Osteoarthritis, Knee, Pain
Conditions
Keywords
Osteoarthritis, Musculoskeletal Diseases, 209978, GSK3858279, Efficacy, Safety, Pharmacokinetics
Brief summary
This is dose-finding study of GSK3858279 in participants with moderate to severe knee osteoarthritis pain. The purpose of this study is to investigate and provide the data necessary to select the optimal effective and safe dose(s) of GSK3858279.
Interventions
DRUGGSK3858279
GSK3858279 will be administered.
DRUGPlacebo
Placebo will be administered.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Participant must be 40 to 80 years of age inclusive * OA of the index knee as defined by symptomatic for ≥ 6 months with a clinical diagnosis of OA as per American College of Rheumatology (ACR) clinical diagnosis criteria. * Kellgren and Lawrence (KL) score ≥ 2 on X-ray in the index knee * An average of the average daily pain score of ≥4 and less than or equal to (≤) 9 by the 11-point NRS (0-10) * Body mass index (BMI) of \< 40 kilogram per meter square (kg/m\^2) (inclusive). * Capable of giving signed informed consent.
Exclusion criteria
* History or presence of cardiovascular, renal, gastrointestinal, lymphatic disorders which in the opinion of the investigator would interfere with the study procedures and/or assessments. * History or current evidence of any inflammatory arthritis such as rheumatoid arthritis, infective arthritis, Paget's disease, osteonecrosis, osteoporotic fracture, or any other joint disease that in the Investigator's opinion would interfere with the assessment of pain and other symptoms of osteoarthritis. * History of significant trauma or surgery to a knee or hip within the last 6 months. * Current immunodeficiency diseases including but not limited to acquired immunodeficiency disorder or immunoglobulin deficiency. * Current or previous active Mycobacterium tuberculosis * History or evidence of clinically significant multiple or severe drug allergies * History of malignancy within the last 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. * Alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN). * Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \< 35 percent (%) * Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) * Evidence of renal insufficiency, indicated by estimated creatinine clearance \< 60 milliliter/ minute (mL/min)/1.73 square meter (m\^2) at screening. * Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weekly Average of Average Daily Knee Pain Intensity Using Numeric Rating Scale at Week 12 | Baseline (Day -7 to Day -1) and at Week 12 | Change from Baseline in knee pain due to Osteoarthritis were reported by weekly average of average daily pain numeric rating scale (NRS) at Week 12. The pain NRS is an 11-point scale (ranging from 0-10) for self-reporting of average daily knee pain where 0 indicates no pain, and 10 indicates the worst possible pain. For each participant, the weekly average of average daily pain score was calculated using the mean value of available daily pain scores falling in the assessment window for each week. A negative change from baseline indicates an improvement in pain. Participants were asked to complete the pain NRS questionnaire at the same time in the evening each day. Baseline scores were assigned based on an average of 7 days prior to day 1 dosing visit. Posterior mean change from baseline, 95 percent (%) credible interval (CI) was derived using Bayesian mixed model repeated measures. The data presented are the posterior mean with 95% confidence interval refers to 95% credible interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in WOMAC Physical Function Subscale Score at Week 12 | Baseline (Day 1) and at Week 12 | The WOMAC function subscale have a recall period of 48 hours and include 17 items of daily function assessments. The total WOMAC physical function subscale score ranges from 0-10 scale; where 0 is no difficulty and 10 is extremely difficult. The WOMAC physical function subscale score was calculated by taking the average of the 17 physical function subscales at each visit. Change from baseline was calculated for each visit as the mean WOMAC function subscale score minus the mean baseline WOMAC function subscale score. Baseline scores for each participant were assigned based on the score measured prior to first dosing on Day1 visit. A negative change from baseline indicated improvement. Posterior mean change from baseline, 95 percent (%) credible interval (CI) was derived using Bayesian mixed model repeated measures. The data presented are the posterior mean change from baseline with a 95% confidence interval refers to 95% Credible Interval. |
