Home / Psoriasis / A First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Intravenous (IV) Dose of GSK2831781 in Healthy Volunteers and Patients With Plaque Psoriasis

A First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Intravenous (IV) Dose of GSK2831781 in Healthy Volunteers and Patients With Plaque Psoriasis

  Purpose

This study is a phase I, randomised, double blind (sponsor unblinded), placebo-controlled, single ascending dose study GSK2831781 administered by IV. GSK2831781 is a humanized Antibody Dependent Cell Cytotoxicity (ADCC) enhanced monoclonal afucosylated antibody that is specific to the Lymphocyte Activation Gene-3 (LAG-3) protein. This is the first administration of GSK2831781 in humans and will evaluate in two parts the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of single IV doses of GSK2831781 administered to healthy subjects previously vaccinated with Bacillus Calmette Guérin (BCG) (Part A delayed type hypersensitivity [DTH] cohorts) and patients with plaque psoriasis (Part B). The inclusion of DTH and psoriasis subjects to explore the mechanism in biopsies and clinical response endpoints in these populations, as well as investigate systemic biomarkers will provide useful information prior to conducting studies in other immune-inflammatory disease which will involve more invasive tissue biopsies. Measuring the pharmacology of GSK2831781 using the depletion of LAG-3+ T-cells in skin biopsies from Tuberculin Purified Protein Derivative (PPD) skin challenge and lesional skin biopsies from patients with psoriasis, will be helpful in understanding of the dose response relationship, which will be important for designing future studies in immuno-inflammatory diseases, including psoriasis. Approximately 67 subjects will be enrolled to complete dosing and critical assessments. The subject numbers will be split to approximately 40 healthy subjects (Part A) and 27 patients with psoriasis (Part B).

Condition Intervention Phase
Psoriasis Biological: GSK2831781 Biological: Placebo Phase 1

Study Type: Interventional
Study Design:Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title:A Randomised, Double Blind (Sponsor Unblinded), Placebo-Controlled, Single Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a IV Dose of GSK2831781 in Healthy Subjects and Patients With Plaque Psoriasis

Resource links provided by NLM:

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:

  • Assessment of safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (No DTH) by measuring Vital signs [ Time Frame: Up to Day 189 ]
    Vital signs will include measurement of systolic and diastolic blood pressure, pulse rate and temperature, taken in semi-supine position after 5 minutes of rest

  • Assessment of safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (DTH) by measuring Vital signs [ Time Frame: Up to Day 219 ]
    Vital signs will include measurement of systolic and diastolic blood pressure, pulse rate and temperature, taken in semi-supine position after 5 minutes of rest

  • Assessment of Safety and tolerability of single IV doses of GSK2831781 in psoriasis patients by measuring Vital signs [ Time Frame: Up to Day 300 ]
    Vital signs will include measurement of systolic and diastolic blood pressure, pulse rate and temperature, taken in semi-supine position after 5 minutes of rest

  • Assessment of safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (No DTH) by measuring 12-Lead Electrocardiogram (ECG) [ Time Frame: Up to Day 189 ]
    Heart rate, PR, QRS, QT, and Electrocardiogram QT interval corrected for heart rate using Fridericia’s formula (QTcF intervals) will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-supine position after 5 minutes rest ECG will be measured continuously during the IV infusion (0-2 hours) with only abnormalities entered into the database

  • Assessment of safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (DTH) by measuring 12-Lead ECGs [ Time Frame: Up to Day 219 ]
    Heart rate, PR, QRS, QT, and QTcF intervals will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-supine position after 5 minutes rest ECG will be measured continuously during the IV infusion (0-2 hours) with only abnormalities entered into the database

  • Assessment of safety and tolerability of single IV doses of GSK2831781 in psoriasis patients by measuring 12-Lead ECGs [ Time Frame: Up to Day 300 ]
    Heart rate, PR, QRS, QT, and QTcF intervals will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-supine position after 5 minutes rest ECG will be measured continuously during the IV infusion (0-2 hours) with only abnormalities entered into the database

  • Safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (No DTH) as assessed by number of subjects with adverse events (AE) [ Time Frame: Up to Day 365 ]
    AEs will be collected from the start of Study Treatment and until the follow-up contact

  • Safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (DTH) as assessed by number of subjects with AEs [ Time Frame: Up to Day 365 ]
    AEs will be collected from the start of Study Treatment and until the follow-up contact

  • Safety and tolerability of single IV doses of GSK2831781 in volunteers with psoriasis, as assessed by number of subjects with AEs [ Time Frame: Up to Day 365 ]
    AEs will be collected from the start of Study Treatment and until the follow-up contact

  • Assessment of Safety and tolerability of single IV doses of GSK2831781 in healthy subjects (No DTH) by measuring inflammatory cytokine levels [ Time Frame: Pre-dose, and at 6, 12, 24 and 48 hours post dose ]
    Cytokines for assessment may include but are not limited to Interleukin (IL)-6, Tumour necrosis factor alpha (TNFa), IL-8 and Interferon-gamma (IFN-gamma)

  • Assessment of Safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (DTH) by measuring inflammatory cytokine levels [ Time Frame: Pre-dose, and at 6, 12, 24 and 48 hours post dose ]
    Cytokines for assessment may include but are not limited to IL-6, TNFa, IL-8 and IFN-gamma

  • Assessment of Safety and tolerability of single IV doses of GSK2831781 in psoriasis patients by measuring inflammatory cytokine levels [ Time Frame: At pre-dose, and at 6, 12, 24 and 48 hours post dose ]
    Cytokines for assessment may include but are not limited to IL-6, TNFa, IL-8 and IFN-gamma

  • Assessment of safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (no DTH) by measuring Laboratory safety data [ Time Frame: Up to Day 189 ]
    Laboratory safety data was assessed in terms of Haematology, Clinical Chemistry and Urinalysis

  • Assessment of safety and tolerability of single IV doses of GSK2831781 in healthy volunteers (DTH) by measuring Laboratory safety data [ Time Frame: Up to Day 219 ]
    Laboratory safety data was assessed in terms of Haematology, Clinical Chemistry and Urinalysis

  • Assessment of safety and tolerability assessment of single IV doses of GSK2831781 in psoriasis patients by measuring Laboratory safety data [ Time Frame: Up to Day 300 ]
    Laboratory safety data was assessed in terms of Haematology, Clinical Chemistry and Urinalysis

Secondary Outcome Measures:

  • Change from baseline [Tuberculin Purified Protein Derivative (PPD) 1st challenge] of induration diameter from re-challenge at 3 days post-dose, in healthy volunteers (DTH) [ Time Frame: Baseline (Day1) and Day32 ]
    The induration of wheals is defined as an elevation and induration that develop as a result of intradermal immunization with PPD, and is measured in the vertical and horizontal plane using the ball point pen technique

  • Duration of induration in the re-challenge (healthy volunteers DTH model) [ Time Frame: Day 30 ]
    The induration of wheals is defined as an elevation and induration that develop as a result of intradermal immunization with PPD. The duration of appearance of induration for the rechallenge dose of PPD is recorded

  • Change from baseline (PPD 1st challenge) of Lymphocyte Activation Gene (LAG)-3+ cells in biopsies of re-challenged skin at 3 days post dose in healthy volunteers (DTH) [ Time Frame: Baseline(Day 1) and Day 32 ]
    A punch biopsy will be taken from the re-challenge site and will be processed for analysis by IHC or other techniques to characterise and count the LAG-3+ cells

  • Change from baseline in LAG-3+ cells in lesional biopsies of psoriasis patients at Day 29 measured by IHC. [ Time Frame: Baseline and Day 29 ]
    A punch biopsy will be taken from one of the sites and processed for analysis by IHC or other techniques to characterise and count the LAG-3+ cells

