A Dose-Finding Study to Evaluate the Efficacy and Safety of GSK3858279 in Adults With Knee Osteoarthritis Pain

Study Overview
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Brief Summary
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This is dose-finding study of GSK3858279 in participants with moderate to severe knee osteoarthritis (OA) 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.

Official Title
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A Multicentre Randomized, Double-blind, Placebo Controlled, Dose-finding, Phase 2 Study (MARS-17) of GSK3858279 in Adult Participants With Moderate to Severe Pain Due to Knee Osteoarthritis

Conditions
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Pain

Intervention / Treatment
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* Drug: GSK3858279
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 millilitre/ minute (mL/min)/1.73 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK3858279 Dose 1<br>Participants will receive GSK3858279 dose 1. | Drug: GSK3858279<br>* GSK3858279 will be administered.<br>|
| Experimental: GSK3858279 Dose 2<br>Participants will receive GSK3858279 dose 2. | Drug: GSK3858279<br>* GSK3858279 will be administered.<br>|
| Experimental: GSK3858279 Dose 3<br>Participants will receive GSK3858279 dose 3. | Drug: GSK3858279<br>* GSK3858279 will be administered.<br>|
| Experimental: GSK3858279 Dose 4<br>Participants will receive GSK3858279 dose 4. | Drug: GSK3858279<br>* GSK3858279 will be administered.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo. | Drug: Placebo<br>* Placebo will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline at Week 12 in weekly average of average daily knee pain intensity, assessed on the Numeric Rating Scale (NRS) | To capture information on the self-reported average knee pain intensity in index knee, over the past 24 hours, participants will be asked to mark their average pain-intensity daily, using the NRS, on an 11-point scale (0-10), with 0 = no pain, and 10 = pain as bad as you can imagine. Daily scores for each participant will be averaged over 7 days to obtain a weekly score. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline at Week 12 in Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score | The WOMAC proprietary set of standardized questionnaires used by health professionals and to evaluate the condition of participants with osteoarthritis of the knee and hip, including pain, stiffness of the joints. The questionnaire covers pain, stiffness and function related to OA in the index knee over the past 48 hours. Participants will respond to each question using an 11- point NRS (0-10), with 0 = no pain/stiffness/difficulty, and 10 = extreme pain/stiffness/difficulty. | Baseline and Week 12 | 
| Change from baseline at Week 12 in WOMAC function subscale score | The WOMAC is a widely used, proprietary set of standardized questionnaires used by health professionals to evaluate the condition of participants with osteoarthritis of the knee and hip, for physical functioning of the joints. The questionnaire covers pain, stiffness and function related to OA in the index knee over the past 48 hours. Participants will respond to each question using an 11- point NRS (0-10), with 0 = no pain/stiffness/difficulty, and 10 = extreme pain/stiffness/difficulty. | Baseline and Week 12 | 
| Change from baseline at Week 12 in patient global assessment of disease (PtGA) | The PtGA is assessment of study participant for disease conditions and intensity of knee OA pain. Participants will respond on a Likert scale ranging from 1-5. Higher scores indicate worse condition. | Baseline and Week 12 | 
| Occurrence of adverse events (AEs), serious AE (SAEs) and AEs of special interest (AESI) | AEs, SAEs, and AESIs will be collected. 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 SAE. AESIs of the study drug includes serious and opportunistic infections, tuberculosis (TB) and TB reactivation, serious hypersensitivity reactions and Injection site reactions. | Up to 31 weeks | 
| Change from Baseline in Haematology Parameters: neutrophils, lymphocytes, monocytes, eosinophils, basophils, white blood cell (WBC), and platelet count (Giga cells per liter) |  | Baseline and up to Week 31 | 
| Change from Baseline in Haematology Parameters: Red blood cell (RBC) count, (Trillion cells per liter) |  | Baseline and up to Week 31 | 
| Change from baseline in haematology parameter: Haemoglobin (Hb) (Grams per liter) |  | Baseline and up to Week 31 | 
| Change from baseline in haematology parameter: Haematocrit (Proportion of red blood cells in blood) |  | Baseline and up to Week 31 | 
| Change from baseline in clinical chemistry parameters: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), Gamma-glutamyl transferase (GGT), and Alkaline Phosphatase (AP) (International units per liter) |  | Baseline and up to Week 31 | 
| Change from baseline in clinical chemistry parameter: Total bilirubin (Micromoles per liter) |  | Baseline and up to Week 31 | 
| 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) | Hematological/clinical chemistry abnormalities summarized according to NCI CTCAE grade | Up to 31 weeks | 
| Population parameters for the model describing the relationship between Dose, PK and response assessed on the NRS | Longitudinal dose-exposure-response (D-E-R) relationship between GSK3858279 dose, PK and weekly average of average daily knee pain intensity, assessed on the Numeric Rating Scale (NRS). Where the pain is scored on a 11-point scale (0-10), with 0 = no pain, and 10 = extreme pain as bad as you can imagine. | At Week 12 | 
| Maximum observed concentration (Cmax) of GSK3858279 | Cmax predicted from the D-E-R model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. | At Week 12 | 
| The amount of time for GSK3858279 to reach Cmax (tmax) | Tmax predicted from the D-E-R model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. | At Week 12 | 
| Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of GSK3858279 | Ctau predicted from the D-E-R model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. | At Week 12 | 
| Average concentration over a dosing interval (Cavg) of GSK3858279 | Cavg predicted from the D-E-R model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. | At Week 12 | 
| Area under the time-concentration curve (AUC) over the dosing interval (0-tau) (AUC[0-tau]) of GSK3858279 | AUC(0-tau) predicted from the D-E-R model fitted to GSK3859279 serum concentration time data collected at the indicated time points for PK analysis. | At Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoarthritis, Musculoskeletal Diseases, 209978, GSK3858279, Efficacy, Safety, Pharmacokinetics