| Change From Baseline in Patient Global Assessment Of Disease (PtGA) at Week 12 | Baseline (Day 1) and at Week 12 | The PtGA is an assessment for disease conditions and intensity of knee osteoarthritis (OA) pain. Participants will respond on a Likert scale ranging from 1-5 based on the question Considering all the ways in which your knee OA affects you, how do you feel your knee OA is doing today? and to identify a number from 1 = very good (asymptomatic and no limitation to normal activities) to 5 = very poor (very severe symptoms which are intolerable and inability to carry out all normal activities). Higher scores indicate worse conditions. Baseline scores for each participant were assigned based on the scores reported prior to first dosing on Day 1 visit. Posterior mean change from baseline, 95 percent (%) credible interval (CI) was derived using Bayesian mixed model repeated measures. The data presented are the posterior mean with a 95% confidence interval refers to 95% Credible Interval. |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | Up to 31 weeks | AEs, SAEs, and AESIs were collected. An AE is any untoward medical occurrence in participant, temporally associated with use of study intervention, whether or not considered related to medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, medically important were categorized as SAEs. The AESIs of the study drug included serious and opportunistic infections, tuberculosis (TB) and TB reactivation, serious hypersensitivity reactions and Injection site reactions. |
| Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Up to 31 weeks | The laboratory measurements included hematology and clinical chemistry. The parameters evaluated were Basophil, Eosinophil, Erythrocyte Mean Corpuscular Hemoglobin, Erythrocyte Mean Corpuscular Volume, Erythrocytes, Hematocrit, Hemoglobin, Lymphocyte, Monocyte, Neutrophils, Platelets and Reticulocytes, Alanine Aminotransferase, Albumin, Alkaline phosphatase, Aspartate Aminotransferase, Bilirubin, Calcium, Creatinine, Direct Bilirubin, Glucose, Potassium, Sodium and Urea. Worst case grade (G) increase from baseline grade was provided for all the laboratory tests that were gradable by National Cancer Institute Common Terminology Criteria (NCI CTCAE, Version 5.0). Data for any participants with the worst-case grade changes (Increase or equal to Grade 3 or Increase to Grade 4) post-baseline are reported. Missing baseline grade was assumed as grade 0. |
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score At Week 12 | Baseline (Day 1) and at Week 12 | The WOMAC pain subscale have a recall period of 48 hours and includes 5 subscales of pain assessment: 1-walking on flat, 2-going up downstairs, 3-at night while in bed, 4-sitting or lying; 5-standing upright. The total WOMAC pain subscale score ranges from 0-10; where 0 is no pain and 10 is extreme pain. The WOMAC pain subscale score was calculated by taking average of the 5 pain subscales at each visit. Change from baseline was calculated for each visit as the mean WOMAC Pain subscale score minus the mean baseline WOMAC Pain subscale score. A negative change from baseline indicates an improvement in pain. Baseline WOMAC scores for each participant were assigned based on the score measured prior to first dosing on Day1 visit. Posterior mean change from baseline, 95 percent (%) credible interval (CI) was derived using Bayesian mixed model repeated measures. The data presented are the posterior mean change from baseline with a 95% confidence interval refers to 95% Credible Interval. |
| Time to Maximum Plasma Concentration (Tmax) of GSK3858279 | Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12 | Tmax predicted from the population PK model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. |
| Pre-Dose (Trough) Concentration at the End of the Dosing Interval (Ctau) of GSK3858279 | Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12 | Ctau predicted from the population PK model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. |
| Average Concentration Over a Dosing Interval (Cavg) of GSK3858279 | Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12 | Cavg predicted from the population PK model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. |
| Area Under the Time-Concentration Curve (AUC) Over the Dosing Interval (0-Tau) (AUC[0-Tau]) of GSK3858279 | Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12 | AUC(0-tau) predicted from the population PK model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. |
| Maximum Concentration (Cmax) of GSK3858279 | Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12 | Blood samples were collected at the indicated time points for pharmacokinetic (PK) analysis of GSK3858279 . Pharmacokinetic analysis was conducted using a model based analysis using all available data. |
Countries
Argentina, Australia, Canada, China, France, Germany, Japan, Mexico, South Africa, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 314 participants were enrolled in the study. Out of which 310 participants were included in the full analysis set (FAS) population.
