Clinical Trials Register

Summary
EudraCT Number:	2015-005800-27
Sponsor's Protocol Code Number:	204957
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-10-03
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2015-005800-27

A.3

Full title of the trial

A randomised, multi-center, double blind (sponsor open), placebo-controlled study to assess the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of GSK3117391 in subjects with moderate to severe, active rheumatoid arthritis

Randomizowane, wieloośrodkowe badanie, prowadzone metodą podwójnie ślepej próby (otwartej próby dla sponsora), kontrolowane placebo mające na celu ocenę skuteczności, bezpieczeństwa, tolerancji, farmakokinetyki i farmakodynamiki preparatu GSK3117391 u pacjentów z aktywną postacią reumatoidalnego zapalenia stawów o nasileniu umiarkowanym do ciężkiego.

A.3.1

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

Study of a new drug’s effect in people with severe rheumatoid arthritis who have not responded sufficiently well to treatment with DMARDs

Badanie działania nowego leku u osób z ciężkim reumatoidalnym zapaleniem stawów,
u których nie wystąpiła wystarczająco korzystna odpowiedź na wcześniejsze leczenie

A.4.1

Sponsor's protocol code number

204957

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 Ltd
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 Ltd
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 Ltd
B.5.2	Functional name of contact point	GSK Clinical Support Help Desk
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	+44 0800 783 9733
B.5.5	Fax number	Not Applicable
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	GSK3117391
D.3.2	Product code	GSK3117391
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not applicable
D.3.9.1	CAS number	1018673-42-1
D.3.9.2	Current sponsor code	GSK3117391
D.3.9.3	Other descriptive name	GSK3117391
D.3.9.4	EV Substance Code	SUB181982
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Rheumatoid Arthritis (RA)

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis (RA) is a chronic, systemic inflammatory autoimmune disease, characterised by a symmetrical polyarthritis that is associated with substantial disability and morbidity.

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of GSK3117391 in subjects with severe RA

E.2.2

Secondary objectives of the trial

-To assess the safety and tolerability of
GSK3117391

-To assess the efficacy of GSK3117391 on other
clinical endpoints

-To assess the pharmacokinetics of GSK3117391

-To investigate the monocyte numbers with GSK3117391

-To assess the effects of GSK3117391 on
biomarkers of inflammation in the blood

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

AGE
1. Age ≥18 years at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. The subject must have a diagnosis of RA according to the 2010 ACR/EULAR classification criteria for RA.
3. Functional class I, II or III defined by the 1992 ACR Classification of Functional Status in RA
4. The subject must have either:
• A EULAR DAS28-CRP of greater than 5.1 at screening and a EULAR DAS 28-ESR (erythrocyte sedimentation rate) of greater than 5.1 on Day 1
or
• A EULAR DAS 28-CRP between 3.2 and 5.1 at screening accompanied by a rheumatoid factor positive test (RF above ULN, ≥15 KU/L) or Anti-Citrullinated Peptide Antibody positive test (ACPA above ULN, ≥20 units) at screening and a EULAR DAS 28-ESR between 3.2 and 5.1 on Day 1
5. Disease duration of >6 months (time from onset of patient-reported symptoms of either pain or stiffness or swelling in hands, feet or wrists).
6. Swollen joint count of ≥6 (66-joint count) and tender joint count of ≥8 (68-joint count) at screening and at day 1
7. The subject must have a CRP serum level of ≥3.1 mg/L at screening and an ESR ≥28 mm/hr at Day 1
8. The subject has had an inadequate response to DMARDs defined as either a lack or loss of efficacy after at least 8 weeks of treatment and/or intolerance and/or toxicity to DMARDs.
WEIGHT
9. Body weight ≥ 45 kg and body mass index (BMI) within the 18.5 - 35 kg/m2 inclusive.

SEX
10. Male or female requirements.

Males:
Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication 91 days after the last dose of study medication.
Male condom plus recommendation for partner to use of one of the contraceptive options as detailed in Appendix 2 (Protocol). This is an all-inclusive list of those methods that meet the following GSK definition of highly effective: having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label. For non-product methods (e.g. male sterility), the investigator determines what is consistent and correct use. The GSK definition is based on that provided by the ICH.
In addition male subjects must not donate sperm for 91 days after the last dose of study medication.
The investigator is responsible for ensuring that subjects understand how to use these methods of contraception properly.

Females:
A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential defined as:
•Pre-menopausal females with one of the following:
•Documented tubal ligation.

