A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), Proof of Mechanism of GSK2618960 in Primary Sjögren's Syndrome (pSS)

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT03239600

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Days)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aims to evaluate the safety, tolerability and PK of repeat dose administration of GSK2618960 in the treatment of pSS. The study will contain two parts, Part I will be open label and Part II will be randomized, double-blind. The minimum duration of Part I & Part II of the study will be 26 and 32 weeks respectively.

Condition or Disease	Intervention/Treatment	Phase
Autoimmune Diseases	Drug: GSK2618960 2 mg/kg Drug: Placebo Drug: Methotrexate	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This is a parallel assignment where in Part II of the study, randomized subject will receive GSK2618960 and placebo drug simultaneously.This is a parallel assignment where in Part II of the study, randomized subject will receive GSK2618960 and placebo drug simultaneously.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

This is a randomized, double blind (sponsor unblind) study and masking will be performed.

Primary Purpose:

Treatment

Official Title:

A Two Part Phase IIa Study, to Evaluate the Safety and Tolerability, Pharmacokinetics, Proof of Mechanism and Potential for Efficacy of an Anti-IL-7 Receptor-α Monoclonal Antibody (GSK2618960) in the Treatment of Primary Sjögren's Syndrome

Actual Study Start Date :

Sep 19, 2017

Actual Primary Completion Date :

Oct 12, 2017

Anticipated Study Completion Date :

Oct 12, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part I & II: GSK2618960 2 milligram per kilogram (mg/kg) GSK2618960 2mg/kg will be administered intravenously (IV) with Methotrexate (MTX)	Drug: GSK2618960 2 mg/kg GSK2618960 solution for injection, 100mg/mL is clear to opalescent, colorless to yellow or pale brown liquid. Drug: Methotrexate MTX dose between 7.5 to 15 mg will be administered in tablet form once in a week till last dose of GSK2618960 to all subjects in Part I and Part II.
Placebo Comparator: Part II: Placebo Placebo will be administered IV with MTX	Drug: Placebo Placebo solution will be administered by IV infusion. Drug: Methotrexate MTX dose between 7.5 to 15 mg will be administered in tablet form once in a week till last dose of GSK2618960 to all subjects in Part I and Part II.

Arm

Intervention/Treatment

Experimental: Part I & II: GSK2618960 2 milligram per kilogram (mg/kg)

GSK2618960 2mg/kg will be administered intravenously (IV) with Methotrexate (MTX)

Drug: GSK2618960 2 mg/kg

GSK2618960 solution for injection, 100mg/mL is clear to opalescent, colorless to yellow or pale brown liquid.

Drug: Methotrexate

MTX dose between 7.5 to 15 mg will be administered in tablet form once in a week till last dose of GSK2618960 to all subjects in Part I and Part II.

Placebo Comparator: Part II: Placebo

Placebo will be administered IV with MTX

Drug: Placebo

Placebo solution will be administered by IV infusion.

Drug: Methotrexate

MTX dose between 7.5 to 15 mg will be administered in tablet form once in a week till last dose of GSK2618960 to all subjects in Part I and Part II.

Outcome Measures

Primary Outcome Measures

Number of subjects with Adverse Events (AEs): Part 1 [Up to Week 29]
An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
Number of subjects with abnormal clinical chemistry values: Part 1 [Up to Week 29]
Samples for clinical chemistry tests will be collected as a measure of safety
Number of subjects with abnormal hematology values: Part 1 [Up to Week 29]
Samples for clinical hematology tests will be collected as a measure of safety
Number of subjects with abnormal urine analysis values: Part 1 [Up to Week 29]
Samples for Urine analysis tests will be collected as a measure of safety
Number of subjects with abnormal findings of body temperature: Part 1 [Up to Week 29]
Body temperature will be measured in a semi-supine position after at least a 5-minute rest.
Number of subjects with abnormal findings of blood pressure: Part 1 [Up to Week 29]
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) will be measured in a semi-supine position after at least a 5-minute rest.
Number of subjects with abnormal findings of pulse rate: Part 1 [Up to Week 29]
Pulse rate will be measured in a semi-supine position after at least a 5-minute rest.
Number of subjects with abnormal findings of respiratory rate: Part 1 [Up to Week 29]
Respiratory rate will be measured in a semi-supine position after at least a 5-minute rest.
Number of subjects with abnormal Electrocardiogram (ECG) findings: Part 1 [Up to Week 29]
Triplicate 12-lead ECGs will be obtained at each time point using an ECG machine
Number of subjects with AEs: Part 2 [Up to Week 35]
An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
Number of subjects with abnormal clinical chemistry values: Part 2 [Up to Week 35]
Samples for clinical chemistry tests will be collected as a measure of safety
Number of subjects with abnormal hematology values: Part 2 [Up to Week 35]
Samples for clinical hematology tests will be collected as a measure of safety
Number of subjects with abnormal urine analysis values: Part 2 [Up to Week 35]
Samples for Urine analysis tests will be collected as a measure of safety
Number of subjects with abnormal findings of body temperature: Part 2 [Up to Week 35]
Body temperature will be measured in a semi-supine position after at least a 5-minute rest.
Number of subjects with abnormal findings of blood pressure: Part 2 [Up to Week 35]
SBP and DBP will be measured in a semi-supine position after at least a 5-minute rest.
Number of subjects with abnormal findings of pulse rate: Part 2 [Up to Week 35]
Pulse rate will be measured in a semi-supine position after at least a 5-minute rest.
Number of subjects with abnormal findings of respiratory rate: Part 2 [Up to Week 35]
Respiratory rate will be measured in a semi-supine position after at least a 5-minute rest.
Number of subjects with abnormal ECG findings: Part 2 [Up to Week 35]
Triplicate 12-lead ECGs will be obtained at each time point using an ECG machine

Secondary Outcome Measures

Plasma concentration of GSK2618960: Part 1 [Day 1: post-infusion; Day 15 and 29: pre-infusion; Day 43: Pre and post-infusion; Day 8, 22, 36, 50, 57, 71, 99 and 127]
Blood samples will be collected prior to start and at the end of infusion at the indicated time points and will be analyzed for PK parameters.
Maximum observed plasma concentration (Cmax) of GSK2618960: Part 1 [Day 1: post-infusion; Day 15 and 29: pre-infusion; Day 43: Pre and post-infusion; Day 8, 22, 36, 50, 57, 71, 99 and 127]
Blood samples will be collected prior to start and at the end of infusion at the indicated time points and will be analyzed for PK parameters.
Minimum observed plasma concentration (Cmin) of GSK2618960: Part 1 [Day 1: post-infusion; Day 15 and 29: pre-infusion; Day 43: Pre and post-infusion; Day 8, 22, 36, 50, 57, 71, 99 and 127]
Blood samples will be collected prior to start and at the end of infusion at the indicated time points and will be analyzed for PK parameters.
Area under the curve (AUC) of GSK2618960: Part 1 [Day 1: post-infusion; Day 15 and 29: pre-infusion; Day 43: Pre and post-infusion; Day 8, 22, 36, 50, 57, 71, 99 and 127]
Blood samples will be collected prior to start and at the end of infusion at indicated time points and will be analyzed for PK parameters.
Number of incidences of Anti-drug antibody (ADA) formation: Part 1 [Up to Week 29]
Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses.
Number of titres of ADA: Part 1 [Up to Week 29]
Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses.
Time to onset of ADA: Part 1 [Up to Week 29]
Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses.
Number of incidences of ADA neutralization: Part 1 [Up to Week 29]
Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses.
Plasma concentration of GSK2618960 : Part 2 [Day 1: post-infusion; Day 15, 29, 43, 57: pre-infusion; Day 71: Pre and post-infusion; Day 8, 22, 36, 50, 64, 78, 85, 113 and 169]
Blood samples will be collected prior to start and at the end of infusion at the indicated time points and will be analyzed for PK parameters
Cmax of GSK2618960: Part 2 [Day 1: post-infusion; Day 15, 29, 43, 57: pre-infusion; Day 71: Pre and post-infusion; Day 8, 22, 36, 50, 64, 78, 85, 113 and 169]
Blood samples will be collected prior to start and at the end of infusion at the indicated time points and will be analyzed for PK parameters.
Cmin of GSK2618960: Part 2 [Day 1: post-infusion; Day 15, 29, 43, 57: pre-infusion; Day 71: Pre and post-infusion; Day 8, 22, 36, 50, 64, 78, 85, 113 and 169]
Blood samples will be collected prior to start and at the end of infusion at the indicated time points and will be analyzed for PK parameters.
AUC of GSK2618960: Part 2 [Day 1: post-infusion; Day 15, 29, 43, 57: pre-infusion; Day 71: Pre and post-infusion; Day 8, 22, 36, 50, 64, 78, 85, 113 and 169]
Blood samples will be collected prior to start and at the end of infusion at indicated time points and will be analyzed for PK parameters.
Number of incidences of ADA formation: Part 2 [Up to Week 35]
Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses.
Number of titres of ADA: Part 2 [Up to Week 35]
Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses.
Time to onset of ADA: Part 2 [Up to Week 35]
Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses.
Number of incidences of ADA neutralization: Part 2 [Up to Week 35]
Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses.
Receptor occupancy (RO) on circulating T cells: Part 2 [Up to Week 35]
Blood samples will be collected from subjects at indicated time points to measure IL-7R alpha occupancy levels.
Percentage inhibition of Signal transducer and activator of transcription 5 (STAT 5) phosphorylation in T cells: Part 2 [Up to Week 35]
Blood samples will be collected from subjects at indicated time points to measure phosphorylation of STAT 5 in response to ex vivo IL-7 stimulation.
Change from Baseline in Focus score: Part 2 [Up to Day 29]
Salivary glands for immunohistochemistry analysis will be evaluated for general appearance and total inflammatory infiltrate (focus score). Salivary gland biopsy will be performed at Baseline and blood samples will be collected at indicated time points.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Part I and Part II: Male and females aged 18-70
Part I and Part II: pSS diagnosis according to the American-European Consensus Group Criteria
Part I and Part II: Documented previous biopsy evidence of salivary gland inflammation consistent with pSS and/or documented history of anti-Ro and/or anti-La antibodies
Part II: Has any of the following abnormalities at screening: hypergammaglobulinaemia [serum Immunoglobulin G (IgG) greater than or equal to 16 gram per liter (g/L); Presence of Rheumatoid factor (RF); Anti Nuclear Antibodies (ANA) titer greater than or equal to 320:1.
Stimulated whole salivary flow greater than 0.1 milliliter per minute (mL/min) at screening.
Symptomatic oral dryness greater than or equal to 5 out of 10 on Visual Analogue Scale (VAS) scale and/or Schirmer test less than 10 millimeter (mm) at screening.

Exclusion Criteria:

Part I and II: Secondary Sjögren's Syndrome
Part I and II: Receiving cyclophosphamide, other biologic, immunosuppressive or immunomodulatory treatments
Part I and II: Active infections, or history of recurrent infections
Part I and II: History of significant medical illness
Part I and II: History of lymphoma