmacokinetics, Pharmacodynamics
Brief summary
This study is designed to assess pharmacokinetics and pharmacodynamics of mepolizumab and reslizumab across an appropriate dose range to inform clinical trial operating characteristics for future clinical pharmacology pharmacodynamics similarity studies. This is a randomized, placebo-controlled, single-dose, parallel arm study in 72 healthy subjects assigned to one of four dose groups (low, intermediate low, intermediate high, and high) of each drug (mepolizumab or reslizumab) or placebo.
Detailed description
This study is designed to assess pharmacokinetics and pharmacodynamics of mepolizumab and reslizumab across an appropriate dose range to inform clinical trial operating characteristics for future clinical pharmacology pharmacodynamics similarity studies. This is a randomized, placebo-controlled, single-dose, parallel arm study in 72 healthy subjects assigned to one of four dose groups (low, intermediate low, intermediate high, and high) of each drug (mepolizumab or reslizumab) or placebo. Mepolizumab doses are 3, 6, 12, or 24 mg. Reslizumab doses are 0.1, 0.2, 0.4, or 0.8 mg/kg. Each arm will include 8 subjects (4 male and 4 female). Subjects will be admitted for treatment on day -1 and receive a single dose of study drug or placebo on day 1. Depending on the treatment arm, subjects will remain in confinement for two weeks and continue follow-up through either day 63 or day 123. Blood samples (approximately 5 mL per sample) will be collected for determination of plasma concentrations for study drug. Additional blood samples will be collected for determination of eosinophil counts (5 mL per sample; pharmacodynamic measure) and exploratory proteomics analyses (5 mL per sample). Safety evaluations will include adverse event (AE) monitoring, vital sign measurements, and physical examinations. All AEs reported by the subject or observed by the investigator or clinical research unit (CRU) staff will be recorded. Any AE reported after the informed consent is signed and before study drug application will be recorded as medical history.
Interventions
BIOLOGICALMepolizumab
Mepolizumab 3 mg administered SC
BIOLOGICALReslizumab
Reslizumab 0.1 mg/kg administered IV
BIOLOGICALPlacebo
Placebo (administered either IV or SC)
Sponsors
Spaulding Clinical Research LLC
Food and Drug Administration (FDA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Masking description
The pharmacist (and designated staff member responsible for confirmation of study drug dose) will be unblinded to subject treatment assignment; however, the pharmacist will not perform any study procedures other than study drug preparation and dispensing. Subjects and staff will be blinded to treatment assignment during confinement, but route of administration will not be blinded. The blind will be maintained through a randomization schedule held by the dispensing pharmacist. Subjects and staff will be informed of a subject's end of study day when discharged from confinement. Subjects and staff will not be informed of the specific treatment arm assignment. The clinical research nurse will administer the study drugs in unit dose containers that are not transparent.
