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Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK2831781 After an Intravenous (IV) Dose in Healthy Japanese and Caucasian Subjects, and a Subcutaneous (SC) Dose in Healthy Caucasian Subjects

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ClinicalTrials.gov Identifier: NCT03965533
Recruitment Status : Completed
First Posted : May 29, 2019
Last Update Posted : February 12, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE May 24, 2019
First Posted Date  ICMJE May 29, 2019
Last Update Posted Date February 12, 2020
Actual Study Start Date  ICMJE June 10, 2019
Actual Primary Completion Date December 10, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 10, 2020)
  • Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 113 days ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization or is a congenital abnormality/birth defect.
  • Number of subjects with abnormal vital signs [ Time Frame: Up to 113 days ]
    Vital signs will be measured in a semi-supine position after 5 minutes rest and will include temperature, systolic, diastolic blood pressure and pulse rate.
  • Number of subjects with abnormal hematology parameters [ Time Frame: Up to 113 days ]
    Blood samples will be collected to measure hematological parameters such as platelet count, red blood cell (RBC) count, white blood cell (WBC) count, hemoglobin, hematocrit, Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), percentage of reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
  • Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to 113 days ]
    Blood samples will be collected to measure clinical chemistry parameters such as blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), glucose (non-fasting), potassium, sodium, calcium, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline phosphatase, Total and direct bilirubin and total protein.
  • Number of subjects with abnormal urinalysis [ Time Frame: Up to 113 days ]
    Urine samples will be collected to measure specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick method and microscopic examination (if blood or protein is abnormal).
  • Number of subjects with abnormal electrocardiogram (ECG) values [ Time Frame: Up to 113 days ]
    Single 12-lead ECG will be obtained in a semi-supine position, after 5 minutes rest using an automated ECG machine and PR, QRS, QT, and corrected QT (QTc) intervals will be measured.
  • Number of subjects with infusion site reaction in Part A [ Time Frame: Pre-dose and 2, 6, 12 and 24 hours post dose ]
    Local tolerability will be assessed in subjects post GSK2831781 Dose-1 IV infusion at indicated time points.
  • Number of subjects with injection site reaction in Part B [ Time Frame: Pre-dose and 2, 4, 6, 12 and 24 hours and at Days 2, 4 and 8 post dose ]
    Local tolerability will be assessed in subjects post GSK2831781 Dose-2 SC injection at indicated time points.
Original Primary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 113 days ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization or is a congenital abnormality/birth defect.
  • Number of subjects with abnormal vital signs [ Time Frame: Up to 113 days ]
    Vital signs will be measured in a semi-supine position after 5 minutes rest and will include temperature, systolic, diastolic blood pressure and pulse rate.
  • Number of subjects with abnormal hematology parameters [ Time Frame: Up to 113 days ]
    Blood samples will be collected to measure hematological parameters such as platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), percentage of reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
  • Number of subjects with abnormal clinical chemistry parameters [ Time Frame: Up to 113 days ]
    Blood samples will be collected to measure clinical chemistry parameters such as blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), glucose (non-fasting), potassium, sodium, calcium, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline phosphatase, Total and direct bilirubin and total protein.
  • Number of subjects with abnormal urinalysis [ Time Frame: Up to 113 days ]
    Urine samples will be collected to measure specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick method and microscopic examination (if blood or protein is abnormal).
  • Number of subjects with abnormal electrocardiogram (ECG) values [ Time Frame: Up to 113 days ]
    Single 12-lead ECG will be obtained in a semi-supine position, after 5 minutes rest using an automated ECG machine and PR, QRS, QT, and corrected QT (QTc) intervals will be measured.
  • Number of subjects with infusion site reaction in Part A [ Time Frame: Pre-dose and 2, 6, 12 and 24 hours post dose ]
    Local tolerability will be assessed in subjects post GSK2831781 Dose-1 IV infusion at indicated time points.