SEX
•Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion.
•Hysterectomy.
•Documented Bilateral Oophorectomy.
•Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] and estradiol levels consistent with menopause [refer to laboratory reference ranges for confirmatory levels]).
NB - Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
b. Females of reproductive potential must have proper and established use of a Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential(FRP) (see Appendix 2) from 28 days prior to the first dose of study medication and until 15 weeks after the last dose of study medication and completion of the follow-up visit. In addition subjects will be required to utilise a barrier method of contraception.
A negative serum hCG pregnancy test at the first screening visit and urine hCG pregnancy test (with a sensitivity of at least 25 IU/L) at the following visits: between Day-7 to -4 (this test may be performed at home), on Day 1 prior to first study medication dose administration, at the weekly study visits, and the follow up visit.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

INFORMED CONSENT
11. Capable of giving signed informed consent as described in Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

E.4

Principal exclusion criteria

CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc INTERVAL)
1. Pregnant or lactating women.
2. Subjects who meet diagnostic criteria for any other rheumatic disease (e.g., lupus erythematosus, gout, psoriatic arthritis).
3. Subjects who have previously been treated with more than 2 of the following:
• targeted synthetic DMARDs whether marketed e.g. baricitinib and tofacitinib, or still under clinical investigation
• biologic DMARDs and their biosimilars whether marketed e.g. adalimumab, etanercept, infliximab, certolizumab, golimumab abatacept, rituximab, tociluzimab, or still under clinical investigation.
4. Subjects with past history of granulomatous disease e.g. leprosy, sarcoidosis.
5. Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, haematological (including clotting disorders), gastrointestinal (including gastrooesophageal ulcers), pulmonary, cardiac (including ischemic heart disease), neurological, or cerebral disease, or other medical conditions that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study.
6. Subjects with any values for monocytes are below the lower limit of normal (LLN) at screening.
7. Haemoglobin <11 g/dL; haematocrit <30%, white blood cell count ≤3,000/mm3 (≤3.0 x 109/L) or ≥14,000/mm3 (≥14 x 109/L); platelet count ≤ 100,000/μL (≤100 x 109/L); absolute neutrophil count ≤2 x 109/L; lymphocyte count <1 x 109/L at screening.
8. ALT and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening.
9. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
10. QTcF or QTcB > 450 msec (based on the average of triplicate ECGs) at screening.
11. Abnormal findings on ECG considered clinically significant by the investigator.
12. A history of carcinoma in situ and malignant disease, except for adequately treated non-invasive cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
13. Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.
14. Abnormal chest X-ray within 12 weeks of Day 1 (locally read and reported by a radiologist) judged by the investigator as clinically-significant.
15. History of infected joint prosthesis at any time, with the prosthesis still in situ. History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary tract infections.
16. Active infections, or history of recurrent infections (excluding recurrent fungal infections of the nail bed), or have required management of acute or chronic infections as follows:
• Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).
• Hospitalisation for treatment of infection within 12 weeks of Day 1.
• Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals, or antiparasitic agents) within 12 weeks of Day 1 or oral antimicrobials within 14 days of Day 1.
17. Any surgical procedure, including bone or joint surgery/synovectomy within 12 weeks prior to Day 1 or any planned surgery within the duration of the study or follow-up period.
18. A vaccination (live or attenuated) within 30 days of Day 1 or BCG vaccination within 365 days of Day 1, or a live vaccination planned during the course of the study.
CONCOMITANT MEDICATIONS
19. The subject has received treatment with the therapies listed in Section 6.11.2(Protocol_ or changes to those treatments in the prescribed timeframe.
20. Other medications (including vitamins, herbal and dietary supplements) will be considered on a case-by-case basis, and will be allowed if in the opinion of the investigator the medication will not interfere with the study procedures or compromise subject safety
RELEVANT HABITS
21. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
22. Smokers who would not be able to refrain from smoking whilst in the clinic.
23. Subjects who cannot refrain from consuming any of the following fruits or juices (alone or in combination): seville oranges, grapefruit, pummelos, or any citrus fruits from 7 days prior to the first dose of study medication until their discharge from the unit after their last dose of study medication.

Refer to protocol for additional points numbered 24 to 31

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in Disease Activity Score DAS28-CRP

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 28

E.5.2

Secondary end point(s)

Safety endpoints:
Adverse events
Vital signs (HR, BP & Temperature)
ECGs
Clinical laboratory tests (haematology, biochemistry and urinalysis)

Efficacy endpoints:
ACR responders (ACR20, ACR50, ACR70)
Number of swollen joints assessed using 28-joint counts
Number of tender/painful joints assessed using 28-joint counts
Change from baseline in DAS28-CRP over time

Pharmacokinetics (PK):
Plasma concentrations and derived PK) parameters of GSK3117391 and GSK3339189

Others:
Changes in monocyte numbers over time
Changes from baseline in biomarkers of inflammation in the blood.

E.5.2.1

Timepoint(s) of evaluation of this end point

At various timepoints throughout the study, up to 14 days post last dose.

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

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

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

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Poland

Romania

Russian Federation

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

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects will not receive any additional treatment from GSK after completion of the
study because other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the poststudy
care of the subject’s medical condition.

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

2016-11-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-12

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-11-18

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