Intervention model description
Subjects will be randomized to one of four dose groups (low, intermediate low, intermediate high, and high) of each drug (mepolizumab or reslizumab) or placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Subject signs an institutional review board approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed. 2. Subject is a healthy man or woman, 18 to 55 years of age, inclusive, who has a body mass index of 18.5 to 29.9 kg/m2, inclusive, at Screening. 3. Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead electrocardiogram (ECG) results, and physical examination findings at screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee). 4. Subject must have a negative test result for alcohol and drugs of abuse at screening and Check-in (Day -1). 5. Subject has a peripheral blood eosinophil count of ≥50 and ≤700 cells per microliter of blood as measured by a standard hematology analyzer. 6. Female subjects must be of non-childbearing potential or, if they are of childbearing potential, they must: 1) have been strictly abstinent for 1 month before Check in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1month after the last application of study drug; OR 2) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before Check in (Day -1) until at least 1 month after the end of the study. 7. Male subjects must agree to practice 1 highly effective method of birth control (as determined by the investigator or designee) from at least 1 month before Check in (Day -1) until at least 1 month after the end of the study. 8. Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study
Exclusion criteria
1. Subject is taking any medication known to affect leukocyte population numbers. 2. Subject is anemic (i.e., with Hct or Hgb less than the lower limit of normal) or has any chronic condition(s) that may impact blood sample collection. 3. Subject has had previous exposure to the biologic mepolizumab or reslizumab. 4. Subject has a history of asthma. 5. Subject has a history of anaphylaxis from environmental exposures such as peanuts or bee stings. 6. Subject has an allergic history that includes urticaria, angioedema or respiratory coughing or bronchospasm. 7. Subject has a history of severe local reactions or generalized erythema from skin allergen testing. 8. Subject is anemic or has any chronic condition(s) that may impact blood sample collection. 9. Subject has used any prescription or nonprescription drugs (including aspirin or NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug. 10. Subjects are currently participating in another clinical study of an investigational drug or are have been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of the compound. 11. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening. 12. Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 48 hours of dosing. Subjects must refrain from ingesting these throughout the study. 13. Subject has any underlying disease or surgical or medical condition (e.g., cancer, human immunodeficiency virus \[HIV\], severe hepatic or renal impairment) that could put the subject at risk or would normally prevent participation in a clinical study. This includes subjects with any underlying medical conditions that put subjects at higher risk for coronavirus disease of 2019 (COVID-19) complications; per current Center for Disease Control and Prevention (CDC) recommendations this includes: * People with chronic lung disease or moderate to severe asthma * People who have serious heart conditions * People who are immunocompromised * Many conditions can cause a person to be immunocompromised, including cancer treatment, smoking, bone marrow or organ transplantation, immune deficiencies, poorly controlled HIV, and prolonged use of corticosteroids and other immune weakening medications * People with severe obesity (body mass index \[BMI\] of 40 or higher) * People with diabetes * People with chronic kidney disease undergoing dialysis * People with liver disease 14. Subject has any signs or symptoms that are consistent with COVID-19. Per current CDC recommendations this includes subjects with the symptoms cough or shortness of breath or difficulty breathing, or at least two of the following symptoms: fever, chills, repeated shaking with chills, muscle pain, headache, sore throat or new loss of taste/smell. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator. 15. Subject tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by a molecular diagnostic test performed prior to admission. 16. Subject has known or suspected allergies or sensitivities to any study drug. 17. Subject has clinical laboratory test results (hematology, serum chemistry) at Screening that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator. 18. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen. 19. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access. 20. Female subjects are pregnant or lactating before enrollment in the study. 21. Subject is known to have, or is suspected to have, a parasitic infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I. | The values and variability of AUEC for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. AUEC was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Calculations were performed using non-compartmental analysis packages available in R software. |
| Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I. | The values and variability of maximal change from baseline for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. Values are percentage change from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Area Under the Effect Curve Versus Dose Emax Models for Mepolizumab or Reslizumab | Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I. | The model parameter (Emax, units percentage change from baseline \* day) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions. |
| Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Mepolizumab | Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, and until Day 123 post-dose for Arms C, D, and I. | The model parameter (ED50, units mg) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions. |
| Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Reslizumab | Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms E, F and until Day 123 post-dose for Arms G, H, and I. | The model parameter (ED50, units mg/kg) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of reslizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions. |
| Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 0 (pre-dose), 1, 4, 12, 24, hours post-dose; once daily from Day 3 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, and H. | The values and variability of Cmax at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. |
| Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Mepolizumab | Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, and until Day 123 post-dose for Arms C, D, and I. | The model parameter (ED50, units mg) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions. |
| Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Reslizumab | Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms E, F and until Day 123 post-dose for Arms G, H, and I. | The model parameter (ED50, units mg/kg) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of reslizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions. |
| Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Maximum Change From Baseline Versus Dose Emax Models With Mepolizumab or Reslizumab | Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I. | The model parameter (Emax, units percentage change from baseline) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions. |
| Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 0 (pre-dose), 1, 4, 12, 24, hours post-dose; once daily from Day 3 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, and H. | The values and variability of AUC at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Mepolizumab Low Dose Single dose of mepolizumab 3 mg SC
Mepolizumab: Mepolizumab 3 mg administered SC | 8 |
| Arm B: Mepolizumab Low Intermediate Dose Single dose of mepolizumab 6 mg SC
Mepolizumab: Mepolizumab 6 mg administered SC | 8 |
| Arm C: Mepolizumab High Intermediate Dose Single dose of mepolizumab 12 mg SC
Mepolizumab: Mepolizumab 12 mg administered SC | 8 |
| Arm D: Mepolizumab High Dose Single dose of mepolizumab 24 mg SC
Mepolizumab: Mepolizumab 24 mg administered SC | 8 |
| Arm E: Reslizumab Low Dose Single dose of reslizumab 0.1 mg/kg IV
Reslizumab: Reslizumab 0.1 mg/kg administered IV | 8 |
| Arm F: Reslizumab Intermediate Low Dose Single dose of reslizumab 0.2 mg/kg IV
Reslizumab: Reslizumab 0.2 mg/kg administered IV | 8 |
| Arm G: Reslizumab High Intermediate Dose Single dose of reslizumab 0.4 mg/kg IV
Reslizumab: Reslizumab 0.4 mg/kg administered IV | 8 |
| Arm H: Reslizumab High Dose Single dose of reslizumab 0.8 mg/kg IV
Reslizumab: Reslizumab 0.8 mg/kg administered IV | 8 |
| Arm I: Placebo Single dose of placebo
Placebo: Placebo (administered either IV or SC) | 8 |
| Total | 72 |
Baseline characteristics
| Characteristic | Arm B: Mepolizumab Low Intermediate Dose | Arm C: Mepolizumab High Intermediate Dose | Arm D: Mepolizumab High Dose | Arm E: Reslizumab Low Dose | Arm F: Reslizumab Intermediate Low Dose | Arm A: Mepolizumab Low Dose | Arm G: Reslizumab High Intermediate Dose | Arm H: Reslizumab High Dose | Arm I: Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 29 years | 33 years | 39 years | 46 years | 36 years | 32 years | 45 years | 49 years | 40 years | 39 years |
| Body Mass Index | 23.7 kg/m^2 | 26.7 kg/m^2 | 24.8 kg/m^2 | 23.9 kg/m^2 | 27.5 kg/m^2 | 25.3 kg/m^2 | 26.2 kg/m^2 | 23.8 kg/m^2 | 27.5 kg/m^2 | 25.6 kg/m^2 |
| Body Weight | 71 kg | 72 kg | 79 kg | 75 kg | 80 kg | 73 kg | 78 kg | 72 kg | 82 kg | 77 kg |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 7 Participants | 7 Participants | 8 Participants | 6 Participants | 6 Participants | 7 Participants | 7 Participants | 7 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 Participants | 5 Participants | 3 Participants | 5 Participants | 3 Participants | 2 Participants | 3 Participants | 33 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 2 Participants | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 6 Participants | 5 Participants | 33 Participants |
| Region of Enrollment United States | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 72 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 21 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 5 Participants | 6 Participants | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 4 / 8 | 3 / 8 | 3 / 8 | 1 / 8 | 3 / 8 | 2 / 8 | 4 / 8 | 6 / 8 | 3 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab
The values and variability of AUEC for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. AUEC was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Calculations were performed using non-compartmental analysis packages available in R software.