  • Composite of GSK2831781 PK parameters following single IV dose in healthy volunteers (no DTH) for 0.0003mg/kg Cohort [ Time Frame: Pre dose, at 0.5, 1, 2, 4, 6, 8, 12 and 24, hours post dose and Follow up (Day 29) ]
    Analysis will be done using the PK parameters of maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma time curve [AUC(0-t), AUC(0-week4) and AUC(0-infinity)], percent AUC extrapolated, Last time point where the concentration is above the limit of quantification (tlast), Systemic clearance (CL), Volume of distribution at steady state (Vss), Mean residence time (MRT), terminal phase elimination rate constant (Lambda z), the number of points used to determine Lambda z and the terminal phase half-life (t1/2)

  • Composite of GSK2831781 PK parameters following single IV dose in healthy volunteers (no DTH) for 0.0015mg/kg Cohort [ Time Frame: Pre dose, at 0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours post dose and Follow up (Day 43) ]
    Analysis will be done using the PK parameters of AUC(0-infinity), AUC(0-t), AUC(0-Week4), percent AUCex, Cmax, tmax, tlast, CL, Vss, MRT, Lambda z, number of points used to determine Lambda z and the t1/2

  • Composite of GSK2831781 PK parameters following single IV dose in healthy volunteers (no DTH) for 0.0075mg/kg Cohort [ Time Frame: Pre dose, at 0.5, 1, 2, 4, 6, 8, 12, 24, 48,72, 168 hours, Day 15 post dose and Follow up (Day 85) ]
    Analysis will be done using the PK parameters of AUC(0-infinity), AUC(0-t), AUC(0-Week4), percent AUCex, Cmax, tmax, tlast, CL, Vss, MRT, Lambda z, number of points used to determine Lambda z and the t1/2

  • Composite of GSK2831781 PK parameters following single IV dose in healthy volunteers (no DTH) for 0.04mg/kg Cohort [ Time Frame: Pre dose, At 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 168 hours, Days 15, 22, 29, 43, 57 post dose and Follow up (Day 147) ]
    Analysis will be done using the PK parameters of AUC(0-infinity), AUC(0-t), AUC(0-Week4), percent AUCex, Cmax, tmax, tlast, CL, Vss, MRT, Lambda z, number of points used to determine Lambda z and the t1/2

  • Composite of GSK2831781 PK parameters following single IV dose in healthy volunteers (no DTH) for 0.15mg/kg Coh [ Time Frame: Pre dose, At 0.5, 1, 2, 4, 6, 8, 12, 24, 48,72, 168 hours, Days 15, 22, 43, 85 post dose and Follow up (Day 189) ]
    Analysis will be done using the PK parameters of AUC(0-infinity), AUC(0-t), AUC(0-Week4), percent AUCex, Cmax, tmax, tlast, CL, Vss, MRT, Lambda z, number of points used to determine Lambda z and the t1/2

  • Composite of GSK2831781 PK parameters following single IV dose in healthy volunteers (DTH) for 0.15mg/kg Cohort [ Time Frame: Pre dose, At 0.5, 1, 2, 4, 6, 8, 12, 24, 48,72, 168 hours, Days 15, 22, 43, 85 post dose and Follow up (Day 219) ]
    Analysis will be done using the PK parameters of AUC(0-infinity), AUC(0-t), AUC(0-Week4), percent AUCex, Cmax, tmax, tlast, CL, Vss, MRT, Lambda z, number of points used to determine Lambda z and the t1/2

  • Composite of GSK2831781 PK parameters following single IV dose for patients with psoriasis in 0.5mg/kg cohort [ Time Frame: Pre dose, at 0.5, 1, 2, 4, 6, 8, 12, 24, 48,72,168 hours, Days 15, 22, 29, 43, 85, 121 post dose and Follow up (Day 230) ]
    Analysis will be done using the PK parameters of AUC(0-infinity), AUC(0-t), AUC(0-Week4), percent AUCex, Cmax, tmax, tlast, CL, Vss, MRT, Lambda z, number of points used to determine Lambda z and the t1/2

