Phase 1
Completed N=48
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
Source: ClinicalTrials.gov NCT03287310 ↗Enrolled (actual)
48
Serious AEs
0.0%
Results posted
Mar 2021
Primary outcomePrimary: Number of Participants With Adverse Events (AEs) and Serious AEs (SAE) — 11; 2; 6; 8 Participants
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Adverse Events (AEs) and Serious AEs (SAE) |
11; 2; 6; 8; 9; 4 | — |
| PRIMARY Number of Participants With Adverse Events of Special Interest (AESI) |
0; 0; 0; 1; 0; 0 | — |
| PRIMARY Change From Baseline in Neutrophil, Lymphocyte, Monocyte, Eosinophil, Basophil and Platelet Count |
-0.006; -0.020; 0.003; -0.003; 0.001; -0.018 | — |
| PRIMARY Change From Baseline in Red Blood Cell Count (RBC) |
-0.08; -0.07; 0.08; 0.00; 0.16; 0.05 | — |
| PRIMARY Change From Baseline in Mean Corpuscle Volume (MCV) |
0.2; 0.2; 0.2; 0.1; -0.3; 1.3 | — |
| PRIMARY Change From Baseline in Mean Corpuscle Hemoglobin (MCH) |
0.03; 0.23; 0.02; -0.04; -0.02; -0.07 | — |
| PRIMARY Change From Baseline in Hemoglobin |
-2.4; 0.3; 3.7; -0.4; 4.3; 0.2 | — |
| PRIMARY Change From Baseline in Hematocrit |
-0.007; -0.001; 0.009; 0.000; 0.011; 0.007 | — |
| PRIMARY Change From Baseline in Clinical Chemistry Parameter: High Sensitivity C-reactive Protein (hsCRP) |
-0.3443; -0.1217; -0.7367; -0.3178; -1.0956; -0.4867 | — |
| PRIMARY Change From Baseline in Clinical Chemistry Parameter of Total Protein and Albumin |
-2.8; -2.3; -0.6; -3.8; 0.7; -0.2 | — |
| PRIMARY Change From Baseline in Clinical Chemistry Parameters Like Total Bilirubin, Direct Bilirubin and Creatinine |
-0.8; -1.3; -1.6; -0.2; 0.0; 1.0 | — |
| PRIMARY Urine Specific Gravity Analysis by Dipstick Method |
1.0200; 1.0125; 1.0120; 1.0265; 1.0280; 1.0150 | — |
| PRIMARY Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) |
-0.3; -2.2; 3.3; -0.9; -1.8; -2.0 | — |
| PRIMARY Change From Baseline in Temperature |
0.05; 0.32; 0.13; 0.30; 0.03; 0.00 | — |
| PRIMARY Change From Baseline in Heart Rate |
2.2; -4.2; -3.3; 0.8; 0.9; 5.2 | — |
| PRIMARY Change From Baseline in Respiration Rate |
0.8; 1.2; 0.0; 0.3; 0.8; 2.2 | — |
| PRIMARY Change From Baseline in Heart Rate: Electrocardiogram (ECG) |
1.4; -4.3; -4.6; 0.2; 0.3; 6.8 | — |
| PRIMARY Change From Baseline in PR Interval, QRS Interval, QT Interval and QT Interval Corrected by Fridericia's Formula (QTcF) Interval |
-4.5; 3.9; 3.5; -4.3; 3.7; -7.5 | — |
| PRIMARY Change From Baseline in Clinical Chemistry Parameters Like Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) |
-0.3; 0.3; 4.0; -1.6; -0.1; -0.7 | — |
| PRIMARY Change From Baseline in Clinical Chemistry Parameter Like Glucose, Calcium, Potassium, Sodium, Blood Urea Nitrogen (BUN), and Magnesium |
0.06; -0.13; 0.14; -0.11; -0.72; 0.20 | — |
| PRIMARY Number of Participants With Presence of Ketones, Glucose, Occult Blood, and Protein |
1; 0; 0; 0; 0; 1 | — |
| PRIMARY Urine Potential of Hydrogen (pH) Analysis by Dipstick Method |
5.00; 7.00; 6.50; 6.00; 5.00; 6.50 | — |
| PRIMARY Absolute Values of Complement (C)3 and C4 |
1.149; 1.182; 1.086; 1.074; 1.137; 1.254 | — |
| SECONDARY Area Under the Curve From Time Zero to Infinity (AUC[0-inf]) of GSK3511294 2 mg and 10 mg |
24.795; 68.904 | — |
| SECONDARY AUC(0-inf) of GSK3511294 30 mg and 100 mg |
