Clinical Trials Register

Summary
EudraCT Number:	2016-004258-14
Sponsor's Protocol Code Number:	201579
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-12-21
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-004258-14

A.3

Full title of the trial

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.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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.

A.3.2

Name or abbreviated title of the trial where available

GSK2618960, PH2a, 2-part, repeat IV dose, Immunogenecity, Safety and PK/PD Study in pSS pts

A.4.1

Sponsor's protocol code number

201579

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GlaxoSmithKline Research & Development Limited
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GlaxoSmithKline Research & Development Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline Research & Development Limited
B.5.2	Functional name of contact point	GSK Clinical Support HelpDesk
B.5.3	Address:
B.5.3.1	Street Address	1-3 Iron Bridge road, Stockley Park West
B.5.3.2	Town/ city	Uxbridge, Middlesex
B.5.3.3	Post code	UB11 1BT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+440209904466
B.5.5	Fax number	+440209904968
B.5.6	E-mail	GSKClinicalSupportHD@GSK.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	GSK2618960
D.3.2	Product code	GSK2618960
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GSK2618960
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	GSK2618960
D.3.9.3	Other descriptive name	GSK2618960
D.3.9.4	EV Substance Code	SUB89641
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Primary Sjögren’s Syndrome

E.1.1.1

Medical condition in easily understood language

Primary Sjögren’s Syndrome

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10021295
E.1.2	Term	IL-7 therapy
E.1.2	System Organ Class	100000004865

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part I
Assess safety and tolerability of repeat intravenous (IV) administration of GSK2618960.

Part II
Assess safety and tolerability of repeat IV administration of GSK2618960

E.2.2

Secondary objectives of the trial

Part I
-Characterise the pharmacokinetics (PK) of GSK2618960 following repeat IV administration.
-Assess immunogenicity of GSK2618960.

Part II
-Characterise the PK of GSK2618960
following repeat IV administration over
12 weeks.
-Assess immunogenicity of GSK2618960.
-Characterise pharmacodynamics following repeat IV administration of GSK2618960
-Effect of repeat administration of GSK2618960 on disease markers in salivary gland tissue.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria (Part I)
A participant will be eligible for inclusion in this study only if all of the following criteria
apply:
AGE
1. Between 18 and 70 years of age at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis of primary Sjögren’s Syndrome according to the American-European
Consensus Group criteria (Vitali, 2002).
3. Documented previous biopsy evidence of salivary gland inflammation consistent with pSS and/or documented history of anti-Ro (SSA) and/or anti-La (SSB) antibodies.
SEX
4. Male and female participants
Male participants
Males with FRP partners must agree to utilize two forms of complementary contraception consisting of one barrier method (male condom or female
diaphragm) and one method from one of the options listed in the Modified List
of Highly Effective Methods for Avoiding Pregnancy in FRP (see Appendix 5) from start of screening until 6 months after termination of MTX administration.
Female participants, where one of the following conditions apply:
a. Non reproductive potential as defined as:
i. pre-menopausal females with one of the following:
-documented tubal ligation
-documented hysteroscopic tubal occlusion
-procedure with followup confirmation of bilateral tubal occlusion
-hysterectomy
-documented bilateral oophorectomy
ii. post-menopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating
hormone (FSH) > 40 million international unit (MIU)/mL and oestradiol < 40 picogram (pg)/mL (< 140 picomol (pmol)/L) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt must discontinue HRT to allow confirmation of postmenopausal
status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation
of their postmenopausal status, they can resume use of HRT during the study.
b. Reproductive potential with:
- negative pregnancy test as determined by serum human chorionic gonadotropin (hCG) test at screening, AND a negative urine pregnancy test on the first day of MTX run-in phase prior to administration, AND during MTX run in phase as per routine monitoring in the MTX label AND negative urine pregnancy test on Day 1 prior to administration of GSK2618960 (or placebo).
- agrees to utilize two forms of complementary contraception consisting of one barrier method (male condom or female diaphragm) and one method from one of the options listed in the Modified List of Highly
Effective Methods for Avoiding Pregnancy in FRP (see Appendix 5) from start of screening until 6 months after termination of MTX administration.
Those participants that were on MTX therapy prior to enrolling into the study, and that were using consistently one contraception method from the list of highly effective methods, will not be required to use a barrier method in addition.
The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception. The investigator or designee should remind patients of the need to comply with the requirements at study visits until the end of the follow-up visits.

Inclusion Criteria (Part II)
A participant will be eligible for inclusion in this study only if all of the following criteria apply:
AGE
6. Between 18 and 70 years of age at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
7. Diagnosis of primary Sjögren’s Syndrome according to the American-European
Consensus Group criteria (Vitali, 2002) duration of <5 years.
8. Documented previous biopsy evidence of salivary gland inflammation consistent with pSS and/or documented history of anti-Ro (SSA) and/or anti-La (SSB) antibodies.
9. Has at least one of the following laboratory abnormalities due to pSS at screening:
a. Hypergammaglobulinaemia (serum IgG ≥16 g/L)
b. Presence of Rheumatoid Factor (RF)
c. Anti Nuclear Antibodies (ANA) titre ≥ 320:1
10. Stimulated whole salivary flow > 0.1 mL/min at screening.
11. Symptomatic oral dryness ≥ 5 out of 10 on Visual Analogue Scale (VAS) scale and/or Schirmer test < 10 mm at screening.
- For below point of the inclusion criteria Part II refer details mentioned in the protocol in page no 36 and 37
SEX
12. Male and female participants.

