A Phase 2 interventional study of GSK3117391 and Placebo in Arthritis, Rheumatoid, sponsored by GlaxoSmithKline. Terminated at 5 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-10-30.
Sponsored by GlaxoSmithKline · Phase 2, Interventional, and Treatment
GSK3117391 has the potential to complement existing therapies in the treatment of chronic inflammatory disorders such as rheumatoid arthritis (RA). This study will evaluate the efficacy, safety and tolerability of oral GSK3117391 (Dose A) administered to subjects with severe RA despite treatment with disease-modifying anti-rheumatic drugs (DMARDs). This is a randomised, double-blind (sponsor open), multicentre, placebo-controlled, parallel group study. The total maximum study duration is approximately 10 weeks. Following a screening period of up to 28 days, subjects will be randomized (1:1) to placebo or GSK3117391 (Dose A) administered orally for a period of 28 days. Subjects will be followed up for 7 to 14 days post final dose. Approximately 40 subjects with severe RA will be randomised into the study.
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Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the following conditions applies:
Females of reproductive potential must have proper and established use of a Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) 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 HCG pregnancy test, (serum at screening visit and urine for subsequent visits) with a sensitivity of at least 25 international units per litre [IU/L]) is required at the screening visit, between Day -7 to -4 and on Day 1 prior to dose administration. Further pregnancy tests are required at the weekly study visits and the follow-up visit.
Exclusion Criteria:
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:
Evidence of active or latent infection with Mycobacterium tuberculosis (TB), as defined by all of the following:
Subjects will receive GSK3117391 (Dose A) for 28 days.
Drug: GSK3117391
Subjects will receive placebo for 28 days.
Drug: Placebo
GSK3117391 (Dose A) is a white, opaque, gelatin capsule.
Placebo is a white, opaque, gelatin capsule.
Change From Baseline in Disease Activity Score for 28 Different Joints With (DAS28) C-reactive Protein (CRP) at Day 28
The DAS28 score is a derived measurement with differential weighing given to each component as: Tender/Painful Joint Count (TJC28) and swollen joint count (SJC28) both scored 0-28 (higher scores indicate higher disease activity), CRP measured in milligrams per liter and Patient's Global Assessment of Arthritis (PtGA) (visual analogue scale with values from 0 \[best\] to 100 \[worst\]). The formula used to calculate DAS28 score was 0.56 multiplied by square root of TJC28 plus 0.28 multiplied by square root of SJC28 plus 0.36 log of (CRP plus 1) plus 0.014 multiplied by PtGA plus 0.96. DAS28 scores ranged from 0 (best) to 10 (worst). A negative change from Baseline value indicated improvement. Baseline was defined at Day 1 (pre-dose). Change from Baseline was post-baseline value minus the value at Baseline. Safety Population consisted of all participants who received at least one dose of study medication. Individual participant data at Day 28 has been presented.
Time frame: Baseline (pre-dose, Day 1) and Day 28
Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect and other situations which involve medical or scientific judgment, and is associated with liver injury and impaired liver function.
Time frame: Up to Day 44
Number of Participants With Vital Signs Values of Potential Clinical Importance (PCI)
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), temperature and heart rate were measured in semi-supine position after 5 minutes rest. The PCI ranges for vitals were as follows; for SBP \<85 or \>160 millimeters of mercury (mmHg), for DBP \<45 or \>100 mmHg, for heart rate \<40 or \>110 beats per minute and for temperature \<36 or \>38 Celsius. The number of participants with vital signs of PCI have been presented.
Time frame: Up to Day 44
Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Twelve-lead ECGs were performed during the study using an automated ECG machine, after 5 minutes of rest. The number of participants with abnormal ECG findings were reported and categorized as clinically significant and not clinically significant. Any value for ECG parameters out of the following normal range was considered as clinically significant abnormality; for PR interval \<110 or \>220 milliseconds, for QRS interval \<75 or \>110 milliseconds and for QT corrected interval \<450 milliseconds.