  • Composite of GSK2831781 PK parameters following single IV dose in patients with psoriasis for 1.5mg/kg cohort [ Time Frame: Pre dose, At 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72,168 hours, Days 15, 22, 29, 36, 43, 57, 85, 121 post dose and Follow up (Day 270) ]
    Analysis will be done using the PK parameters of AUC(0-infinity), AUC(0-t), AUC(0-Week4), percent AUCex, Cmax, tmax, tlast, CL, Vss, MRT, Lambda z, number of points used to determine Lambda z and the t1/2

  • Composite of GSK2831781 PK parameters following single IV dose in subjects with psoriasis for 5mg/kg cohort [ Time Frame: Pre dose, At 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72,168 hours, Days 15, 22, 29, 43, 57, 71, 85, 121 post dose and Follow up (Day 300) ]
    Analysis will be done using the PK parameters of AUC(0-infinity), AUC(0-t), AUC(0-Week4), percent AUCex, Cmax, tmax, tlast, CL, Vss, MRT, Lambda z, number of points used to determine Lambda z and the t1/2

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of healthy volunteers (no DTH) For 0.0003MG/KG Cohort [ Time Frame: Up to Day 29 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated immunoelectrochemiluminescent (ECL) assays. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of healthy subjects (no DTH) For 0.0015MG/KG Cohort [ Time Frame: Up to Day 43 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated immunoelectrochemiluminescent (ECL) assays. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of healthy volunteers (no DTH) For 0.0075MG/KG Cohort [ Time Frame: Up to Day 85 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated immunoelectrochemiluminescent (ECL) assays. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of healthy volunteers (no DTH) For 0.004MG/KG Cohort [ Time Frame: Up to Day 147 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated immunoelectrochemiluminescent (ECL) assays. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of healthy volunteers (no DTH) For 0.15MG/KG Cohort [ Time Frame: Up to Day 189 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated immunoelectrochemiluminescent (ECL) assays. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of healthy volunteers (DTH) For 0.15MG/KG Cohort [ Time Frame: Up to Day 219 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated immunoelectrochemiluminescent (ECL) assays. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of volunteers with psoriasis in 0.5 MG/KG cohort [ Time Frame: Up to Day 230 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated ECL assay. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of patients with psoriasis in 1.5 MG/KG cohort [ Time Frame: Up to Day 270 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated ECL assay. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • Immunogenicity of single IV dose of GSK2831781, measured in terms of antibodies to GSK2831781 in serum of patients with psoriasis in 5 MG/KG cohort [ Time Frame: Up to Day 300 ]
    Samples will be analyzed for the presence of anti-GSK2831781 antibodies using a validated ECL assay. Confirmed positive samples will be titrated to obtain the titre of the anti-GSK2831781 antibodies

  • To evaluate the effect of a single IV dose of GSK2831781 on disease activity in patients with psoriasis by measuring the change from baseline and actual Psoriasis Area Severity Index (PASI) scores at Day 15, 29, 43, 85 and 121 [ Time Frame: Baseline, Up to Day 300 ]
    PASI score is a 0-6 point rating scale which is used to measure the psoriatic involvement for each area of the body (head, upper extremities, trunk, lower extremities)

  • To evaluate the effect of a single IV dose of GSK2831781on disease activity in psoriasis patients by measuring the proportion of subjects achieving >=50 % and >=75 % improvement from baseline in PASI score at Day 15, 29, 43, 85 and 121 (PASI 50 and 75) [ Time Frame: Baseline, Up to Day 300 ]
    PASI score is a 0-6 point rating scale which is used to measure the psoriatic involvement for each area of the body (head, upper extremities, trunk, lower extremities)

  • To evaluate the effect of a single IV dose of GSK2831781on disease activity in patients with psoriasis by measuring the change from baseline and actual Psoriatic Lesion Severity Scores (PLSS) at Day 15, 29, 43, 85 and 121 [ Time Frame: Baseline, Up to Day 300 ]
    PLSS is a 0 to 4 point rating scale for lesions and is the sum of the erythema, scaling and induration, measured by a qualified dermatologist