E.4

Principal exclusion criteria

Exclusion Criteria (Part I)
A participant will not be eligible for inclusion in this study if any of the following criteria
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)
1. Diagnosis of Sjögren’s syndrome (SS) associated with other immune-mediated disorders, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, IgG4 or Graft versus Host disease.
2. Any history of the following systemic manifestations of primary Sjögren’s syndrome: vasculitis, central nervous system (CNS).
3. Contraindications to MTX according to SPC.
4. Any history of acute renal failure, tubulointerstitial nephritis, glomerulonephritis or presence of chronic kidney disease.
Patients with history of distal tubular acidosis are allowed, provided the patients are asymptomatic at the time of screening, MTX run-in period and baseline.
5. Any history of lymphoma or fixed unilateral or bilateral parotid gland swelling suggestive of lymphoma.
6. Monoclonal gammopathy as defined by: IgA or IgM monoclonal gammopathy, or abnormal Free Light Chain ratio, or serum M-protein>20 g/L.
7. Previous major organ transplant or haematopoietic stem cell transplantation.
8. Previous head or neck irradiation.
9. Leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence
of metastatic disease for 3 years
10. Breast cancer within the past 10 years.
11. Positive serology for:
-HIV
-Hepatitis C (HCV) or presence of HCV ribonucleic acid (RNA)
-Hepatitis B (HB), defined as HB surface antigen positive (HBsAg+) OR HB core antibody positive (HBcAb+)
12. Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, chest X-rays (posterior anterior and lateral), and TB testing: either a positive tuberculin skin test (TST; defined as a skin induration <5 mm at 48 to 72 hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or a positive (not indeterminate) QuantiFERON-TB Gold test.
Note: The choice to perform a TST or a QuantiFERON-TB Gold test will be made by the investigator according to local licensing and standard of care. The QuantiFERON-TB
Gold test can only be used in countries where it is licensed, and the use of this test is dependent on previous treatment(s). This test may not be suitable if previous treatment(s) produced significant immunosupression.
13. Active infections, or history of recurrent infections or have required management of acute or chronic infections, as follows:
a. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes
zoster and atypical mycobacteria). OR
b. Discharged from hospitalization for treatment of infection within 30 days of screening.
OR
c. Use of parenteral (IV or intramuscular [IM])antimicrobials (antibacterials, antivirals, antifungals, or antiparasitic agents) within 30 days of screening or oral antimicrobials within 30 days of first day of MTX run-in.
14. Clinically significant multiple or severe drug allergies or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major,linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and
exfoliative dermatitis).
15. History of an anaphylactic reaction to parenteral administration of human proteins or monoclonal antibodies or serum sickness.
16. History of significant medical illness (or planned surgical procedure) that would interfere with the study procedures and or assessments e.g severe heart failure (New York Heart Association, Class III) or other severe, uncontrolled disease, uncontrolled hypertension, uncontrolled diabetes or other uncontrolled disease.
17. Confirmed Progressive Multifocal Leukoencephalopathy (PML) or neurological findings consistent with PML that are not otherwise explained.
18. Liver function tests: alanine aminotransferase (ALT) >1.2xULN ; aspartate aminotransferase (AST) > 1.2xULN total bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening.
19. White blood cell count <2.0 x 109/L, absolute neutrophil count <1.0 x 109/L, lymphocyte count <0.5 x 109/L, Hemoglobin < 100 g/L, platelet counts < 125 x 109/L at screening.
20. Presence of cryoglobulins at screening.
21. Presence of beta2microglobulin at screening.
22. Serum concentrations of complement components C3 and C4< Lower reference limit.
23. Estimated Glomerular Filtration Rate (eGFR), Modifications of Diet in Renal Diseases (MDRD) ≤ 90 mL/min/1.73 m2 at screening.

Refer protocol page 34-35 for the continuation points of exclusion criteria Part I and for exclusion criteria Part II refer protocol page 37-40

E.5 End points

E.5.1

Primary end point(s)

Same primary endpoints for Part 1 and 2: Adverse Events (AEs), Clinical laboratory values (Haematology; Clinical Chemistry, Urinalysis), Vital Signs, Electrocardiogram (ECG)

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety data will be reviewed frequently during study and overall analysis at end of study

E.5.2

Secondary end point(s)

Part 1:
1)
-GSK2618960 Plasma concentrations
-GSK2618960 PK parameters, including, but not limited to, maximum concentration (Cmax), minimum concentration (Cmin), Area Under the Curve (AUC) during dosing intervals, where appropriate,
2)
-Incidence, titres and time to onset of anti drug antibodies (ADA)
-Incidence of neutralising ADA (binding at the complementarity determining regions (CDRs))

Part 2:
1)
-GSK2618960 Plasma concentrations
-GSK2618960 Plasma PK parameters, including, but not limited to, Cmax, Cmin, AUC during dosing intervals, where appropriate; 2)
-Incidence, titres and time to onset of ADA
-Incidence of neutralising ADA (binding at the CDRs);

3)
-RO on circulating T cells over time
-Percentage inhibition of STAT5 phosphorylation in T cells over time;
4) Change from baseline in Focus Score

E.5.2.1

Timepoint(s) of evaluation of this end point

All data will be reviewed frequently during study for safety and overall analysis at end of study

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability
Immunogenicity

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Part II- Double blind

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	21
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	1
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	4
F.4.2	For a multinational trial
F.4.2.1	In the EEA	22
F.4.2.2	In the whole clinical trial	22

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-01-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-10-12

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