Pre-assignment details
Of 314 participants enrolled, 4 participants were randomized but did not receive study dose, hence were excluded from the FAS.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo SC injection once per week for 16 weeks. | 105 |
| GSK3858279 - 60 mg Weekly Participants received GSK3858279 60 mg SC injection once per week for 16 weeks. | 50 |
| GSK3858279 - 240 mg Every 2 Weeks Participants received GSK3858279 240 mg SC injection every other week for 16 weeks. Placebo was given in the intervening week to maintain the blinding. | 51 |
| GSK3858279 - 240 mg Weekly Participants received GSK3858279 240 mg SC injection once per week for 16 weeks. | 51 |
| GSK3858279 - 360 mg Weekly Participants received GSK3858279 360 mg SC injection once per week for 16 weeks. | 53 |
| Total | 310 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Randomized, not treated | 2 | 1 | 0 | 1 | 0 |
| Overall Study | STUDY TERMINATED BY SPONSOR | 68 | 34 | 33 | 34 | 32 |
| Overall Study | Withdrawal by Subject | 8 | 3 | 3 | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo | GSK3858279 - 60 mg Weekly | GSK3858279 - 240 mg Every 2 Weeks | GSK3858279 - 240 mg Weekly | GSK3858279 - 360 mg Weekly | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 63.7 YEARS STANDARD_DEVIATION 7.93 | 65.6 YEARS STANDARD_DEVIATION 9.11 | 63.6 YEARS STANDARD_DEVIATION 8.84 | 64.0 YEARS STANDARD_DEVIATION 8.99 | 64.5 YEARS STANDARD_DEVIATION 8.14 | 64.2 YEARS STANDARD_DEVIATION 8.47 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 18 Participants | 7 Participants | 7 Participants | 7 Participants | 11 Participants | 50 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 5 Participants | 3 Participants | 3 Participants | 8 Participants | 24 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized WHITE | 81 Participants | 37 Participants | 39 Participants | 39 Participants | 33 Participants | 229 Participants |
| Sex: Female, Male Female | 64 Participants | 35 Participants | 39 Participants | 33 Participants | 40 Participants | 211 Participants |
| Sex: Female, Male Male | 41 Participants | 15 Participants | 12 Participants | 18 Participants | 13 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 105 | 0 / 50 | 0 / 51 | 0 / 51 | 0 / 53 |
| other Total, other adverse events | 37 / 105 | 14 / 50 | 25 / 51 | 20 / 51 | 22 / 53 |
| serious Total, serious adverse events | 4 / 105 | 3 / 50 | 0 / 51 | 1 / 51 | 2 / 53 |
Outcome results
Primary
Change From Baseline in Weekly Average of Average Daily Knee Pain Intensity Using Numeric Rating Scale at Week 12
Change from Baseline in knee pain due to Osteoarthritis were reported by weekly average of average daily pain numeric rating scale (NRS) at Week 12. The pain NRS is an 11-point scale (ranging from 0-10) for self-reporting of average daily knee pain where 0 indicates no pain, and 10 indicates the worst possible pain. For each participant, the weekly average of average daily pain score was calculated using the mean value of available daily pain scores falling in the assessment window for each week. A negative change from baseline indicates an improvement in pain. Participants were asked to complete the pain NRS questionnaire at the same time in the evening each day. Baseline scores were assigned based on an average of 7 days prior to day 1 dosing visit. Posterior mean change from baseline, 95 percent (%) credible interval (CI) was derived using Bayesian mixed model repeated measures. The data presented are the posterior mean with 95% confidence interval refers to 95% credible interval.
