Safety and Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD) and Efficacy of Repeat Doses of GSK2982772 in Subjects With Moderate to Severe Rheumatoid Arthritis (RA)

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02858492
• Date of registration: 20/07/2016
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: Safety and Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD) and Efficacy of Repeat Doses of GSK2982772 in Subjects With Moderate to Severe Rheumatoid Arthritis (RA)
• Scientific title: A Multicenter, Randomized, Double-blind (Sponsor-unblinded), Placebo-controlled Study to Investigate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2982772 in Subjects With Moderate to Severe Rheumatoid Arthritis
• Date of first enrolment: October 17, 2016
• Target sample size: 52
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02858492
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

Germany, Italy, Poland, Russian Federation, Spain, United Kingdom

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion criteria

Inclusion Criteria:

- Between 18 and 75 years of age inclusive, at the time of signing the informed consent.

- Subjects that do not have any medical conditions, other than moderate to severe RA,
that in the opinion of the Investigator put the subject at unacceptable risk or
interfere with study assessments or integrity of the data. These medical conditions
should be stable at the time of screening and are expected to remain stable for the
duration of the study.

- Subject has had a confirmed diagnosis of rheumatoid arthritis according to the revised
2010 ACR-EULAR classification criteria.

- Disease duration of >=12 weeks (time from onset of patient-reported symptoms of either
pain or stiffness or swelling in hands, feet or wrists) at screening.

- Swollen joint count of >=4 (28-joint count) and tender joint count >=4 (28-joint
count) at screening.

- Subject has a DAS28 CRP disease activity score of >= 3.2 and CRP >= 5.0 mg/liter (L)
(>=4.76 nanomole (nmol)/L) at screening.

- Subject must have received at least 12 weeks of non-biologic DMARD monotherapy or
MTX/DMARD combination therapy prior to screening and must be on stable dose throughout
the study.

- Subject is naive to any biological therapies for RA or subject may have had previous
exposure to a single anti-tumor necrosis factor (TNF) biologic agent which was
discontinued for reasons other than primary non-response more than 8 weeks (or 5 half
lives whichever is longer) from first dose.

- For subjects who have consented to synovial joint biopsy:

• Subject has an involved knee, wrist, or ankle suitable for biopsy, as assessed by a
rheumatologist at screening.

- A body mass index (BMI) within range of 18.5 - 35 kilogram/meter^2 (Kg/m^2)
(inclusive) at screening.

- Male and female subjects Males: Male subjects with female partners of child bearing
potential must comply with the contraception requirements specified in the protocol.

Females: A female subject is eligible to participate if she is not pregnant (as confirmed
by a negative serum human chorionic gonadotropin [HCG] test), not lactating, and at least
one of the following conditions applies:

- Non-reproductive potential as defined as pre-menopausal females with either documented
tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up
confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral
Oophorectomy. For Postmenopausal females as 12 months of spontaneous amenorrhea in
questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)
and estradiol levels consistent with menopause. 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 enrollment..

- Reproductive potential and agrees to follow one of the options listed in the Modified
List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive
Potential (FRP) from 30 days prior to the first dose of study medication and until at
least 30 days after the last dose of study medication and completion of the follow-up
visit.

- The Investigator is responsible for ensuring that subjects understand how to
properly use these methods of contraception.

- Capable of giving signed informed consent as described in the protocol which
includes compliance with the requirements and restrictions listed in the consent
form and in this protocol.

Exclusion Criteria:

- Subject with a positive anti-double stranded deoxyribonucleic acid (DNA [anti-dsDNA])
and confirmed diagnosis of systemic lupus erythematosus (SLE).

- Subject with current history of Suicidal Ideation Behavior (SIB) as measured using the
Columbia Suicide Severity Rating Scale (C-SSRS) or a history of attempted suicide.

- An active infection, or a history of infections as follows:

- Hospitalization for treatment of infection within 60 days before first dose (Day
1).

- Currently on any suppressive therapy for a chronic infection (such as
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical
mycobacteria).

- Use of parenteral (intravenous [IV] or intramuscular) antibiotics
(antibacterials, antivirals, antifungals, or antiparasitic agents) for an
infection within 60 days before first dose.

- A history of opportunistic infections within 1 year of screening (e.g.
pneumocystis jirovecii, cytomegalovirus [CMV] pneumonitis, aspergillosis). This
does not include infections that may occur in immunocompetent individuals, such
as fungal nail infections or vaginal candidiasis, unless it is of an unusual
severity or recurrent nature.

- Recurrent or chronic infection or other active infection that, in the opinion of
the Investigator might cause this study to be detrimental to the patient.

- History of Tuberculosis (TB), irrespective of treatment status.

- A positive diagnostic TB test at screening defined as a positive QuantiFERON-TB
Gold test or T-spot test. In cases where the QuantiFERON or T-spot test is
indeterminate, the subject may have the test repeated once, but they will not be
eligible for the study unless the second test is negative. In cases where the
QuantiFERON or T-spot test is positive, but a locally-read follow up chest x-ray,
shows no evidence of current or previous pulmonary tuberculosis, the subject may
be eligible for the study at the discretion of the Investigator and GSK Medical
Monitor.