  • Number of subjects with injection site reaction in Part B [ Time Frame: Pre-dose and 2, 4, 6, 12 and 24 hours and at Days 2, 4 and 8 post dose ]
    Local tolerability will be assessed in subjects post GSK2831781 Dose-2 SC injection at indicated time points.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Area under the concentration-time curve from time 0 to t [AUC(0-t)] of GSK2831781 in Part A [ Time Frame: Pre-dose, 1, 2, 6, 12, 24 hours on Day 1; Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Maximum observed plasma concentration (Cmax) of GSK2831781 in Part A [ Time Frame: Pre-dose, 1, 2, 6, 12, 24 hours on Day 1; Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Time of occurrence of Cmax (tmax) of GSK2831781 in Part A [ Time Frame: Pre-dose, 1, 2, 6, 12, 24 hours on Day 1; Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • AUC(0-t) of GSK2831781 in Part B [ Time Frame: Pre-dose and on Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Cmax of GSK2831781 in Part B [ Time Frame: Pre-dose and on Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Tmax of GSK2831781 in Part B [ Time Frame: Pre-dose and on Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • Bioavailability (F) of GSK2831781 in Part B [ Time Frame: Pre-dose and on Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112 post dose ]
    Blood samples for PK analysis will be collected at the indicated time points.
  • PK/PD relationship between plasma PK of GSK2831781 and LAG3+ T cells in blood over time [ Time Frame: Up to 113 days ]
    A population PK/PD analysis will be performed based on the safety population. This will investigate PK, Soluble LAG3 (sLAG3) and cell depletion data.
  • Anti-drug antibodies (ADAs) to GSK2831781 over time [ Time Frame: Up to 113 days ]
    Serum samples will be collected from all subjects to evaluate the presence of ADA using a tiered approach.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK2831781 After an Intravenous (IV) Dose in Healthy Japanese and Caucasian Subjects, and a Subcutaneous (SC) Dose in Healthy Caucasian Subjects
Official Title  ICMJE A Randomised, Double-blind, Placebo-controlled Phase I Study of the Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Intravenous Dose of GSK2831781 in Healthy Japanese and Caucasian Participants, and a Single Subcutaneous Dose of GSK2831781 in Healthy Caucasian Participants
Brief Summary This is a double-blind, placebo-controlled, randomized, parallel group, two-part study where single IV doses of GSK2831781 will be administered to healthy Japanese and Caucasian subjects in part A and SC doses will be administered to healthy Caucasian subjects in part B. GSK2831781 is a humanized, antibody-dependent cell cytotoxicity (ADCC) enhanced depleting monoclonal antibody that is specific to the lymphocyte activation gene-3 (LAG3) protein. LAG3 is a transmembrane receptor, which is upregulated on T cells following activation. The objective of the study is to assess the safety, tolerability, PK, PD and immunogenicity post administration of GSK2831781 in healthy subjects. The duration of the study is approximately 147 days for each subject enrolled. Approximately 36 subjects will be enrolled in the study, 16 subjects in Part A and 20 subjects in Part B.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Healthy Volunteers
Intervention  ICMJE
  • Drug: GSK2831781
    GSK2831781 will be available as Dose-1 and Dose-2 as IV infusion or SC injection. Subjects will receive GSK2831781 Dose-1 IV diluted in 0.9% saline or GSK2831781 SC as multiples of Dose-2 SC.
  • Drug: Placebo
    Placebo will be 0.9% saline solution which will be administered in subjects as IV infusion or SC injection.
Study Arms  ICMJE
  • Experimental: Subjects receiving GSK2831781 in Part A
    Subjects will be administered with Dose-1 IV of GSK2831781 as an infusion in both healthy Japanese and Caucasian groups.
    Intervention: Drug: GSK2831781
  • Placebo Comparator: Subjects receiving placebo-Part A
    Subjects randomized into healthy Japanese and Caucasian groups will be administered with matching placebo to GSK2831781 Dose-1 IV infusion.
    Intervention: Drug: Placebo
  • Experimental: Subjects receiving GSK2831781- Part B
    Healthy Caucasian subjects will be administered with GSK2831781 Dose-2 SC injection or Dose-1 SC injection.
    Intervention: Drug: GSK2831781
  • Placebo Comparator: Subjects receiving placebo in Part B
    Healthy Caucasian subjects will be randomized to receive masked placebo of either Dose-1 or dose-2 SC injection.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 8, 2020)
37
Original Estimated Enrollment  ICMJE
 (submitted: May 24, 2019)
36
Actual Study Completion Date  ICMJE December 10, 2019
Actual Primary Completion Date December 10, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and 12-lead ECGs. A subject with a clinical abnormality or laboratory parameter(s) outside the reference range for the population being studied that is not specifically listed in the inclusion or exclusion criteria may be included if the Investigator (in consultation with the Medical Monitor if required) agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or interpretation.