Time frame: Baseline (Day -7 to Day -1) and at Week 12
Population: The analysis was performed on the full analysis set (FAS) that included all randomized participants who received at least one dose of study intervention. Only those participants who had a measured outcome used in estimation or imputed outcome based on composite intercurrent event strategy at the current time point were included in the overall number of participants analyzed field.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Weekly Average of Average Daily Knee Pain Intensity Using Numeric Rating Scale at Week 12 | -2.13 Scores on Scale |
| GSK3858279 - 60 mg Weekly | Change From Baseline in Weekly Average of Average Daily Knee Pain Intensity Using Numeric Rating Scale at Week 12 | -1.66 Scores on Scale |
| GSK3858279 - 240 mg Every 2 Weeks | Change From Baseline in Weekly Average of Average Daily Knee Pain Intensity Using Numeric Rating Scale at Week 12 | -1.88 Scores on Scale |
| GSK3858279 - 240 mg Weekly | Change From Baseline in Weekly Average of Average Daily Knee Pain Intensity Using Numeric Rating Scale at Week 12 | -1.74 Scores on Scale |
| GSK3858279 - 360 mg Weekly | Change From Baseline in Weekly Average of Average Daily Knee Pain Intensity Using Numeric Rating Scale at Week 12 | -2.03 Scores on Scale |
95% CI: [-0.23, 1.17]Mixed Models Analysis
95% CI: [-0.46, 0.95]Mixed Models Analysis
95% CI: [-0.31, 1.1]Mixed Models Analysis
95% CI: [-0.6, 0.8]Mixed Models Analysis
Secondary
Area Under the Time-Concentration Curve (AUC) Over the Dosing Interval (0-Tau) (AUC[0-Tau]) of GSK3858279
AUC(0-tau) predicted from the population PK model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis.
Time frame: Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12
Population: The analysis was performed on PK set which included all randomized participants in the Safety Population who had at least 1 dose of GSK3858279 and at least 1 non-missing PK assessment (Non-quantifiable values were considered as non-missing values). Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Time-Concentration Curve (AUC) Over the Dosing Interval (0-Tau) (AUC[0-Tau]) of GSK3858279 | 25362.8 day*ng/mL | Geometric Coefficient of Variation 51 |
| GSK3858279 - 60 mg Weekly | Area Under the Time-Concentration Curve (AUC) Over the Dosing Interval (0-Tau) (AUC[0-Tau]) of GSK3858279 | 100469.4 day*ng/mL | Geometric Coefficient of Variation 48 |
| GSK3858279 - 240 mg Every 2 Weeks | Area Under the Time-Concentration Curve (AUC) Over the Dosing Interval (0-Tau) (AUC[0-Tau]) of GSK3858279 | 82325.8 day*ng/mL | Geometric Coefficient of Variation 53 |
| GSK3858279 - 240 mg Weekly | Area Under the Time-Concentration Curve (AUC) Over the Dosing Interval (0-Tau) (AUC[0-Tau]) of GSK3858279 | 118983.5 day*ng/mL | Geometric Coefficient of Variation 42 |
Secondary
Average Concentration Over a Dosing Interval (Cavg) of GSK3858279
Cavg predicted from the population PK model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis.
Time frame: Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12
Population: The analysis was performed on PK set which included all randomized participants in the Safety Population who had at least 1 dose of GSK3858279 and at least 1 non-missing PK assessment (Non-quantifiable values were considered as non-missing values). Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Average Concentration Over a Dosing Interval (Cavg) of GSK3858279 | 3623.3 ng/mL | Geometric Coefficient of Variation 51 |
| GSK3858279 - 60 mg Weekly | Average Concentration Over a Dosing Interval (Cavg) of GSK3858279 | 7176.4 ng/mL | Geometric Coefficient of Variation 48 |
| GSK3858279 - 240 mg Every 2 Weeks | Average Concentration Over a Dosing Interval (Cavg) of GSK3858279 | 11760.8 ng/mL | Geometric Coefficient of Variation 53 |
| GSK3858279 - 240 mg Weekly | Average Concentration Over a Dosing Interval (Cavg) of GSK3858279 | 16997.6 ng/mL | Geometric Coefficient of Variation 42 |
Secondary
Change From Baseline in Patient Global Assessment Of Disease (PtGA) at Week 12
The PtGA is an assessment for disease conditions and intensity of knee osteoarthritis (OA) pain. Participants will respond on a Likert scale ranging from 1-5 based on the question Considering all the ways in which your knee OA affects you, how do you feel your knee OA is doing today? and to identify a number from 1 = very good (asymptomatic and no limitation to normal activities) to 5 = very poor (very severe symptoms which are intolerable and inability to carry out all normal activities). Higher scores indicate worse conditions. Baseline scores for each participant were assigned based on the scores reported prior to first dosing on Day 1 visit. Posterior mean change from baseline, 95 percent (%) credible interval (CI) was derived using Bayesian mixed model repeated measures. The data presented are the posterior mean with a 95% confidence interval refers to 95% Credible Interval.
