Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Pharmacodynamic Biomarkers to Support Biosimilar Development: PCSK9 Inhibitors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04189484
Recruitment Status : Recruiting
First Posted : December 6, 2019
Last Update Posted : January 12, 2021
Sponsor:
Collaborator:
Spaulding Clinical Research LLC
Information provided by (Responsible Party):
Food and Drug Administration (FDA)

Brief Summary:

This study is designed to assess pharmacokinetics and pharmacodynamics of evolocumab and alirocumab 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 (evolocumab and alirocumab ) or placebo.


Condition or disease Intervention/treatment Phase
Healthy Subjects Pharmacokinetics Pharmacodynamics Biological: Evolocumab Biological: Alirocumab Biological: Placebo Phase 1

Detailed Description:

This study is designed to assess pharmacokinetics and pharmacodynamics of evolocumab and alirocumab, two monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), 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 (evolocumab or alirocumab) or placebo. Evolocumab doses are 21, 35, 70, and 140 mg. Reslizumab doses are 15, 25, 50, and 100 mg . 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 one week and continue follow-up through day 42, 56, or 84.

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 lipid analysis and determination of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) (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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
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 (evolocumab or alirocumab) 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. 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 subcutaneous study drug in unit dose containers that are not transparent.

Primary Purpose: Other
Official Title: Pharmacodynamic Biomarkers to Support Biosimilar Development: Clinical Study 2: PCSK9 Inhibitors - Alirocumab and Evolocumab
Actual Study Start Date : January 6, 2020
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : April 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Evolocumab

Arm Intervention/treatment
Experimental: Arm A: Evolocumab low dose
Single dose of evolocumab 21 mg subcutaneous (SC)
Biological: Evolocumab
Evolocumab 21 mg administered SC

Experimental: Arm B: Evolocumab intermediate low dose
Single dose of evolocumab 35 mg SC
Biological: Evolocumab
Evolocumab 35 mg administered SC

Experimental: Arm C: Evolocumab intermediate high dose
Single dose of evolocumab 70 mg SC
Biological: Evolocumab
Evolocumab 70 mg administered SC

Experimental: Arm D: Evolocumab high dose
Single dose of evolocumab 140 mg SC
Biological: Evolocumab
Evolocumab 140 mg administered SC

Experimental: Arm E: Alirocumab low dose
Single dose of alirocumab 15 mg SC
Biological: Alirocumab
Alirocumab 15 mg administered SC

Experimental: Arm F: Alirocumab intermediate low dose
Single dose of alirocumab 25 mg SC
Biological: Alirocumab
Alirocumab 25 mg administered SC

Experimental: Arm G: Alirocumab intermediate high dose
Single dose of alirocumab 50 mg SC
Biological: Alirocumab
Alirocumab 50 mg administered SC

Experimental: Arm H: Alirocumab high dose
Single dose of alirocumab 100 mg SC
Biological: Alirocumab
Alirocumab 100 mg administered SC

Placebo Comparator: Arm I: Placebo
Single dose of placebo SC
Biological: Placebo
Placebo administered SC




Primary Outcome Measures :
  1. Area under effect curve (AUEC) for LDL-C for evolocumab and alirocumab [ Time Frame: 42, 56, or 84 days, depending on treatment arm ]
    The values and variability of AUEC for LDL-C at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab

  2. Maximum change from baseline for LDL-C for evolocumab and alirocumab [ Time Frame: 42, 56, or 84 days, depending on treatment arm ]
    The values and variability of maximum change from baseline for LDL-C at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab


Secondary Outcome Measures :
  1. AUEC for Apolipoprotein B (ApoB) for evolocumab and alirocumab [ Time Frame: 42, 56, or 84 days, depending on treatment arm ]
    The values and variability of AUEC for ApoB at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab

  2. Maximum change from baseline for apoB for evolocumab and alirocumab [ Time Frame: 42, 56, or 84 days, depending on treatment arm ]
    The values and variability of maximal difference at a single time-point for ApoB at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab

  3. Maximum concentration (Cmax) for evolocumab and alirocumab [ Time Frame: 42, 56, or 84 days, depending on treatment arm ]
    The values and variability of Cmax at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab

  4. Area under the curve (AUC) for evolocumab and alirocumab [ Time Frame: 42, 56, or 84 days, depending on treatment arm ]
    The values and variability of AUC at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab

  5. Pharmacodynamic model parameters (maximum effect [Emax]) for evolocumab and alirocumab [ Time Frame: 42, 56, or 84 days, depending on treatment arm ]
    Model parameters (Emax) calculated after combining data from low, intermediate low, intermediate high, and high doses of evolocumab or alirocumab with placebo data.

  6. Pharmacodynamic model parameters (half maximum effect concentration [EC50]) for evolocumab and alirocumab [ Time Frame: 42, 56, or 84 days, depending on treatment arm ]
    Model parameters (EC50) calculated after combining data from low, intermediate low, intermediate high, and high doses of evolocumab or alirocumab with placebo data.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Subject signs an institutional review board (IRB)-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 32 kg/m2, inclusive, at Screening.
  3. Subject has a LDL-C level >=100 and <=190 mg/dL inclusive, at Screening.
  4. 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).
  5. Subject must have a negative test result for alcohol and drugs of abuse at screening and Check-in (Day -1).
  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 1 month 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 last application of study drug.
  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 last application of study drug.
  8. Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures as to complete the study.

Exclusion Criteria:

  1. Subject is taking cholesterol medication (e.g. statins).
  2. Subject is anemic (i.e., with hematocrit or hemoglobin 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 evolocumab or alirocumab.
  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 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.
  9. 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.
  10. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening.
  11. 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.
  12. 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 (BMI of 40 or higher)
    • People with diabetes
    • People with chronic kidney disease undergoing dialysis
    • People with liver disease
  13. 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.
  14. Subject tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by a molecular diagnostic test performed prior to admission.
  15. Subject has known or suspected allergies or sensitivities to any study drug.
  16. Subject has clinical laboratory test results (hematology, serum chemistry lipid panel and comprehensive metabolic panel) at Screening that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator.
  17. Subject has a positive test result at Screening for human immunodeficiency virus (HIV) 1 or 2 antibody, hepatitis C virus load, hepatitis C virus antibodies, or hepatitis B surface antigen.
  18. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access.
  19. Female subjects are pregnant or lactating before enrollment in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04189484


Contacts
Layout table for location contacts
Contact: Jennifer Nehls 608.320.4075 Jennifer.nehls@spauldingclinical.com

Locations
Layout table for location information
United States, Wisconsin
Spaulding Clinical Research Recruiting
West Bend, Wisconsin, United States, 53095
Contact: Jennifer Nehls    608-320-4075    Jennifer.nehls@spauldingclinical.com   
Sponsors and Collaborators
Food and Drug Administration (FDA)
Spaulding Clinical Research LLC
Investigators
Layout table for investigator information
Principal Investigator: Colleen Nalepinski, MPAS, PA-C Spaulding Clinical Research LLC
Layout table for additonal information
Responsible Party: Food and Drug Administration (FDA)
ClinicalTrials.gov Identifier: NCT04189484    
Other Study ID Numbers: SCR-007
First Posted: December 6, 2019    Key Record Dates
Last Update Posted: January 12, 2021
Last Verified: January 2021
Individual Participant Data (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
Statistical Analysis Plan (SAP)
Time Frame: April, 2022. Materials will be available indefinitely

Layout table for additional information
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
Keywords provided by Food and Drug Administration (FDA):
Pharmacokinetics
Pharmacodynamics
Additional relevant MeSH terms:
Layout table for MeSH terms
Evolocumab
Antibodies, Monoclonal
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Immunologic Factors
Physiological Effects of Drugs