Time frame: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Mepolizumab Low Dose | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -1804 Percentage change from baseline * day | Standard Deviation 1425 |
| Arm B: Mepolizumab Low Intermediate Dose | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -195 Percentage change from baseline * day | Standard Deviation 1568 |
| Arm C: Mepolizumab High Intermediate Dose | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -1456 Percentage change from baseline * day | Standard Deviation 1951 |
| Arm D: Mepolizumab High Dose | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -1428 Percentage change from baseline * day | Standard Deviation 2442 |
| Arm E: Reslizumab Low Dose | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -1748 Percentage change from baseline * day | Standard Deviation 1888 |
| Arm F: Reslizumab Intermediate Low Dose | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -1075 Percentage change from baseline * day | Standard Deviation 1312 |
| Arm G: Reslizumab High Intermediate Dose | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -3313 Percentage change from baseline * day | Standard Deviation 4506 |
| Arm H: Reslizumab High Dose | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -2905 Percentage change from baseline * day | Standard Deviation 1423 |
| Arm I: Placebo | Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab | -1409 Percentage change from baseline * day | Standard Deviation 3410 |
Primary
Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab
The values and variability of maximal change from baseline for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. Values are percentage change from baseline.
Time frame: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Mepolizumab Low Dose | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -72 Percentage change from baseline | Standard Deviation 73 |
| Arm B: Mepolizumab Low Intermediate Dose | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -63 Percentage change from baseline | Standard Deviation 14 |
| Arm C: Mepolizumab High Intermediate Dose | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -82 Percentage change from baseline | Standard Deviation 23 |
| Arm D: Mepolizumab High Dose | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -85 Percentage change from baseline | Standard Deviation 14 |
| Arm E: Reslizumab Low Dose | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -79 Percentage change from baseline | Standard Deviation 9 |
| Arm F: Reslizumab Intermediate Low Dose | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -67 Percentage change from baseline | Standard Deviation 27 |
| Arm G: Reslizumab High Intermediate Dose | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -75 Percentage change from baseline | Standard Deviation 25 |
| Arm H: Reslizumab High Dose | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -77 Percentage change from baseline | Standard Deviation 25 |
| Arm I: Placebo | Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab | -41 Percentage change from baseline | Standard Deviation 15 |
Secondary
Area Under the Curve (AUC) for Mepolizumab and Reslizumab
The values and variability of AUC at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab.
Time frame: 0 (pre-dose), 1, 4, 12, 24, hours post-dose; once daily from Day 3 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, and H.
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Mepolizumab Low Dose | Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 17.6 μg/mL*day | Geometric Coefficient of Variation 73 |
| Arm B: Mepolizumab Low Intermediate Dose | Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 21.7 μg/mL*day | Geometric Coefficient of Variation 153 |
| Arm C: Mepolizumab High Intermediate Dose | Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 38.1 μg/mL*day | Geometric Coefficient of Variation 21 |
| Arm D: Mepolizumab High Dose | Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 61.8 μg/mL*day | Geometric Coefficient of Variation 46 |
| Arm E: Reslizumab Low Dose | Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 150 μg/mL*day | Geometric Coefficient of Variation 109 |
| Arm F: Reslizumab Intermediate Low Dose | Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 152 μg/mL*day | Geometric Coefficient of Variation 239 |
| Arm G: Reslizumab High Intermediate Dose | Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 450 μg/mL*day | Geometric Coefficient of Variation 72 |
| Arm H: Reslizumab High Dose | Area Under the Curve (AUC) for Mepolizumab and Reslizumab | 420 μg/mL*day | Geometric Coefficient of Variation 70 |
Secondary
Maximum Concentration (Cmax) for Mepolizumab and Reslizumab
The values and variability of Cmax at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab.
Time frame: 0 (pre-dose), 1, 4, 12, 24, hours post-dose; once daily from Day 3 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, and H.