208.308; 846.686 | — |
| SECONDARY AUC(0-inf) of GSK3511294 300 mg |
1873.657 | — |
| SECONDARY Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC[0-t]) of GSK3511294 2 mg and 10 mg |
18.369; 62.101 | — |
| SECONDARY AUC(0-t) of GSK3511294 30 mg and 100 mg |
201.434; 830.245 | — |
| SECONDARY AUC(0-t) of GSK3511294 300 mg |
1855.619 | — |
| SECONDARY Area Under the Concentration-time Curve From Time Zero to Week 4 (AUC[0-Week 4]) of GSK3511294 |
6.856; 19.685; 62.994; 292.698; 676.055 | — |
| SECONDARY Area Under the Concentration-time Curve From Time Zero to Week 12 (AUC[0-Week 12]) of GSK3511294 |
16.102; 48.389; 148.798; 663.984; 1445.726 | — |
| SECONDARY Area Under the Concentration-time Curve From Time Zero to Week 26 (AUC [0-Week 26]) of GSK3511294 |
21.829; 64.453; 199.893; 805.359; 1789.451 | — |
| SECONDARY Percentage of AUC (0-inf) Obtained by Extrapolation (%AUCex) of GSK3511294 2 mg and 10 mg |
24.3560; 7.7705 | — |
| SECONDARY %AUCex of GSK3511294 30 mg and 100 mg |
2.9636; 1.4162 | — |
| SECONDARY %AUCex of GSK3511294 300 mg |
0.9096 | — |
| SECONDARY Maximum Observed Concentration (Cmax) of GSK3511294 2 mg and 10 mg |
0.3400; 0.8759 | — |
| SECONDARY Cmax of GSK3511294 30 mg and 100 mg |
2.8101; 12.2471 | — |
| SECONDARY Cmax of GSK3511294 300 mg |
28.5987 | — |
| SECONDARY Time of Occurrence of Cmax (Tmax) of GSK3511294 2 mg and 10 mg |
10.966; 7.956 | — |
| SECONDARY Tmax of GSK3511294 30 mg and 100 mg |
13.943; 13.970 | — |
| SECONDARY Tmax of GSK3511294 300 mg |
13.909 | — |
| SECONDARY Time of Last Quantifiable Concentration (Tlast) of GSK3511294 2 mg and 10 mg |
84.47; 176.46 | — |
| SECONDARY Tlast of GSK3511294 30 mg and 100 mg |
182.01; 252.00 | — |
| SECONDARY Tlast of GSK3511294 300 mg |
279.99 | — |
| SECONDARY Apparent Clearance Following Subcutaneous Dosing (CL/F) of GSK3511294 2 mg and 10 mg |
0.08066; 0.14513 | — |
| SECONDARY CL/F of GSK3511294 30 mg and 100 mg |
0.14402; 0.11811 | — |
| SECONDARY CL/F of GSK3511294 300 mg |
0.16011 | — |
| SECONDARY Apparent Volume of Distribution After Subcutaneous Administration (Vd/F) of GSK3511294 2 mg and 10 mg |
6.113; 9.193 | — |
| SECONDARY Vd/F of GSK3511294 30 mg and 100 mg |
7.812; 6.630 | — |
| SECONDARY Vd/F of GSK3511294 300 mg |
9.337 | — |
| SECONDARY Terminal Phase Elimination Rate Constant (Lambda_z) of GSK3511294 2 mg and 10 mg |
0.013195; 0.015787 | — |
| SECONDARY Lambda_z of GSK3511294 30 mg and 100 mg |
0.018435; 0.017813 | — |
| SECONDARY Lambda_z of GSK3511294 300 mg |
0.017148 | — |
| SECONDARY Terminal Phase Half-life (t1/2) of GSK3511294 2 mg and 10 mg |
52.531; 43.907 | — |
| SECONDARY T1/2 of GSK3511294 30 mg and 100 mg |
37.599; 38.913 | — |
| SECONDARY T1/2 of GSK3511294 300 mg |
40.422 | — |
| SECONDARY Ratio to Baseline in Absolute Blood Eosinophil Count |
1.083; 0.562; 0.522; 0.434; 0.496; 0.466 | — |
| SECONDARY Number of Participants With Anti-drug Antibody (ADA) Binding to GSK3511294 |
12; 6; 5; 4; 7; 5 | — |
| SECONDARY Titers of Binding ADA to GSK3511294 |
80.0; 160.0; 80.0; 80.0 | — |
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 = 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 tim
Data sourced from ClinicalTrials.gov (NCT03287310). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.