Time frame: Baseline (Day 1) and at Week 12
Population: The analysis was performed on FAS population which included all randomized participants who received at least one dose of study intervention. Only those participants who had a measured outcome used in estimation or imputed outcome based on composite intercurrent event strategy at the current time point were included in the overall number of participants analyzed field.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Patient Global Assessment Of Disease (PtGA) at Week 12 | -0.55 Scores on Scale |
| GSK3858279 - 60 mg Weekly | Change From Baseline in Patient Global Assessment Of Disease (PtGA) at Week 12 | -0.57 Scores on Scale |
| GSK3858279 - 240 mg Every 2 Weeks | Change From Baseline in Patient Global Assessment Of Disease (PtGA) at Week 12 | -0.55 Scores on Scale |
| GSK3858279 - 240 mg Weekly | Change From Baseline in Patient Global Assessment Of Disease (PtGA) at Week 12 | -0.55 Scores on Scale |
| GSK3858279 - 360 mg Weekly | Change From Baseline in Patient Global Assessment Of Disease (PtGA) at Week 12 | -0.55 Scores on Scale |
Secondary
Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score At Week 12
The WOMAC pain subscale have a recall period of 48 hours and includes 5 subscales of pain assessment: 1-walking on flat, 2-going up downstairs, 3-at night while in bed, 4-sitting or lying; 5-standing upright. The total WOMAC pain subscale score ranges from 0-10; where 0 is no pain and 10 is extreme pain. The WOMAC pain subscale score was calculated by taking average of the 5 pain subscales at each visit. Change from baseline was calculated for each visit as the mean WOMAC Pain subscale score minus the mean baseline WOMAC Pain subscale score. A negative change from baseline indicates an improvement in pain. Baseline WOMAC scores for each participant were assigned based on the score measured prior to first dosing on Day1 visit. Posterior mean change from baseline, 95 percent (%) credible interval (CI) was derived using Bayesian mixed model repeated measures. The data presented are the posterior mean change from baseline with a 95% confidence interval refers to 95% Credible Interval.
Time frame: Baseline (Day 1) and at Week 12
Population: The analysis was performed on FAS population which included all randomized participants who received at least one dose of study intervention. Only those participants who had a measured outcome used in estimation or imputed outcome based on composite intercurrent event strategy at the current time point were included in the overall number of participants analyzed field.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score At Week 12 | -2.16 Scores on Scale |
| GSK3858279 - 60 mg Weekly | Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score At Week 12 | -2.13 Scores on Scale |
| GSK3858279 - 240 mg Every 2 Weeks | Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score At Week 12 | -2.21 Scores on Scale |
| GSK3858279 - 240 mg Weekly | Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score At Week 12 | -1.95 Scores on Scale |
| GSK3858279 - 360 mg Weekly | Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score At Week 12 | -1.93 Scores on Scale |
Secondary
Change From Baseline in WOMAC Physical Function Subscale Score at Week 12
The WOMAC function subscale have a recall period of 48 hours and include 17 items of daily function assessments. The total WOMAC physical function subscale score ranges from 0-10 scale; where 0 is no difficulty and 10 is extremely difficult. The WOMAC physical function subscale score was calculated by taking the average of the 17 physical function subscales at each visit. Change from baseline was calculated for each visit as the mean WOMAC function subscale score minus the mean baseline WOMAC function subscale score. Baseline scores for each participant were assigned based on the score measured prior to first dosing on Day1 visit. A negative change from baseline indicated improvement. Posterior mean change from baseline, 95 percent (%) credible interval (CI) was derived using Bayesian mixed model repeated measures. The data presented are the posterior mean change from baseline with a 95% confidence interval refers to 95% Credible Interval.