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Mepolizumab Low Dose | Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 0.36 μg/mL | Geometric Coefficient of Variation 74 |
| Arm B: Mepolizumab Low Intermediate Dose | Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 0.53 μg/mL | Geometric Coefficient of Variation 54 |
| Arm C: Mepolizumab High Intermediate Dose | Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 1.21 μg/mL | Geometric Coefficient of Variation 23 |
| Arm D: Mepolizumab High Dose | Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 2.05 μg/mL | Geometric Coefficient of Variation 27 |
| Arm E: Reslizumab Low Dose | Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 3.1 μg/mL | Geometric Coefficient of Variation 10 |
| Arm F: Reslizumab Intermediate Low Dose | Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 5.2 μg/mL | Geometric Coefficient of Variation 35 |
| Arm G: Reslizumab High Intermediate Dose | Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 12.3 μg/mL | Geometric Coefficient of Variation 26 |
| Arm H: Reslizumab High Dose | Maximum Concentration (Cmax) for Mepolizumab and Reslizumab | 18.7 μg/mL | Geometric Coefficient of Variation 20 |
Secondary
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Mepolizumab
The model parameter (ED50, units mg) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Time frame: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, and until Day 123 post-dose for Arms C, D, and I.
Population: Analysis population for each group was limited to those subjects administered mepolizumab or placebo (the mepolizumab group) who completed the study. Results from subjects administered placebo were used in all analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Mepolizumab Low Dose | Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Mepolizumab | 31.3 mg |
Secondary
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Reslizumab
The model parameter (ED50, units mg/kg) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of reslizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Time frame: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms E, F and until Day 123 post-dose for Arms G, H, and I.
Population: Analysis population for each group was limited to those subjects administered reslizumab or placebo (reslizumab group) who completed the study. Results from subjects administered placebo were used in all analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Mepolizumab Low Dose | Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Reslizumab | 0.31 mg/kg |
Secondary
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Mepolizumab
The model parameter (ED50, units mg) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Time frame: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, and until Day 123 post-dose for Arms C, D, and I.
Population: Analysis population for each group was limited to those subjects administered mepolizumab or placebo (the mepolizumab group) who completed the study. Results from subjects administered placebo were used in all analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Mepolizumab Low Dose | Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Mepolizumab | 3.8 mg |
Secondary
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Reslizumab
The model parameter (ED50, units mg/kg) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of reslizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Time frame: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms E, F and until Day 123 post-dose for Arms G, H, and I.
Population: Analysis population for each group was limited to those subjects administered reslizumab or placebo (reslizumab) who completed the study. Results from subjects administered placebo were used in all analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Mepolizumab Low Dose | Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Reslizumab | 0.04 mg/kg |
Secondary
Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Area Under the Effect Curve Versus Dose Emax Models for Mepolizumab or Reslizumab
The model parameter (Emax, units percentage change from baseline \* day) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Time frame: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.
Population: Analysis population for each group was limited to those subjects administered mepolizumab or placebo (the mepolizumab group) or administered reslizumab or placebo (reslizumab group) who completed the study. Results from subjects administered placebo were used in all analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Mepolizumab Low Dose | Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Area Under the Effect Curve Versus Dose Emax Models for Mepolizumab or Reslizumab | 10840 Percentage change from baseline * day |
| Arm B: Mepolizumab Low Intermediate Dose | Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Area Under the Effect Curve Versus Dose Emax Models for Mepolizumab or Reslizumab | 10446 Percentage change from baseline * day |
Secondary
Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Maximum Change From Baseline Versus Dose Emax Models With Mepolizumab or Reslizumab
The model parameter (Emax, units percentage change from baseline) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Time frame: Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.
Population: Analysis population for each group was limited to those subjects administered mepolizumab or placebo (the mepolizumab group) or administered reslizumab or placebo (reslizumab) who completed the study. Results from subjects administered placebo were used in all analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Mepolizumab Low Dose | Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Maximum Change From Baseline Versus Dose Emax Models With Mepolizumab or Reslizumab | 85 Percentage change from baseline |
| Arm B: Mepolizumab Low Intermediate Dose | Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Maximum Change From Baseline Versus Dose Emax Models With Mepolizumab or Reslizumab | 86 Percentage change from baseline |