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

• Register: EUCTR
• Last refreshed on: 5 March 2018
• Main ID: EUCTR2015-005800-27-PL
• Date of registration: 03/10/2016
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research & Development Ltd
• Public title: Study of a new drug’s effect in people with severe rheumatoid arthritis who have not responded sufficiently well to treatment with DMARDs
• Scientific title: 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
• Date of first enrolment: 08/11/2016
• Target sample size: 40
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005800-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Poland, Romania, Russian Federation

Contacts

• Name: GSK Clinical Support Help Desk
• Affiliation: GlaxoSmithKline Research & Development Ltd

• Name: GSK Clinical Support Help Desk
• Affiliation: GlaxoSmithKline Research & Development Ltd

Key inclusion & exclusion criteria

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 di
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 3

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Rheumatoid Arthritis (RA)
MedDRA version: 20.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Name: GSK3117391
Product Code: GSK3117391
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not applicable
CAS Number: 1018673-42-1
Current Sponsor code: GSK3117391
Other descriptive name: GSK3117391
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: -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

Main Objective: To assess the efficacy of GSK3117391 in subjects with severe RA

Timepoint(s) of evaluation of this end point: Day 28

Primary end point(s): Change from baseline in Disease Activity Score DAS28-CRP

Secondary Outcome(s)

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.

Timepoint(s) of evaluation of this end point: At various timepoints throughout the study, up to 14 days post last dose.

Secondary ID(s)

204957

Source(s) of Monetary Support

GlaxoSmithKline Research & Development Ltd