  • Change from baseline and actual Physical Global Assessment (PGA) scores in patients with psoriasis at Day 15, 29, 43, 85 and 121 [ Time Frame: Baseline, Up to Day 121 ]
    A 7-point scoring system will be used to measure the severity of psoriatic lesions over the whole body, at the time of the evaluation will be performed

  • Proportion of patients in each PGA score category among patients with psoriasis, at Day 15, 29, 43, 85 and 121 [ Time Frame: Baseline, Up to Day 121 ]
    Number of volunteers in each PGA score category will be measured

Estimated Enrollment:67
Actual Study Start Date:July 30, 2014
Estimated Study Completion Date:August 15, 2018
Estimated Primary Completion Date:August 15, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Healthy Subjects (no DTH)

One subject will be dosed with GSK2831781 (0.0003 mg/kg) and one with placebo. Depending on the safety data obtained for 28 days post dose along with the available PK data, a dose escalation may be done to the next planned dose (0.0015 , 0.0075, 0.04, 0.15 mg/kg). In case safety findings are noted then the cohort may be expanded to a maximum cohort size of 6:3 (GSK2831781: placebo) or the escalation will be stopped.
Biological: GSK2831781

GSK2831781 (100 milligram (mg)/mL) and its dilutions (Diluent – 0.9 percent saline solution containing 0.015 percent Polysorbate 80) as clear or opalescent, colourless, yellow to brown liquid solution administered by IV over approximately 2 hours.

Biological: Placebo

Commercial saline solution administered by IV over approximately 2 hours
Experimental: Healthy Subjects (DTH)

Sentinel subjects (one dosed with GSK2831781 (0.0003 mg/kg) and one with placebo) will be used in the cohort. Following a review of safety data up to 48 hours post dose, an additional 5 active (GSK2831781) and 1 placebo subject will be dosed (no more than 2 subjects per day with dosing separated by at least 1 hour). After reviewing the safety data for 28 days the healthy subjects (DTH) will be escalated to the planned dose of GSK2831781 (0.0075, 0.04, 0.15 mg/kg) in 6:3 ratio with placebo.
Biological: GSK2831781

GSK2831781 (100 milligram (mg)/mL) and its dilutions (Diluent – 0.9 percent saline solution containing 0.015 percent Polysorbate 80) as clear or opalescent, colourless, yellow to brown liquid solution administered by IV over approximately 2 hours.

Biological: Placebo

Commercial saline solution administered by IV over approximately 2 hours
Experimental: Subjects with Psoriasis

Sentinel subjects (one dosed with GSK2831781 and one with placebo) will be used in the cohort. Following a review of safety data up to 48 hours post dose, an additional 5 active (GSK2831781) and 2 placebo subjects will be dosed (no more than 2 subjects per day with dosing separated by at least 1 hour). All subsequent cohorts do not require stratification for pre-existing ADAs. After reviewing the safety data for 28 days for minimum of 8 out of 9 subjects within the cohort and all subjects have completed dosing and the inpatient monitoring until Day 4, the subjects with psoriasis will be escalated to the planned dose of GSK2831781 (1.5 and 5 mg/kg) in 6:3 ratio with placebo.
Biological: GSK2831781

GSK2831781 (100 milligram (mg)/mL) and its dilutions (Diluent – 0.9 percent saline solution containing 0.015 percent Polysorbate 80) as clear or opalescent, colourless, yellow to brown liquid solution administered by IV over approximately 2 hours.

Biological: Placebo

Commercial saline solution administered by IV over approximately 2 hours

About

Check Also

Risankizumab Therapy Versus Placebo for Subjects With Psoriasis in the Russian Federation (IMMPRESS)

Study Description Go to  Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Brief Summary: The purpose of this study is to assess the safety and efficacy of risankizumab compared to placebo in subjects with moderate to severe chronic plaque psoriasis in the Russian Federation. Condition …

Leave a Reply

Your email address will not be published. Required fields are marked *