  • Between 18 and 65 years of age inclusive, at the time of signing the informed consent.
  • Body weight >=40 kilogram (kg) and body mass index (BMI) <=30 kilogram per meter square (kg/m^2).
  • Male.
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • Japanese ancestry, defined as having been born in Japan, being descendants of four ethnic Japanese grandparents and two ethnic Japanese parents, holding a Japanese passport or identity papers, and being able to speak Japanese. Subjects should have lived outside Japan for less than 10 years at the time of screening.
  • Caucasian ancestry, defined as Caucasian descent as evidenced by appearance and verbal confirmation of familial heritage (a subject has 2 Caucasian parents and 4 Caucasian grandparents).

Exclusion Criteria:

  • History or presence of a disease that in the opinion of the investigator constitutes a risk when taking the study intervention or interfering with study assessment or interpretation of the data.
  • A medical history of severe allergic reaction, angioedema, anaphylaxis, clinically significant drug hypersensitivity reaction, or autoimmune or immunodeficiency disorder.
  • An active infection or a history of serious infections as follows:

    1. Use of antimicrobials (antibacterials, antivirals, antifungals or antiparasitic agents) for an infection within 30 days before first dose. Topical treatments may be allowed at the Medical Monitor's discretion.
    2. A history of opportunistic infections.
    3. Recurrent or chronic infection, or other active infection, that in the opinion of the Investigator might cause this study to be detrimental to the subject.
    4. Symptomatic herpes zoster within 3 months prior to screening.
    5. History of tuberculosis (TB) (active or latent) irrespective of treatment status.
    6. A positive diagnostic TB test at screening (defined as a positive QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the subject may have the test repeated once and if their second test is negative they will be eligible. In the event a second test is also indeterminate, the investigator has the option to undertake purified protein derivative (PPD) testing. If the PPD reaction is <5 millimeter (mm) at 48 to 72 hours, then the subject is eligible. If the reaction is >=5 mm, or PPD testing is not undertaken, the subject is not eligible.
  • Any planned major surgical procedure during the study.
  • A history of malignant neoplasm within the last 10 years, except for fully treated nonmetastatic basal or squamous cell cancers of the skin (within 3 years) that shows no evidence of recurrence.
  • Use of prescription or non-prescription drugs (including recreational drugs and herbal medications) within 7 days or 5 half-lives (whichever is longer) prior to dosing, unless in the opinion of the investigator, the medication will not interfere with the study or compromise subject safety. Paracetamol (acetaminophen) at doses of <=4 grams per day, and occasional use of non-steroidal anti-inflammatory drugs (NSAIDs) at licensed doses, are permitted.
  • Received live vaccination within 4 weeks of Day 1, or plan to receive a live vaccination during the study until follow-up.
  • Previous exposure to GSK2831781, or hypersensitivity to any excipients in the clinical formulation of GSK2831781.
  • Treatment with biologic agents (such as monoclonal antibodies) within 3 months or 5 half-lives (whichever is longer) prior to dosing.
  • Participation in a clinical trial and has received an investigational medicinal product (IMP) within the following time period prior to screening in the current study: 3 months, 5 half-lives, or twice the duration of the biological effect of the IMP (whichever is longer).
  • Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
  • Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 3 months.
  • Neutrophil or lymphocyte counts below the normal range.
  • eGFR by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) calculation <=90 milliliter per minute per 1.73 meter square (mL/min/1.73m^2) at screening.
  • ALT >2x upper limit of normal (ULN) and bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening.
  • Other clinically significant abnormalities of laboratory assessments, as judged by the Investigator and/or GSK Medical Monitor, that could affect the safety of the subject, or the interpretation of the data from the study.
  • Presence of hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb), or positive hepatitis C antibody result at screening (Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C ribonucleic acid [RNA] test is obtained).
  • Positive serology for human immunodeficiency virus (HIV) at screening.
  • Positive pre-study drug/alcohol screen.
  • QTc >450 millisecond (msec), based on the mean of triplicate ECGs. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF; preferred method), or another method, machine or overread.
  • History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units. One unit is equivalent to 8 grams (g) of alcohol: a halfpint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
  • Unstable lifestyle factors, to the extent that in the opinion of the investigator they would interfere with the ability of a subject to complete the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Gender Eligibility Description: Male subjects will be included in the study
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03965533
Other Study ID Numbers  ICMJE 207823
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP