First Time in Human (FTIH) Study to Evaluate Safety, Tolerability, Immunogenicity, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK3511294 Administered Subcutaneously (SC) in Subjects With Mild to Moderate Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: GSK3511294; Placebo; Salbutamol/albuterol
Intervention description: GSK3511294 will be available as a clear or opalescent, colorless or yellow to brown solution for injection at unit dose strength of 150 milligrams per milliliter (mg/mL). GSK3511294 will be diluted in 0.9% weight by volume (w/v) sodium chloride to achieve the desired concentration for administration. GSK3511294 will be administered by SC injection.; Matching Placebo will consist of 0.9% w/v sodium chloride which will be administered by the SC route.; Salbutamol/albuterol will be supplied to all subjects for use as rescue medication during the study.
Intervention MeSH terms: Albuterol
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a multi-center, double-blind study in which subjects will be allocated to five cohorts. The subjects in each cohort will be randomized to receive GSK3511294 and placebo in a ratio of 3:1. In each cohort, dosing will be staggered: one subject will receive GSK3511294 and one subject will receive placebo at least 72 hours before the remaining subjects in that cohort are dosed. The remaining subjects will be dosed if the review of all safety data up to 72 hours after dosing of the first two subjects in each cohort is satisfactory.
Masking: Double (Participant, Investigator)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: eosinophils; pharmacokinetics; First time in Human; GSK3511294; pharmacodynamics; asthma

Summary:

      GSK3511294 is a humanized monoclonal antibody antagonist of Interleukin (IL)-5 which is known
      to block binding of IL-5 to the IL-5 receptor complex, causing a reduction in the circulating
      population of eosinophils. This is a single ascending dose FTIH study to investigate safety,
      tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK3511294,
      administered SC in subjects with mild to moderate asthma maintained on a low-medium daily
      dose of inhaled corticosteroids (ICS) or ICS/long acting beta-agonist (LABA), and short
      acting beta-agonist (SABA). The subjects will attend a pre-screen visit of up to 12 weeks
      before dosing for assessment of blood eosinophils. Eligible subjects with blood eosinophils
      >=200 cells per microliter (cells/µL) will undergo a screening period of up to 4 weeks. The
      subjects will then be randomized into 5 cohorts. In each cohort, the subjects will be
      randomized to receive a single dose of GSK3511294 or placebo in a ratio of 3:1. The follow-up
      period will be up to 40 weeks post dose and will be dose-dependent. The scheduled maximum
      duration for each subject will be up to 44 weeks including up to 28 days of screening.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects should be between 18 and 65 years of age inclusive, at the time of signing
             the informed consent.

          -  Blood eosinophils of >= 200 cells/µL at screening.

          -  A physician diagnosis of asthma (mild or moderate, as defined by the Global Initiative
             for Asthma [GINA], 2017) at least 12 months prior to the start of the study. The
             reason for diagnosis of asthma should be documented in the subject's source data,
             including relevant history and investigations - specifically evidence of airway
             hyper-responsiveness, airflow variation (peak flow rate or forced expiratory volume in
             one second [FEV1]) or reversible airflow obstruction should also be documented in the
             subject's source data.

          -  A screening pre-bronchodilator FEV1 >= 60% of predicted normal value.

          -  Asthma Control Test score > 19.

          -  hsCRP of < 10 milligrams per liter (mg/L) at screening.

          -  Otherwise healthy (other than the acceptable conditions of asthma and other atopic
             diseases, including allergic rhinitis and atopic dermatitis) based on a screening
             medical history, physical examination, vital signs, ECG assessment, pulmonary function
             testing, and clinical laboratory results.

          -  Maintained controlled on as needed SABA and one of the following: a) stable dose of
             ICS; b) stable dose of combination therapy: ICS/LABA.

          -  Body weight >= 50 kilograms (kg), and body mass index (BMI) of 19-32 kilograms per
             square meter (kg/m^2) inclusive.

          -  Male and female subjects. a) a female subject is eligible to participate if she is not
             pregnant, not breastfeeding, and not a woman of childbearing potential. b) as
             GSK3511294 is a monoclonal antibody that is not anticipated to interact directly with
             Deoxyribonucleic acid (DNA) or other chromosomal material with minimal exposure
             through semen expected, male subjects will not be required to use contraception during
             the study, nor are they prohibited from donating sperm.

          -  Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions of the study.

        Exclusion Criteria:

          -  Any asthma exacerbation requiring systemic corticosteroids within 12 weeks of
             screening, or that resulted in overnight hospitalization requiring additional
             treatment for asthma within 6 months prior to screening.

          -  A history of life-threatening asthma defined as an asthma episode that required
             intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic
             seizures within the last 5 years.

          -  Significant pulmonary diseases, other than asthma, including (but not limited to):
             pneumonia previously requiring hospital admission, pulmonary fibrosis,
             bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive
             pulmonary disease, or other significant respiratory abnormalities.

          -  Suspected or confirmed bacterial or viral infection (including tuberculosis) of the
             upper or lower respiratory tract, sinus or middle ear that occurred within and/or has
             not resolved within 4 weeks of screening that: led to a change in asthma management or
             in the opinion of the Investigator, is expected to affect the subject's asthma status
             or the subject's ability to participate in the study.

          -  Positive for hepatitis B surface antigen (HBsAg) at screening.

          -  Positive hepatitis C antibody test result at screening, or within 3 months prior to
             first dose of study treatment.

          -  Known immunodeficiency (other than that explained by the use of corticosteroids),
             including a positive test for human immunodeficiency virus (HIV) antibody at
             screening.

          -  Latent or chronic infections (example, genital herpes, urinary tract infections) or at
             risk of infection (example, significant trauma or infection within the 90 days before
             screening).

          -  Opportunistic infection within 6 months prior to screening (example, a non-tuberculous
             mycobacterial infection or cytomegalovirus, pneumocystosis, aspergillosis).

          -  Parasitic infestation within 6 months prior to screening, or have travelled to a
             country with a high prevalence of such infections in the 6 months before screening, or
             intend to do so in the year after dosing.

          -  Live vaccine within 4 weeks prior to screening, or intention to receive live vaccine
             during the study.

          -  Corrected QT by Fridericia's formula (QTcF) interval > 450 milliseconds (msec)

          -  A personal history of severe hypertension, arrhythmia, Right Bundle Branch Block, or
             Left Bundle Branch Block, or a family history of sudden unexplained death, long QT,
             familial cardiac syndrome, or cardiomyopathy.

          -  ALT >1.5 times upper limit of normal (ULN).

          -  Bilirubin >1.5 times ULN. Isolated bilirubin >1.5 times ULN is acceptable if bilirubin
             is fractionated and direct bilirubin <35%.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Any history or presence of clinically relevant cardiac or cardiovascular,
             gastrointestinal, hepatic, renal, metabolic, hematological, neurological,
             osteomuscular, articular, psychiatric, systemic, ocular, or infectious disease or
             immunodeficiency, or signs of acute illness, or any other illness or condition that,
             in the opinion of the investigator (in consultation with the medical monitor), would
             adversely affect the subject's participation in this study.

          -  A previous history of cancer in remission for less than 5 years prior to screening
             (except for localized carcinoma of the skin that had been resected for cure) or
             current malignancy.

          -  A positive drug/alcohol test before dosing, OR any history of drug abuse OR regular
             alcohol consumption within 6 months of the study defined as: An average weekly intake
             of > 14 units alcohol. One unit is equivalent to 8 grams (g) of alcohol: a half-pint
             (equivalent to 240 milliliters [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL)
             measure of spirits.

          -  Current smokers or ex-smokers who have given up smoking for < 12 months and/or have a
             smoking pack history of > 5 pack years (1 pack year = 20 cigarettes per day for 1 year
             or 5 cigarettes per day for 4 years).

          -  Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or
             nicotine-containing products within 6 months prior to screening.

          -  Anticipated non-availability and/or risk of non-compliance with study visits and
             procedures, or unwillingness or inability to follow the study specific procedures.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dosing day in the current
             study: 3 months, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Exposure to more than 4 investigational medicinal products within 12 months prior to
             the first dosing day.

          -  History of sensitivity to any of the study medications, or its components, or a
             history of drug reaction or other allergy that, in the opinion of the investigator or
             Medical Monitor, contraindicates their participation.

          -  Major surgery within 90 days prior to screening, or planned in-patient surgery or
             hospitalization during the study period

          -  Donation or loss of blood or blood products in excess of 500 mL within the 3 months
             before dosing.

          -  History of renal disease, abnormal kidney function or evidence of persisting or
             clinically relevant protein or blood on urinalysis.

          -  History or signs of immunologically active disease (including the presence of low C3
             or low C4) or thrombocytopenia.

          -  History of vasculitis.

          -  Subjects are excluded if they are undergoing desensitization therapy, or have received
             any of the following medications as indicated prior to screening: anti- Immunoglobulin
             E (IgE) therapy (within 6 months); anti-IL5 (within 6 months); oral or injectable
             corticosteroids (within 8 weeks); long acting muscarinic antagonist (LAMA) or
             leukotriene receptor antagonist (LTRA) therapy (within 8 weeks); drugs that can
             prolong the QT interval.

          -  Subjects who are employees of the sponsor or clinical unit are excluded.

          -  Vulnerable subjects, e.g., participants kept in detention, protected adults under
             guardianship, trusteeship and soldiers, or participants committed to an institution by
             governmental or juridical order.