Chemokine (C-C motif) ligand 20 (CCL20) is a protein involved in attracting immune cells including subsets of T cells (for example Th17 cells), B cells, natural killer cells and dendritic cells to inflamed tissues in conditions such as psoriasis (Ps) and psoriatic arthritis (PsA). CCL20 acts by binding and activating the chemokine receptor 6 (CCR6) present on the surface of the inflammatory cells. Levels of CCL20 are increased in inflamed tissues in psoriasis (Ps) and inflammatory arthritis. GSK3050002 is a humanized Immunoglobulin G (Ig)G monoclonal antibody, which binds to and neutralizes the action of human CCL20. The hypothesis is that GSK3050002 will reduce the movement of inflammatory cells into tissues affected by Ps or PsA, thereby leading to an improvement in disease activity. The primary objective of this multi-centre, randomized, double-blind (sponsor open), placebo-controlled trial is to evaluate the safety and tolerability of repeat doses of GSK3050002, and to understand the mechanism of action (by taking skin and synovial biopsy samples) and potential for clinical efficacy of GSK3050002 in subjects with PsA. A minimum of 18 subjects and up to a maximum of 30 subjects will be randomised into the study to either GSK3050002 or placebo in a 2:1 ratio to ensure that approximately 18 evaluable subjects complete the study. The total duration of participation in the study will be approximately 21 weeks from screening to last study visit.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
The 3 mL glass vial contains white to off-white lyophilized powder which requires reconstitution with sterile water for injection.Prepared as 100 milligrams per milliliter (mg/mL) solution; lower concentrations prepared by dilution with 0.9% weight by volume (w/v) sodium chloride Injection for infusion.
Normal saline (0.9% sodium chloride) will be used as placebo.
GSK Investigational Site
Oxford, United Kingdom
Number of subjects with Adverse Events (AE)
An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time frame: Up to Day 116
Number of subjects with Serious Adverse Events
An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is an important medical event that jeopardizes the subjects or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, and is associated with drug-induced liver injury.
Time frame: Up to Day 116
Composite of clinical laboratory assessments as a measure of safety and tolerability.
Clinical laboratory assessments will include hematology, clinical chemistry and urinalysis.
Time frame: Up to Day 116
Composite of vital signs as a measure of safety and tolerability.
Vital signs to be measured in semi-supine position after at least 5 minutes rest and will include temperature, systolic and diastolic blood pressure, and pulse rate.
Time frame: Up to Day 116
Electrocardiogram (ECG) assessment as a measure of safety and tolerability.
A single 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) intervals.
Time frame: Up to Day 116
GSK3050002- CCL20 complex levels in serum
Blood samples will be collected on baseline (Day-10 to -1), at pre-dose and at 120 minutes post start of infusion, immediately after infusion has ceased on D 15 and D 29, D 43, D 85, D 113 +/- 3 days
Time frame: Baseline and Up to Day 116
Change from baseline in the number of CD3+ T cells synovial tissue and skin biopsy in samples
Synovial and skin lesion biopsy tissue will be collected and evaluated for general appearance and inflammatory infiltrate including CD3+ T-cells
Time frame: Baseline and Day 43
Change from baseline in Disease Activity Score 28 (DAS28)
DAS28 is a composite arthritis disease activity index comprising swollen and tender joint count (28 joints), patient global assessment of disease activity, and C-reactive protein.
Time frame: Baseline and Up to Day 116
Changes in American College of Rheumatology (ACR) responders
ACR is a composite score of the patient assessment of joint pain, the patient global assessment of disease activity, the physician global assessment of disease activity, the 66/68 swollen/tender joint count, the Disability Index of the Health Assessment Questionnaire (HAQ-DI) questionnaire, and C-reactive protein. The ACR is reported as % improvement (20%, 50% or 70%), between two discrete timepoints, as calculated by improvement in the 66/68 swollen/tender joint count, and improvement in at least three of the remaining five composite parameters.
Time frame: Baseline and Up to Day 116
Changes from baseline in Psoriatic Arthritis Disease Activity Score (PASDAS)
PASDAS is a composite disease activity index for psoriatic arthropathies comprising the 66/68 swollen/tender joint count, patient global assessment of disease activity, physician global assesment of disease activity, Leeds enthesitis index, dactylitis score, SF-36 questionnaire and C-reactive protein
Time frame: Baseline and Up to Day 116
Changes in Psoriasis Lesion Severity Score (PLSS)
The PLSS is the sum of the erythema, scaling and plaque thickness scores.
Time frame: Baseline and Up to Day 116
Changes in Psoriasis Area Severity Index (PASI)
The PASI scoring system is a widely-used standard clinical tool for assessing the severity of psoriasis that takes into account the overall severity of erythema (redness), thickness (induration), and scale, as well as the extent of body surface area (BSA) affected with psoriasis. Higher scores indicate more severe disease. PASI is a static measurement made without reference to previous scores
Time frame: Baseline and Up to Day 116
Incidences of serum anti- GSK3050002 antibody levels
Serum samples will be collected from all subjects at pre-dose and various time points post-dosing. An assay for detecting Anti-drug Antibodies (ADAs) against GSK3050002 will be done using validated electrochemiluminescent (ECL) bridging assay and the Meso-Scale Discovery (MSD) technology.
Time frame: Baseline and Up to Day 116
Titres of serum anti- GSK3050002 antibody levels
The serum which contain potential anti-GSK3050002 antibodies will be confirmed by immunocompetition using excess drug. Confirmed samples with ADA will be further analyzed for titers.
Time frame: Baseline and Up to Day 116
Maximum serum concentrations (Cmax) after repeat dosing of GSK3050002
Blood samples were collected at pre-dose and at 120 minutes post start of infusion, immediately after infusion has ceased on Day (D)1, D15, and D29. Blood samples were also collected D 8, D 22, D 43, D 57, D 85 and D 113 +/-3 days.
Time frame: Up to Day 116
Area under curve over the dosing interval AUC (0- tau) after repeat dosing of GSK3050002
Blood samples were collected at pre-dose and at 120 minutes post start of infusion, immediately after infusion has ceased on Day (D)1, D15, and D29. Blood samples were also collected D 8, D 22, D 43, D 57, D 85 and D 113 +/-3 days.
Time frame: Up to Day 116
Systemic clearance (CL) after repeat dosing of GSK3050002
Blood samples were collected at pre-dose and at 120 minutes post start of infusion, immediately after infusion has ceased on Day (D)1, D15, and D29. Blood samples were also collected D 8, D 22, D 43, D 57, D 85 and D 113 +/-3 days.
Time frame: Up to Day 116
Volume of distribution (V) after repeat dosing of GSK3050002
Blood samples were collected at pre-dose and at 120 minutes post start of infusion, immediately after infusion has ceased on Day (D)1, D15, and D29. Blood samples were also collected D 8, D 22, D 43, D 57, D 85 and D 113 +/-3 days.
Time frame: Up to Day 116
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