Time frame: Baseline (Day 1) and at Week 12
Population: The analysis was performed on FAS population which included all randomized participants who received at least one dose of study intervention. Only those participants who had a measured outcome used in estimation or imputed outcome based on composite intercurrent event strategy at the current time point were included in the overall number of participants analyzed field.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change From Baseline in WOMAC Physical Function Subscale Score at Week 12 | -1.94 Scores on Scale |
| GSK3858279 - 60 mg Weekly | Change From Baseline in WOMAC Physical Function Subscale Score at Week 12 | -1.99 Scores on Scale |
| GSK3858279 - 240 mg Every 2 Weeks | Change From Baseline in WOMAC Physical Function Subscale Score at Week 12 | -1.56 Scores on Scale |
| GSK3858279 - 240 mg Weekly | Change From Baseline in WOMAC Physical Function Subscale Score at Week 12 | -1.65 Scores on Scale |
| GSK3858279 - 360 mg Weekly | Change From Baseline in WOMAC Physical Function Subscale Score at Week 12 | -1.65 Scores on Scale |
Secondary
Maximum Concentration (Cmax) of GSK3858279
Blood samples were collected at the indicated time points for pharmacokinetic (PK) analysis of GSK3858279 . Pharmacokinetic analysis was conducted using a model based analysis using all available data.
Time frame: Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12
Population: The analysis was performed on PK set which included all randomized participants in the Safety Population who had at least 1 dose of GSK3858279 and at least 1 non-missing PK assessment (Non-quantifiable values were considered as non-missing values). Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Concentration (Cmax) of GSK3858279 | 4603.1 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 48 |
| GSK3858279 - 60 mg Weekly | Maximum Concentration (Cmax) of GSK3858279 | 12330.0 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 47 |
| GSK3858279 - 240 mg Every 2 Weeks | Maximum Concentration (Cmax) of GSK3858279 | 15383.5 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 51 |
| GSK3858279 - 240 mg Weekly | Maximum Concentration (Cmax) of GSK3858279 | 22169.0 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 40 |
Secondary
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI)
AEs, SAEs, and AESIs were collected. An AE is any untoward medical occurrence in participant, temporally associated with use of study intervention, whether or not considered related to medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, medically important were categorized as SAEs. The AESIs of the study drug included serious and opportunistic infections, tuberculosis (TB) and TB reactivation, serious hypersensitivity reactions and Injection site reactions.
Time frame: Up to 31 weeks
Population: The analysis was performed on safety population which included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | SAEs | 4 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AEs | 69 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AESIs | 14 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | SAEs | 3 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AEs | 29 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AESIs | 3 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AEs | 32 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | SAEs | 0 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AESIs | 4 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AEs | 32 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AESIs | 2 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | SAEs | 1 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | SAEs | 2 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AEs | 34 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs of Special Interest (AESI) | AESIs | 12 Participants |
Secondary
Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE)
The laboratory measurements included hematology and clinical chemistry. The parameters evaluated were Basophil, Eosinophil, Erythrocyte Mean Corpuscular Hemoglobin, Erythrocyte Mean Corpuscular Volume, Erythrocytes, Hematocrit, Hemoglobin, Lymphocyte, Monocyte, Neutrophils, Platelets and Reticulocytes, Alanine Aminotransferase, Albumin, Alkaline phosphatase, Aspartate Aminotransferase, Bilirubin, Calcium, Creatinine, Direct Bilirubin, Glucose, Potassium, Sodium and Urea. Worst case grade (G) increase from baseline grade was provided for all the laboratory tests that were gradable by National Cancer Institute Common Terminology Criteria (NCI CTCAE, Version 5.0). Data for any participants with the worst-case grade changes (Increase or equal to Grade 3 or Increase to Grade 4) post-baseline are reported. Missing baseline grade was assumed as grade 0.