Time frame: Up to Day 44
Number of Participants With Values for Clinical Chemistry Parameters of PCI
Blood samples were collected for analysis of clinical chemistry parameters. The PCI ranges were for Albumin \<30 millimoles/Liter (mmol/L), Calcium (\<2 or \>2.75 mmol/L), Creatinine (\>44.2 mmol/L), Glucose (\<3 or \>9 mmol/L), Magnesium (\<0.5 or \>1.23 mmol/L), Phosphorus (\<0.8 or \> 1.6 mmol/L), Potassium (\<3 or \> 5.5 mmol/L), Sodium (\<130 or 150 mmol/L), Total carbon-dioxide (\<18 or \> 32 mmol/L), Alanine aminotransferase (\>= 2x Upper Limit of Normal \[ULN\]), Aspartate aminotransferase (\>=2x ULN), alkaline phosphatase (\>=2x ULN), and total bilirubin (\>=1.5xULN). The number of participants with values for clinical chemistry parameters of PCI have been presented
Time frame: Up to Day 44
Number of Participants With Values for Hematology Parameters of PCI
Blood samples were collected for analysis of hematology parameters. PCI ranges were for platelets (\< 50 or \>550 × 10\^9 cells/L), white blood cell count (\<3 or \>14 × 10\^9 cells/L), hemoglobin (\<90 or \>180 g/L), hematocrit (if proportion of red blood cells in blood was \<0.3 or \>0.54), lymphocytes (\<0.5 × 10\^9 cells/L), neutrophils (\<1.0 × 10\^9 cells/L) and monocytes (\<0.2 or 1.5 × 10\^9 cells/L). The number of participants with values for hematology parameters of PCI have been presented.
Time frame: Up to Day 44
Number of Participants With Abnormal Findings for Urinalysis Parameters
Urine samples were collected for the analysis of specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones at specified time points. The number of participants with abnormal urinalysis findings have been presented.
Time frame: Up to Day 44
Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Criteria
A participant was considered to be a responder according to the ACR20 criteria if the participant had at least 20% improvement in both the tender joint count and swollen joint count measures, and 20% improvement in at least 3 of the following 5 measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. This analysis was planned but data was not collected , as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Up to Day 44
Percentage of Participants Achieving ACR 50, Criteria
A participant was considered to be a responder according to the ACR50 criteria if the participant had at least 50% improvement in both the tender joint count and swollen joint count measures, and 50% improvement in at least 3 of the following 5 measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. This analysis was planned but data was not collected , as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Up to Day 44
Percentage of Participants Achieving ACR 70, Criteria
A participant was considered to be a responder according to the ACR70 criteria if the participant had at least 70% improvement in both the tender joint count and swollen joint count measures, and 70% improvement in at least 3 of the following 5 measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. This analysis was planned but data was not collected , as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Up to Day 44
Number of Swollen Joints Assessed Using 28-joint Counts
The total number of joints ranging from 0 to 28 joints with a present swelling were assessed. The following 28 joints were taken into account for SJC28: Shoulder (2 joints), Knee (2), Elbow (2), Wrist (2), Fingers (Joints for proximal interphalangeal \[PIP\] and metacarpophalangeal \[MCP\]: 20). No missing observations were considered. Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
Time frame: Days 1, 7, 14, 21, 28 and Follow-up (Day 44)
Number of Tender/Painful Joints Assessed Using 28-joint Counts
The total number of joints ranging from 0 to 28 joints with a present tenderness were assessed. The following 28 joints were taken into account for TJC28: Shoulder (2 joints), Knee (2), Elbow (2), Wrist (2), Fingers (PIP and MCP: 20). No missing observations were considered. Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
Time frame: Days 1, 7, 14, 21, 28 and Follow-up (Day 44)
Change From Baseline in DAS28-CRP Over Time
The DAS28 score is a derived measurement with differential weighing given to each component as: TJC28 and SJC28 both scored 0-28 (higher scores indicate higher disease activity), CRP measured in milligrams per liter and PtGA (visual analogue scale with values from 0 \[best\] to 100 \[worst\]). The formula used to calculate DAS28 score was 0.56 multiplied by square root of TJC28 plus 0.28 multiplied by square root of SJC28 plus 0.36 log of (CRP plus 1) plus 0.014 multiplied by PtGA plus 0.96. DAS28 scores ranged from 0 (best) to 10 (worst). A negative change from Baseline value indicated improvement. Baseline was defined at Day 1 (pre-dose). Change from Baseline was post-baseline value minus the value at Baseline. Only data available at specified visit with respect to the participant has been presented.
Time frame: Baseline (pre-dose, Day 1) and Days 7, 14, 21, 28, Follow-up (Day 44)
Assessment of Disease Activity Using Patient's Global Assessment of Arthritis (PtGA)
Participants completed the global assessment of disease activity using the PtGA item using visual analogue scale (VAS) ranging from "0" (none) to "100" (extremely active), respectively. Individual participant score has been presented. Only data available at specified visit with respect to the participant has been presented.