- Electrocardiogram QT interval corrected for heart rate (QTc) > 450 milliseconds (msec)
or QTc > 480 msec for subjects with bundle branch block at screening.

The QTc is the QT interval corrected for heart rate according to either Bazett's formula
(QTcB), Fridericia's formula (QTcF), or another method, machine or manual over read. The
specific formula that will be used to determine eligibility and discontinuation for an
individual subject should be determined and documented prior to initiation of the study. In
other words, several different formulae cannot be used to calculate the QTc for an
individual subject and then the lowest QTc value used to include or discontinue the subject
from the


Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Arthritis, Rheumatoid

Intervention(s)

Drug: GSK2982772 60 mg

Drug: Placebo

Primary Outcome(s)

Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time Points [Time Frame: Baseline (Day 1 pre-dose), Days 8, 15, 29, 43, 57, 71 and 85]

Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method [Time Frame: Up to Day 112]

Change From Baseline in Vital Sign-heart Rate at Indicated Time Points [Time Frame: Baseline (Day 1 pre-dose), Days 8, 15, 29, 43, 57, 71 and 85]

Number of Participants With Worst Case Clinical Chemistry Parameters of Potential Clinical Importance (PCI) [Time Frame: Up to Day 112]

Change From Baseline in Respiratory Rate at Indicated Time Points [Time Frame: Baseline (Day 1 pre-dose), Days 8, 15, 29, 43, 57, 71 and 85]

Number of Participants With Worst Case Hematology Parameters of PCI [Time Frame: Up to Day 112]

Number of Participants With Non-serious Adverse Events (nSAEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability [Time Frame: Up to Day 112]

Change From Baseline in ECG PR Interval, QRS Duration, QT Interval, QTcB and QTcF at Indicated Time Points [Time Frame: Baseline (Day 1 pre-dose), Days 8, 15, 29, 43, 57, 71 and 85]

Change From Baseline in Body Temperature at Indicated Time Points [Time Frame: Baseline (Day 1 pre-dose), Days 8, 15, 29, 43, 57, 71 and 85]

Change From Baseline in Electrocardiogram (ECG) Heart Rate at Indicated Time Points [Time Frame: Baseline (Day 1 pre-dose), Days 8, 15, 29, 43, 57, 71 and 85]

Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Microscopy Method [Time Frame: Up to Day 112]

Secondary Outcome(s)

Change From Baseline in Bone Edema by Modified CARLOS [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Number of Participants Achieving Categorical DAS28-CRP Response Using European League Against Rheumatism [EULAR] Response [Time Frame: Day 85]

Percent Change From Baseline in Migration Inhibitory Factor (MIF) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Bone Edema by OMERACT-RAMRIS Scoring System [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Percent Change From Baseline in Monocyte Chemo Attractant Protein-1 (MCP-1) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Bone Erosions by the Rheumatoid Arthritis MRI Quantitative (RAMRIQ) Scoring System [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Percent Change From Baseline in Myeloid-related Protein 8/14 (MRP8/14) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Exchange Rate (Ktrans) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Percent Change From Baseline in Matrix Metalloproteinase-1 (MMP-1), MMP-3, and MMP-13 [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Bone Edema by RAMRIQ Scoring System [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Bone Erosion Total Score by "Outcome Measures in Rheumatology, Rheumatoid Arthritis Magnetic Resonance Image Scoring System (OMERACT-RAMRIS)" Scoring System [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Joint Space Narrowing by Modified CARLOS [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Interstitial Volume (Ve) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Trough Plasma Concentration of GSK2982772 on Day 85 [Time Frame: Day 85]

Change From Baseline in Joint Space Narrowing by OMERACT-RAMRIS Scoring System [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) Scores [Time Frame: Baseline (Day 1 pre-dose) and Day 85]

Change From Baseline in Synovitis by Modified CARLOS [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Synovitis by OMERACT-RAMRIS Scoring System [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Pre-dose Plasma Concentrations of GSK2982772 on Days 8 and 43 [Time Frame: Pre-dose on Day 8 and Day 43]

Change From Baseline in Bone Erosions by Modified Cartilage Loss Scoring System (CARLOS) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Number of Participants Achieving Categorical American College of rheumatology20/50/70 (ACR20/50/70) Response [Time Frame: Day 85]

Percent Change From Baseline in C-Reactive Protein (CRP) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Synovitis by RAMRIQ Scoring System [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Post-dose Plasma Concentrations of GSK2982772 on Days 1, 8, and 43 at 1, 2, 4 and 6 Hours [Time Frame: Days 1, 8 and 43: 1, 2, 4 and 6 hours post-dose]

Change From Baseline in Joint Space Narrowing by RAMRIQ Scoring System [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Fractional Volume of Blood Plasma (Vp) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Initial Rate of Enhancement (IRE) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Change From Baseline in Maximal Signal Intensity Enhancement (ME) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Percent Change From Baseline in Interleukin 6 (IL6) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Percent Change From Baseline in Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) [Time Frame: Baseline (Day 1 pre-dose), Days 43 and 85]

Pre-dose Plasma Concentrations of Methotrexate on Days 1, 8 and 43 [Time Frame: Pre-dose on Days 1, 8 and 43]

Secondary ID(s)

2016-000912-13

203168

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 01/11/2019
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02858492