Pharmacodynamic Biomarkers to Support Biosimilar Development: Interleukin-5 Antagonists

• ClinicalTrials.gov Identifier: NCT04183192
• Recruitment Status: Completed
• First Posted: December 3, 2019
• Last Update Posted: August 23, 2021
• Sponsor: Food and Drug Administration (FDA)
• Collaborator: Spaulding Clinical Research LLC
• Information provided by (Responsible Party): Food and Drug Administration (FDA)

Tracking Information

• First Submitted Date: November 27, 2019
• First Posted Date: December 3, 2019
• Last Update Posted Date: August 23, 2021
• Actual Study Start Date: February 17, 2020
• Actual Primary Completion Date: April 4, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 27, 2019)

Area under effect curve and maximum change from baseline for eosinophils for mepolizumab and reslizumab [ Time Frame: 63 or 123 days, depending on treatment arm ]

1. The values and variability of standard pharmacodynamic metrics (AUEC and maximal difference at a single time-point) for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 27, 2019)

• Maximum concentration and area under the curve for mepolizumab and reslizumab [ Time Frame: 63 or 123 days, depending on treatment arm ]
  1. The values and variability of pharmacokinetic characteristics (Cmax and area under the curve of free drug concentration) at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab.
• Pharmacodynamic model parameters for mepolizumab and reslizumab [ Time Frame: 63 or 123 days, depending on treatment arm ]
  2. Parameters (Emax, and EC50) calculated by the model after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pharmacodynamic Biomarkers to Support Biosimilar Development: Interleukin-5 Antagonists
• Official Title: Pharmacodynamic Biomarkers to Support Biosimilar Development: Clinical Study 1: Interleukin-5 Antagonists - Mepolizumab and Reslizumab

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.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
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

Masking: Double (Participant, 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.

Primary Purpose: Other

Condition

• Healthy Subjects
• Pharmacokinetics
• Pharmacodynamics

Intervention

• Biological: Mepolizumab
  Mepolizumab 3 mg administered SC
• Biological: Mepolizumab
  Mepolizumab 6 mg administered SC
• Biological: Mepolizumab
  Mepolizumab 12 mg administered SC
• Biological: Mepolizumab
  Mepolizumab 24 mg administered SC
• Biological: Reslizumab
  Reslizumab 0.1 mg/kg administered IV
• Biological: Reslizumab
  Reslizumab 0.2 mg/kg administered IV
• Biological: Reslizumab
  Reslizumab 0.4 mg/kg administered IV
• Biological: Reslizumab
  Reslizumab 0.8 mg/kg administered IV
• Biological: Placebo
  Placebo (administered either IV or SC)

Study Arms

• Experimental: Arm A: Mepolizumab low dose
  Single dose of mepolizumab 3 mg SC
  Intervention: Biological: Mepolizumab
• Experimental: Arm B: Mepolizumab low intermediate dose
  Single dose of mepolizumab 6 mg SC
  Intervention: Biological: Mepolizumab
• Experimental: Arm C: Mepolizumab high intermediate dose
  Single dose of mepolizumab 12 mg SC
  Intervention: Biological: Mepolizumab
• Experimental: Arm D: Mepolizumab high dose
  Single dose of mepolizumab 24 mg SC
  Intervention: Biological: Mepolizumab
• Experimental: Arm E: Reslizumab low dose
  Single dose of reslizumab 0.1 mg/kg IV
  Intervention: Biological: Reslizumab
• Experimental: Arm F: Reslizumab intermediate low dose
  Single dose of reslizumab 0.2 mg/kg IV
  Intervention: Biological: Reslizumab
• Experimental: Arm G: Reslizumab high intermediate dose
  Single dose of reslizumab 0.4 mg/kg IV
  Intervention: Biological: Reslizumab
• Experimental: Arm H: Reslizumab high dose
  Single dose of reslizumab 0.8 mg/kg IV
  Intervention: Biological: Reslizumab
• Placebo Comparator: Arm I: Placebo
  Single dose of placebo
  Intervention: Biological: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 27, 2019): 72
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: April 4, 2021
• Actual Primary Completion Date: April 4, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04183192
• Other Study ID Numbers: SCR-006
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Plan is to make data from the study publicly available as a part of manuscript publication. In addition, the protocol and statistical analysis plan will be made available online at this site as well as any eventual publications.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: April, 2022. Materials will be available indefinitely.

• Current Responsible Party: Food and Drug Administration (FDA)
• Original Responsible Party: Same as current
• Current Study Sponsor: Food and Drug Administration (FDA)
• Original Study Sponsor: Same as current
• Collaborators: Spaulding Clinical Research LLC

Investigators

• Principal Investigator: Jennifer Deering, MSN, APNP; Spaulding Clinical Research LLC

• PRS Account: Food and Drug Administration (FDA)
• Verification Date: August 2021