Time frame: Days 1, 7, 14, 21, 28 and Follow-up (Day 44)
Change From Baseline in CRP
Blood samples were collected at indicated time points for the analysis of CRP. Change from Baseline, was defined as the post-baseline value minus the value at Baseline. Baseline was defined as the value from the Day 1 (pre-dose). Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
Time frame: Baseline (pre-dose, Day 1) and Days 7, 14, 21, 28, Follow-up (Day 44)
Plasma Concentrations of GSK3117391 and GSK3339189
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. The Pharmacokinetic (PK) Population was defined as participants in the Safety Population who received an active dose and for whom a PK sample was obtained and analyzed. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Maximum Observed Blood Concentration (Cmax) of GSK3117391 and GSK3339189
Cmax was defined as the maximum concentration of drug in the plasma. Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified time points. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Time to Cmax (Tmax)of GSK3117391 and GSK3339189
Tmax was defined as time required to achieve Cmax for drug, in the plasma. Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25 hour, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC[0-t]) of GSK3117391 and GSK3339189
Blood samples were planned to be collected for GSK3117391, and its acid metabolite GSK3339189, at the specified time points. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25 hour, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
AUC From Time Zero to the Time of Next Dosing (AUC[0- Tau]) of GSK3117391 and GSK3339189
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
AUC From Time Zero to Infinity (AUC[0-infinity]) of GSK3117391 and GSK3339189
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Apparent Terminal Phase Half-life (t1/2) of GSK3117391 and GSK3339189
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Trough Concentration (Ctau) of GSK3117391 and GSK3339189
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Observed Accumulation Ratio (Ro) of GSK3117391 and GSK3339189
Blood samples were planned to be collected for GSK3117391, and its acid metabolite GSK3339189, at the specified timepoints. Accumulation ratio was planned to be determined from the ratio of AUC from time zero to time of next dosing (AUC \[0-tau\]) following single dose administration /AUC (0-tau) on repeat dose administration. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Apparent Total Clearance (CL/F) of GSK3117391 and GSK3339189
CL/F, describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). Blood samples, were planned to be collected for GSK3117391, and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Apparent Volume of Distribution (V/F) of GSK3117391 and GSK3339189
V/F, is defined as the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma. Blood samples, were planned to be collected for GSK3117391, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 1) and 24 hours (Day 2) post-dose; pre-dose, 0.25, 0.5, 1, 4, and 8 hours (Day 3) post-dose; pre-dose (Day 7); pre-dose (Day 21); pre-dose, 0.25, 0.5, 1, 2, 4, 6, 10 hours (Day 27) and 24 hours post-dose
Change From Baseline in Monocyte Count
Blood samples were collected at the indicated time points for the analysis of monocytes. Change from Baseline was defined as the post-Baseline value minus the value at Baseline. Baseline was defined as the value from the Day 1 (pre-dose). Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
Time frame: Baseline (pre-dose, Day 1); 1, 4, 6, 10 Hours on Day 1; Day 2 (24 Hours); Pre-dose, 1, 4, 8 Hours on Day 3; Pre-dose on Day 7; Day 14; Pre-dose on Day 21; Pre-dose, 1, 4, 6, 10 Hours on Day 27; Day 28 (24 Hours); Day 30 (72 Hours) and Day 44 (Follow-up)
Changes From Baseline in Soluble Cytokine
Change from Baseline, was defined as the post-Baseline value minus the value at Baseline. Baseline was defined as the value from the Day 1 (pre-dose). Blood samples were planned to be analyzed by flow cytometry for cell markers to determine any changes after treatment with GSK3117391. This analysis was planned but the assay was not performed due to sample size being too small at the time of early study termination.
Time frame: Baseline (pre-dose, Day 1) and up to 44 Days
Changes From Baseline in Myeloid-related Protein 8/14 (MRP8/14)
Blood samples were collected at the indicated time points and analyzed by flow cytometry for cell markers to determine any changes after treatment with GSK3117391. Change from Baseline was defined as the post-Baseline value minus the value at Baseline. Baseline was defined as the value from the Day 1 (pre-dose). Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
Time frame: Baseline (pre-dose, Day 1); 1, 4, 10 Hours on Day 1; Day 2 (24 Hours); Pre-dose, 8 Hours on Day 3; Pre-dose on Day 7; Day 14; Pre-dose on Day 21; Pre-dose on Day 27; Day 28 (24 Hours) and Day 44 (Follow-up)
This study was conducted in participants with severe, active rheumatoid arthritis receiving GSK3117391, 40 milligrams (mg) or placebo at one center in Poland and one in Romania.
| Milestone | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Started | 2 | 1 |
| Completed | 1 | 1 |
| Not completed | 1 | 0 |
| Withdrew: Protocol-defined stop criteria reached | 1 | 0 |
The DAS28 score is a derived measurement with differential weighing given to each component as: Tender/Painful Joint Count (TJC28) and swollen joint count (SJC28) both scored 0-28 (higher scores indicate higher disease activity), CRP measured in milligrams per liter and Patient's Global Assessment of Arthritis (PtGA) (visual analogue scale with values from 0 \[best\] to 100 \[worst\]). The formula used to calculate DAS28 score was 0.56 multiplied by square root of TJC28 plus 0.28 multiplied by square root of SJC28 plus 0.36 log of (CRP plus 1) plus 0.014 multiplied by PtGA plus 0.96. DAS28 scores ranged from 0 (best) to 10 (worst). A negative change from Baseline value indicated improvement. Baseline was defined at Day 1 (pre-dose). Change from Baseline was post-baseline value minus the value at Baseline. Safety Population consisted of all participants who received at least one dose of study medication. Individual participant data at Day 28 has been presented.
| Units on a scale | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Change From Baseline in Disease Activity Score for 28 Different Joints With (DAS28) C-reactive Protein (CRP) at Day 28 | -0.38 | -1.73 |
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect and other situations which involve medical or scientific judgment, and is associated with liver injury and impaired liver function.
| Participants | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Any non-SAE | 2 | 0 |
| Any SAE | 0 | 0 |
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), temperature and heart rate were measured in semi-supine position after 5 minutes rest. The PCI ranges for vitals were as follows; for SBP \<85 or \>160 millimeters of mercury (mmHg), for DBP \<45 or \>100 mmHg, for heart rate \<40 or \>110 beats per minute and for temperature \<36 or \>38 Celsius. The number of participants with vital signs of PCI have been presented.
| Participants | Placebo | GSK3117391, 40 mg |
|---|---|---|
| SBP | 0 | 0 |
| DBP | 0 | 0 |
| Heart rate | 0 | 0 |
| Temperature | 0 | 0 |
Twelve-lead ECGs were performed during the study using an automated ECG machine, after 5 minutes of rest. The number of participants with abnormal ECG findings were reported and categorized as clinically significant and not clinically significant. Any value for ECG parameters out of the following normal range was considered as clinically significant abnormality; for PR interval \<110 or \>220 milliseconds, for QRS interval \<75 or \>110 milliseconds and for QT corrected interval \<450 milliseconds.
| Participants | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Abnormal-clinically significant | 0 | 0 |
| Abnormal-Not clinically significant | 1 | 0 |
Blood samples were collected for analysis of clinical chemistry parameters. The PCI ranges were for Albumin \<30 millimoles/Liter (mmol/L), Calcium (\<2 or \>2.75 mmol/L), Creatinine (\>44.2 mmol/L), Glucose (\<3 or \>9 mmol/L), Magnesium (\<0.5 or \>1.23 mmol/L), Phosphorus (\<0.8 or \> 1.6 mmol/L), Potassium (\<3 or \> 5.5 mmol/L), Sodium (\<130 or 150 mmol/L), Total carbon-dioxide (\<18 or \> 32 mmol/L), Alanine aminotransferase (\>= 2x Upper Limit of Normal \[ULN\]), Aspartate aminotransferase (\>=2x ULN), alkaline phosphatase (\>=2x ULN), and total bilirubin (\>=1.5xULN). The number of participants with values for clinical chemistry parameters of PCI have been presented
| Participants | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Number of Participants With Values for Clinical Chemistry Parameters of PCI | 0 | 0 |
Blood samples were collected for analysis of hematology parameters. PCI ranges were for platelets (\< 50 or \>550 × 10\^9 cells/L), white blood cell count (\<3 or \>14 × 10\^9 cells/L), hemoglobin (\<90 or \>180 g/L), hematocrit (if proportion of red blood cells in blood was \<0.3 or \>0.54), lymphocytes (\<0.5 × 10\^9 cells/L), neutrophils (\<1.0 × 10\^9 cells/L) and monocytes (\<0.2 or 1.5 × 10\^9 cells/L). The number of participants with values for hematology parameters of PCI have been presented.
| Participants | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Number of Participants With Values for Hematology Parameters of PCI | 1 | 1 |
Urine samples were collected for the analysis of specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones at specified time points. The number of participants with abnormal urinalysis findings have been presented.
| Participants | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Number of Participants With Abnormal Findings for Urinalysis Parameters | 0 | 0 |
A participant was considered to be a responder according to the ACR20 criteria if the participant had at least 20% improvement in both the tender joint count and swollen joint count measures, and 20% improvement in at least 3 of the following 5 measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. This analysis was planned but data was not collected , as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
A participant was considered to be a responder according to the ACR50 criteria if the participant had at least 50% improvement in both the tender joint count and swollen joint count measures, and 50% improvement in at least 3 of the following 5 measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. This analysis was planned but data was not collected , as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
A participant was considered to be a responder according to the ACR70 criteria if the participant had at least 70% improvement in both the tender joint count and swollen joint count measures, and 70% improvement in at least 3 of the following 5 measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. This analysis was planned but data was not collected , as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
The total number of joints ranging from 0 to 28 joints with a present swelling were assessed. The following 28 joints were taken into account for SJC28: Shoulder (2 joints), Knee (2), Elbow (2), Wrist (2), Fingers (Joints for proximal interphalangeal \[PIP\] and metacarpophalangeal \[MCP\]: 20). No missing observations were considered. Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
| Swollen joints | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Participant 1; Day 1; n=1,0 | 7 | — |
| Participant 1; Day 7; n=1,0 | 2 | — |
| Participant 1; Follow-up (Day 44); n=1,0 | 1 | — |
| Participant 2; Day 1; n=1,0 | 8 | — |
| Participant 2; Day 7; n=1,0 | 7 | — |
| Participant 2; Day 14; n=1,0 | 4 | — |
| Participant 2; Day 21; n=1,0 | 1 | — |
| Participant 2; Day 28; n=1,0 | 1 | — |
| Participant 2; Follow-up (Day 44); n=1,0 | 1 | — |
| Participant 3; Day 1;n=0,1 | — | 28 |
| Participant 3; Day 7;n=0,1 | — | 18 |
| Participant 3; Day 14;n=0,1 | — | 12 |
| Participant 3; Day 21;n=0,1 | — | 7 |
| Participant 3; Day 28;n=0,1 | — | 11 |
| Participant 3; Follow-up (Day 44);n=0,1 | — | 5 |
The total number of joints ranging from 0 to 28 joints with a present tenderness were assessed. The following 28 joints were taken into account for TJC28: Shoulder (2 joints), Knee (2), Elbow (2), Wrist (2), Fingers (PIP and MCP: 20). No missing observations were considered. Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
| Tender/painful joints | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Participant 1; Day 1; n=1, 0 | 12 | — |
| Participant 1; Day 7; n=1, 0 | 8 | — |
| Participant 1; Follow-up (Day 44); n=1, 0 | 1 | — |
| Participant 2; Day 1; n=1, 0 | 9 | — |
| Participant 2; Day 7; n=1, 0 | 7 | — |
| Participant 2; Day 14; n=1, 0 | 5 | — |
| Participant 2; Day 21; n=1, 0 | 7 | — |
| Participant 2; Day 28; n=1, 0 | 4 | — |
| Participant 2; Follow-up (Day 44); n=1, 0 | 1 | — |
| Participant 3; Day 1; n=0,1 | — | 28 |
| Participant 3; Day 7; n=0,1 | — | 26 |
| Participant 3; Day 14; n=0,1 | — | 19 |
| Participant 3; Day 21; n=0,1 | — | 18 |
| Participant 3; Day 28; n=0,1 | — | 19 |
| Participant 3; Follow-up (Day 44); n=0,1 | — | 8 |
The DAS28 score is a derived measurement with differential weighing given to each component as: TJC28 and SJC28 both scored 0-28 (higher scores indicate higher disease activity), CRP measured in milligrams per liter and PtGA (visual analogue scale with values from 0 \[best\] to 100 \[worst\]). The formula used to calculate DAS28 score was 0.56 multiplied by square root of TJC28 plus 0.28 multiplied by square root of SJC28 plus 0.36 log of (CRP plus 1) plus 0.014 multiplied by PtGA plus 0.96. DAS28 scores ranged from 0 (best) to 10 (worst). A negative change from Baseline value indicated improvement. Baseline was defined at Day 1 (pre-dose). Change from Baseline was post-baseline value minus the value at Baseline. Only data available at specified visit with respect to the participant has been presented.
| Scores on a Scale | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Participant 1; Day 7 ;n=1, 0 | -0.48 | — |
| Participant 1; Follow-up (Day 44) ;n=1, 0 | -2.84 | — |
| Participant 2; Day 7 ;n=1, 0 | -0.24 | — |
| Participant 2; Day 14 ;n=1, 0 | -0.96 | — |
| Participant 2; Day 21 ;n=1, 0 | -0.77 | — |
| Participant 2; Day 28 ;n=1, 0 | -0.38 | — |
| Participant 2; Follow-up (Day 44) ;n=1, 0 | -2.30 | — |
| Participant 3; Day 7 ;n=0, 1 | — | -0.79 |
| Participant 3; Day 14 ;n=0, 1 | — | -1.35 |
| Participant 3; Day 21 ;n=0, 1 | — | -1.54 |
| Participant 3; Day 28 ;n=0, 1 | — | -1.73 |
| Participant 3; Follow-up (Day 44) ;n=0, 1 | — | -2.59 |
Participants completed the global assessment of disease activity using the PtGA item using visual analogue scale (VAS) ranging from "0" (none) to "100" (extremely active), respectively. Individual participant score has been presented. Only data available at specified visit with respect to the participant has been presented.
| Scores on a Scale | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Participant 1; Day 1; n=1, 0 | 58 | — |
| Participant 1; Day 7; n=1, 0 | 73 | — |
| Participant 1; Follow-up (Day 44); n=1, 0 | 25 | — |
| Participant 2; Day 1; n=1, 0 | 87 | — |
| Participant 2; Day 7; n=1, 0 | 86 | — |
| Participant 2; Day 14; n=1, 0 | 71 | — |
| Participant 2; Day 21; n=1, 0 | 78 | — |
| Participant 2; Day 28; n=1, 0 | 96 | — |
| Participant 2; Follow-up (Day 44); n=1, 0 | 33 | — |
| Participant 3; Day 1; n=0,1 | — | 100 |
| Participant 3; Day 7; n=0,1 | — | 82 |
| Participant 3; Day 14; n=0,1 | — | 79 |
| Participant 3; Day 21; n=0,1 | — | 74 |
| Participant 3; Day 28; n=0,1 | — | 72 |
| Participant 3; Follow-up (Day 44); n=0,1 | — | 62 |
Blood samples were collected at indicated time points for the analysis of CRP. Change from Baseline, was defined as the post-baseline value minus the value at Baseline. Baseline was defined as the value from the Day 1 (pre-dose). Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
| Milligrams per liter | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Participant 1; Day 7; n=1, 0 | 0.50 | — |
| Participant 1; Follow-up (Day 44); n=1, 0 | -11.20 | — |
| Participant 2; Day 7; n=1, 0 | 0.50 | — |
| Participant 2; Day 14; n=1, 0 | -1.60 | — |
| Participant 2; Day 21; n=1, 0 | 1.60 | — |
| Participant 2; Day 28; n=1, 0 | 30.20 | — |
| Participant 2; Follow-up (Day 44); n=1, 0 | 2.20 | — |
| Participant 3; Day 7; n=0,1 | — | -14.00 |
| Participant 3; Day 14; n=0,1 | — | -3.10 |
| Participant 3; Day 21; n=0,1 | — | 23.40 |
| Participant 3; Day 28; n=0,1 | — | -22.40 |
| Participant 3; Follow-up (Day 44); n=0,1 | — | 26.70 |
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. The Pharmacokinetic (PK) Population was defined as participants in the Safety Population who received an active dose and for whom a PK sample was obtained and analyzed. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Cmax was defined as the maximum concentration of drug in the plasma. Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified time points. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Tmax was defined as time required to achieve Cmax for drug, in the plasma. Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Blood samples were planned to be collected for GSK3117391, and its acid metabolite GSK3339189, at the specified time points. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Blood samples were planned to be collected for GSK3117391 and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Blood samples were planned to be collected for GSK3117391, and its acid metabolite GSK3339189, at the specified timepoints. Accumulation ratio was planned to be determined from the ratio of AUC from time zero to time of next dosing (AUC \[0-tau\]) following single dose administration /AUC (0-tau) on repeat dose administration. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
CL/F, describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). Blood samples, were planned to be collected for GSK3117391, and its acid metabolite GSK3339189, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
V/F, is defined as the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma. Blood samples, were planned to be collected for GSK3117391, at the specified timepoints. This analysis was planned but was not performed as the sample size was too small and study was terminated pre-maturely, by the sponsor following internal review.
No measurements were reported for this outcome.