Time frame: Up to 31 weeks
Population: The analysis was performed on safety population which included all participants who received at least 1 dose of study treatment. The overall number of participants analyzed represents only those participants available at the specified time points and evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 3 | 2 Participants |
| Placebo | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | AST, Increase to Grade 3 | 0 Participants |
| Placebo | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 3 | 0 Participants |
| Placebo | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 4 | 0 Participants |
| Placebo | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 4 | 1 Participants |
| Placebo | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Lymphocyte count decreased, worsening to Grade 3 | 0 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Lymphocyte count decreased, worsening to Grade 3 | 1 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | AST, Increase to Grade 3 | 0 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 4 | 0 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 3 | 1 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 3 | 0 Participants |
| GSK3858279 - 60 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 4 | 0 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 3 | 0 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 4 | 1 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Lymphocyte count decreased, worsening to Grade 3 | 0 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | AST, Increase to Grade 3 | 0 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 3 | 0 Participants |
| GSK3858279 - 240 mg Every 2 Weeks | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 4 | 0 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 3 | 1 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 3 | 1 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 4 | 1 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Lymphocyte count decreased, worsening to Grade 3 | 0 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 4 | 0 Participants |
| GSK3858279 - 240 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | AST, Increase to Grade 3 | 1 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 4 | 0 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Creatine Kinase, Worsening to Grade 3 | 0 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 3 | 1 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | AST, Increase to Grade 3 | 0 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Lymphocyte count decreased, worsening to Grade 3 | 0 Participants |
| GSK3858279 - 360 mg Weekly | Number of Participants With Greater Than or Equal to (>=) Grade 3 Hematological/Clinical Chemistry Abnormalities According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) | Gamma Glutamyl Transferase, Worsening to Grade 4 | 0 Participants |
Secondary
Pre-Dose (Trough) Concentration at the End of the Dosing Interval (Ctau) of GSK3858279
Ctau predicted from the population PK model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis.
Time frame: Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12
Population: The analysis was performed on PK set which included all randomized participants in the Safety Population who had at least 1 dose of GSK3858279 and at least 1 non-missing PK assessment (Non-quantifiable values were considered as non-missing values). Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pre-Dose (Trough) Concentration at the End of the Dosing Interval (Ctau) of GSK3858279 | 2449.9 ng/mL | Geometric Coefficient of Variation 63 |
| GSK3858279 - 60 mg Weekly | Pre-Dose (Trough) Concentration at the End of the Dosing Interval (Ctau) of GSK3858279 | 3076.6 ng/mL | Geometric Coefficient of Variation 59 |
| GSK3858279 - 240 mg Every 2 Weeks | Pre-Dose (Trough) Concentration at the End of the Dosing Interval (Ctau) of GSK3858279 | 7224.0 ng/mL | Geometric Coefficient of Variation 60 |
| GSK3858279 - 240 mg Weekly | Pre-Dose (Trough) Concentration at the End of the Dosing Interval (Ctau) of GSK3858279 | 11037.5 ng/mL | Geometric Coefficient of Variation 52 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of GSK3858279
Tmax predicted from the population PK model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis.
Time frame: Pre-dose: Day 1, Weeks 1, 2, 4, 8, 10, 11 and 12
Population: The analysis was performed on PK set which included all randomized participants in the Safety Population who had at least 1 dose of GSK3858279 and at least 1 non-missing PK assessment (Non-quantifiable values were considered as non-missing values). Only those participants with data available at specified time points have been analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Maximum Plasma Concentration (Tmax) of GSK3858279 | 1.454 Day |
| GSK3858279 - 60 mg Weekly | Time to Maximum Plasma Concentration (Tmax) of GSK3858279 | 1.751 Day |
| GSK3858279 - 240 mg Every 2 Weeks | Time to Maximum Plasma Concentration (Tmax) of GSK3858279 | 1.412 Day |
| GSK3858279 - 240 mg Weekly | Time to Maximum Plasma Concentration (Tmax) of GSK3858279 | 1.377 Day |