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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Autoimmune Diseases

Intervention / Treatment
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* Drug: GSK2618960 2 mg/kg
* Drug: Placebo
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a parallel assignment where in Part II of the study, randomized subject will receive GSK2618960 and placebo drug simultaneously.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I & II: GSK2618960 2 milligram per kilogram (mg/kg)<br>GSK2618960 2mg/kg will be administered intravenously (IV) with Methotrexate (MTX) | Drug: GSK2618960 2 mg/kg<br>* GSK2618960 solution for injection, 100mg/mL is clear to opalescent, colorless to yellow or pale brown liquid.<br>Drug: Methotrexate<br>* 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.<br>|
| Placebo Comparator: Part II: Placebo<br>Placebo will be administered IV with MTX | Drug: Placebo<br>* Placebo solution will be administered by IV infusion.<br>Drug: Methotrexate<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with Adverse Events (AEs): Part 1 | 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. | Up to Week 29 | 
| Number of subjects with abnormal clinical chemistry values: Part 1 | Samples for clinical chemistry tests will be collected as a measure of safety | Up to Week 29 | 
| Number of subjects with abnormal hematology values: Part 1 | Samples for clinical hematology tests will be collected as a measure of safety | Up to Week 29 | 
| Number of subjects with abnormal urine analysis values: Part 1 | Samples for Urine analysis tests will be collected as a measure of safety | Up to Week 29 | 
| Number of subjects with abnormal findings of body temperature: Part 1 | Body temperature will be measured in a semi-supine position after at least a 5-minute rest. | Up to Week 29 | 
| Number of subjects with abnormal findings of blood pressure: Part 1 | Systolic blood pressure (SBP) and diastolic blood pressure (DBP) will be measured in a semi-supine position after at least a 5-minute rest. | Up to Week 29 | 
| Number of subjects with abnormal findings of pulse rate: Part 1 | Pulse rate will be measured in a semi-supine position after at least a 5-minute rest. | Up to Week 29 | 
| Number of subjects with abnormal findings of respiratory rate: Part 1 | Respiratory rate will be measured in a semi-supine position after at least a 5-minute rest. | Up to Week 29 | 
| Number of subjects with abnormal Electrocardiogram (ECG) findings: Part 1 | Triplicate 12-lead ECGs will be obtained at each time point using an ECG machine | Up to Week 29 | 
| Number of subjects with AEs: Part 2 | 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. | Up to Week 35 | 
| Number of subjects with abnormal clinical chemistry values: Part 2 | Samples for clinical chemistry tests will be collected as a measure of safety | Up to Week 35 | 
| Number of subjects with abnormal hematology values: Part 2 | Samples for clinical hematology tests will be collected as a measure of safety | Up to Week 35 | 
| Number of subjects with abnormal urine analysis values: Part 2 | Samples for Urine analysis tests will be collected as a measure of safety | Up to Week 35 | 
| Number of subjects with abnormal findings of body temperature: Part 2 | Body temperature will be measured in a semi-supine position after at least a 5-minute rest. | Up to Week 35 | 
| Number of subjects with abnormal findings of blood pressure: Part 2 | SBP and DBP will be measured in a semi-supine position after at least a 5-minute rest. | Up to Week 35 | 
| Number of subjects with abnormal findings of pulse rate: Part 2 | Pulse rate will be measured in a semi-supine position after at least a 5-minute rest. | Up to Week 35 | 
| Number of subjects with abnormal findings of respiratory rate: Part 2 | Respiratory rate will be measured in a semi-supine position after at least a 5-minute rest. | Up to Week 35 | 
| Number of subjects with abnormal ECG findings: Part 2 | Triplicate 12-lead ECGs will be obtained at each time point using an ECG machine | Up to Week 35 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of GSK2618960: Part 1 | 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. | 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 | 
| Maximum observed plasma concentration (Cmax) of GSK2618960: Part 1 | 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. | 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 | 
| Minimum observed plasma concentration (Cmin) of GSK2618960: Part 1 | 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. | 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 | 
| Area under the curve (AUC) of GSK2618960: Part 1 | 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. | 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 | 
| Number of incidences of Anti-drug antibody (ADA) formation: Part 1 | Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses. | Up to Week 29 | 
| Number of titres of ADA: Part 1 | Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses. | Up to Week 29 | 
| Time to onset of ADA: Part 1 | Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses. | Up to Week 29 | 
| Number of incidences of ADA neutralization: Part 1 | Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses. | Up to Week 29 | 
| Plasma concentration of GSK2618960 : Part 2 | 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 | 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 | 
| Cmax of GSK2618960: Part 2 | 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. | 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 | 
| Cmin of GSK2618960: Part 2 | 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. | 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 | 
| AUC of GSK2618960: Part 2 | 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. | 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 | 
| Number of incidences of ADA formation: Part 2 | Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses. | Up to Week 35 | 
| Number of titres of ADA: Part 2 | Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses. | Up to Week 35 | 
| Time to onset of ADA: Part 2 | Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses. | Up to Week 35 | 
| Number of incidences of ADA neutralization: Part 2 | Serum samples will be collected from subjects prior to infusion and various time points post-infusion to carry out immunogenicity and immune-complex analyses. | Up to Week 35 | 
| Receptor occupancy (RO) on circulating T cells: Part 2 | Blood samples will be collected from subjects at indicated time points to measure IL-7R alpha occupancy levels. | Up to Week 35 | 
| Percentage inhibition of Signal transducer and activator of transcription 5 (STAT 5) phosphorylation in T cells: Part 2 | 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. | Up to Week 35 | 
| Change from Baseline in Focus score: Part 2 | 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. | Up to Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-IL-7 Receptor-alpha Monoclonal Antibody, Safety, GSK2618960, Primary Sjögren's Syndrome