Blood samples were collected at the indicated time points for the analysis of monocytes. Change from Baseline was defined as the post-Baseline value minus the value at Baseline. Baseline was defined as the value from the Day 1 (pre-dose). Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
| Giga cells per liter | GSK3339189 | GSK3117391, 40 mg |
|---|---|---|
| Participant 1; Day 1; 1 Hour; n=1,0 | -0.11 | — |
| Participant 1;Day 1; 4 Hours; n=1,0 | -0.04 | — |
| Participant 1;Day 1; 6 Hours; n=1,0 | -0.34 | — |
| Participant 1;Day 1; 10 Hours; n=1,0 | -0.13 | — |
| Participant 1;Day 3; Pre-dose; n=1,0 | -0.68 | — |
| Participant 1;Day 3; 1 Hour; n=1,0 | -0.59 | — |
| Participant 1; Day 3; 4 Hours; n=1,0 | -0.56 | — |
| Participant 1; Day 3; 8 Hours; n=1,0 | -0.02 | — |
| Participant 1;Day 7; Pre-dose; n=1,0 | -0.25 | — |
| Participant 1;Follow-up (Day 44); n=1,0 | 0.10 | — |
| Participant 2; Day 1; 1 Hour; n=1,0 | 0.25 | — |
| Participant 2;Day 1; 4 Hours; n=1,0 | 0.27 | — |
| Participant 2;Day 1; 6 Hours; n=1,0 | 0.24 | — |
| Participant 2;Day 1; 10 Hours; n=1,0 | 0.31 | — |
| Participant 2;Day 2; 24 Hours; n=1,0 | 0.05 | — |
| Participant 2;Day 3; Pre-dose; n=1,0 | 0.27 | — |
| Participant 2;Day 3; 1 Hour; n=1,0 | 0.27 | — |
| Participant 2; Day 3; 4 Hours; n=1,0 | 0.24 | — |
| Participant 2; Day 3; 8 Hours; n=1,0 | 0.05 | — |
| Participant 2;Day 7; Pre-dose; n=1,0 | 0.23 | — |
| Participant 2;Day 14; n=1,0 | 0.02 | — |
| Participant 2;Day 21; Pre-dose; n=1,0 | 0.12 | — |
| Participant 2;Day 27; Pre-dose; n=1,0 | 0.02 | — |
| Participant 2;Day 27; 1 Hour; n=1,0 | 0.23 | — |
| Participant 2;Day 27; 4 Hours; n=1,0 | 0.02 | — |
| Participant 2;Day 27; 6 Hours; n=1,0 | -0.28 | — |
| Participant 2;Day 27; 10 Hours; n=1,0 | 0.28 | — |
| Participant 2;Day 28; 24 Hours; n=1,0 | 0.30 | — |
| Participant 2; Day 30; 72 Hours; n=1,0 | 0.02 | — |
| Participant 2; Follow-up (Day 44); n=1,0 | 0.09 | — |
| Participant 3; Day 1; 1 Hour; n=0,1 | — | -0.84 |
| Participant 3;Day 1; 4 Hours; n=0,1 | — | -0.14 |
| Participant 3;Day 1; 6 Hours; n=0,1 | — | 0.29 |
| Participant 3;Day 1; 10 Hours; n=0,1 | — | 0.30 |
| Participant 3;Day 2; 24 Hours; n=0,1 | — | 0.29 |
| Participant 3;Day 3; Pre-dose; n=0,1 | — | -0.96 |
| Participant 3;Day 3; 1 Hour; n=0,1 | — | -0.77 |
| Participant 3; Day 3; 8 Hours; n=0,1 | — | -0.90 |
| Participant 3;Day 7; Pre-dose; n=0,1 | — | -0.79 |
| Participant 3;Day 14; n=0,1 | — | -1.11 |
| Participant 3;Day 21; Pre-dose; n=0,1 | — | -0.91 |
| Participant 3;Day 27; Pre-dose; n=0,1 | — | 0.10 |
| Participant 3;Day 27; 1 Hour; n=0,1 | — | -0.99 |
| Participant 3;Day 27; 4 Hours; n=0,1 | — | -0.97 |
| Participant 3;Day 27; 6 Hours; n=0,1 | — | -0.14 |
| Participant 3;Day 27; 10 Hours; n=0,1 | — | -1.06 |
| Participant 3;Day 28; 24 Hours; n=0,1 | — | -0.94 |
| Participant 3; Day 30; 72 Hours; n=0,1 | — | -0.91 |
| Participant 3; Follow-up (Day 44); n=0,1 | — | -0.70 |
Change from Baseline, was defined as the post-Baseline value minus the value at Baseline. Baseline was defined as the value from the Day 1 (pre-dose). Blood samples were planned to be analyzed by flow cytometry for cell markers to determine any changes after treatment with GSK3117391. This analysis was planned but the assay was not performed due to sample size being too small at the time of early study termination.
No measurements were reported for this outcome.
Blood samples were collected at the indicated time points and analyzed by flow cytometry for cell markers to determine any changes after treatment with GSK3117391. Change from Baseline was defined as the post-Baseline value minus the value at Baseline. Baseline was defined as the value from the Day 1 (pre-dose). Individual participant data has been presented. Only data available at specified visit with respect to the participant has been presented.
| Milligram per liter | Placebo | GSK3117391, 40 mg |
|---|---|---|
| Participant 1; Day 1; 1 Hour; n=1,0 | -0.36 | — |
| Participant 1;Day 1; 4 Hours; n=1,0 | -0.57 | — |
| Participant 1;Day 1; 10 Hours; n=1,0 | -0.46 | — |
| Participant 1;Day 2; 24 Hours; n=1,0 | -0.52 | — |
| Participant 1;Day 3; Pre-dose; n=1,0 | -0.21 | — |
| Participant 1; Day 3; 8 Hours; n=1,0 | -0.21 | — |
| Participant 1;Day 7; Pre-dose; n=1,0 | -0.39 | — |
| Participant 1; Follow-up (Day 44); n=1,0 | -1.22 | — |
| Participant 2; Day 1; 1 Hour; n=1,0 | 0.27 | — |
| Participant 2;Day 1; 4 Hours; n=1,0 | -1.13 | — |
| Participant 2;Day 1; 10 Hours; n=1,0 | 0.37 | — |
| Participant 2;Day 2; 24 Hours;n=1,0 | -2.34 | — |
| Participant 2;Day 3; Pre-dose; n=1,0 | 0.20 | — |
| Participant 2; Day 3; 8 Hours;n=1,0 | -0.31 | — |
| Participant 2;Day 7; Pre-dose; n=1,0 | 2.29 | — |
| Participant 2;Day 14;n=1,0 | 3.76 | — |
| Participant 2;Day 21; Pre-dose; n=1,0 | -0.78 | — |
| Participant 2;Day 27; Pre-dose; n=1,0 | 0.67 | — |
| Participant 2;Day 28; 24 Hours; n=1,0 | -2.51 | — |
| Participant 2;Follow-up (Day 44); n=1,0 | -1.43 | — |
| Participant 3; Day 1; 1 Hour; n=0,1 | — | -0.53 |
| Participant 3;Day 1; 4 Hours; n=0,1 | — | 0.32 |
| Participant 3;Day 1; 10 Hours; n=0,1 | — | 0.89 |
| Participant 3;Day 2; 24 Hours; n=0,1 | — | 0.64 |
| Participant 3;Day 3; Pre-dose; n=0,1 | — | 2.95 |
| Participant 3; Day 3; 8 Hours; n=0,1 | — | 7.06 |
| Participant 3;Day 7; Pre-dose; n=0,1 | — | 5.21 |
| Participant 3;Day 14; n=0,1 | — | 4.14 |
| Participant 3;Day 21; Pre-dose; n=0,1 | — | 5.90 |
| Participant 3;Day 27; Pre-dose; n=0,1 | — | 1.41 |
| Participant 3;Day 28; 24 Hours; n=0,1 | — | -1.85 |
| Participant 3;Follow-up (Day 44); n=0,1 | — | -0.71 |
Collected over All non-SAEs and SAEs were collected from start of the study treatment (Day 1) up to Day 44.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 0/2 (0%) | 0/2 (0%) | 2/2 (100%) |
| GSK3117391, 40 mg | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) |
| Event | Placebo | GSK3117391, 40 mg |
|---|---|---|
| LeukopeniaBlood and lymphatic system disorders | 1/2 | 0/1 |
| Rheumatoid arthritisMusculoskeletal and connective tissue disorders | 1/2 | 0/1 |
| Age, Continuous(Years) | Placebo | GSK3117391, 40 mg | Total |
|---|---|---|---|
| Mean | 58.5 ± 14.85 | 46 ± NA | 54.3 ± 12.74 |
| Sex: Female, Male(Participants) | Placebo | GSK3117391, 40 mg | Total |
|---|---|---|---|
| Female | 2 | 1 | 3 |
| Male | 0 | 0 | 0 |
| Race/Ethnicity, Customized(Participants) | Placebo | GSK3117391, 40 mg | Total |
|---|---|---|---|
| White - White/Caucasian/European Heritage | 2 | 1 | 3 |
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GlaxoSmithKline