Long-term Safety and Efficacy of GSK3196165 (Otilimab) in the Treatment of Rheumatoid Arthritis (RA)

Study Overview
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Brief Summary
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RA is a chronic, systemic inflammatory autoimmune disease which requires treatment for a long time period, hence it is important to study the long-term safety and efficacy of the continuous treatment with GSK3196165 over several years. This is a Phase 3, multicenter, parallel group treatment and long-term extension study primarily to assess safety with efficacy assessment as a secondary objective. Adult participants with RA who have completed the treatment phase of a qualifying GSK3196165 clinical studies (Phase 3 studies contRAst 1 (201790: NCT03980483), contRAst 2 (201791: NCT03970837) and contRAst 3 (202018: NCT04134728) and who, in investigator's judgement will benefit from extended treatment with GSK3196165 will be included in this study (contRAst X [209564: NCT04333147]). Participants will continue to receive the same background conventional synthetic disease modifying anti-rheumatic drug(s) [csDMARD(s)] treatment as they received in their qualifying study. Eligible participants will be enrolled to receive weekly GSK3196165 90 milligrams (mg) or 150 mg by subcutaneous (SC) injection. The anticipated study duration is approximately 4 years which will enable participants to receive treatment with GSK3196165 until it is expected to become commercially available. Approximately 3000 participants from the qualifying studies will participate in this long-term extension study

Official Title
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A Multi-centre Long-term Extension Study to Assess the Safety and Efficacy of GSK3196165 in the Treatment of Rheumatoid Arthritis

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Biological: Otilimab (GSK3196165)
* Drug: csDMARD(s)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with rheumatoid arthritis who are aged >=18 years at the time of signing informed consent, who have completed one of the qualifying GSK3196165 clinical studies and who, in the opinion of the investigator, may benefit from treatment with GSK3196165. Body weight >=40 kilograms (kg). Male or female participants are eligible to participate as long as they meet the contraceptive eligibility criteria and agree to abide by the contraceptive requirements. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. For participants on methotrexate (MTX): must be willing to continue treatment with oral folic acid (at least 5 mg/week) or equivalent while receiving MTX (mandatory co-medication for MTX treatment). Exclusion Criteria: Had study intervention permanently discontinued at any time during a qualifying study except any participant with a new diagnosis of latent Mycobacterium tuberculosis (TB) at the end of study assessment in a qualifying study and currently undertaking or willing to complete at least 4 weeks of anti-TB treatment off study treatment, per world health organization (WHO) or national guidelines prior to re-commencing therapy and complete the remainder of anti-TB treatment while on study. Evidence of latent TB (as documented by a positive QuantiFERON-TB Gold plus test or T-SPOT.TB test, no findings on medical history or clinical examination consistent with active TB, and a normal chest radiograph) except for participants that Are currently undertaking or willing to complete at least 4 weeks of anti-TB therapy off study treatment, as per WHO or national guidelines prior to re- commencing study treatment and agree to complete the remainder of anti-TB treatment while in the study or Had documented evidence of satisfactory anti-TB treatment as per WHO or national guidelines following review by a physician specializing in TB on entry to a qualifying study. Current or previous active TB regardless of treatment. Were temporarily discontinued from study intervention at the time of the final study visit of a qualifying study and, in the opinion of the investigator, participation in the extension study poses an unacceptable risk for the participant's participation. A new cancer or malignancy except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured by the investigator. Have developed any lymphoproliferative disorder during a qualifying study, such as Epstein Barr Virus (EBV) related lymphoproliferative disorder, or signs and symptoms suggestive of current lymphatic disease. Have significant uncontrolled cardiovascular, cerebrovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neuropsychiatric disorders, or abnormal laboratory values that developed during a qualifying study that, in the opinion of the investigator, poses an unacceptable risk for the participant's participation. Participants who are expected to be non-compliant with restrictions on medications and vaccinations prior to the study, during the study or during the 8-week safety follow-up of the study. Participants who are currently participating in any interventional clinical study other than a qualifying GSK3196165 clinical study. Abnormal chest radiograph within the last 12 weeks judged by the investigator as clinically-significant. Pregnant or lactating, or women planning to become pregnant or initiating breastfeeding. History of sensitivity to any of the study treatments, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Participants who received GSK3196165 in their qualifying study will continue in this study on the same dose. Participants who received a comparator (tofacitinib or sarilumab) in their qualifying study will be centrally randomized using interactive response technology (IRT) in a ratio of 1:1 to either GSK3196165 90 mg or 150 mg.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving GSK3196165 in qualifying study<br>Participants receiving GSK3196165 in their qualifying study will continue to receive GSK3196165 at the same dose level (90 mg or 150 mg weekly) in this study. | Biological: Otilimab (GSK3196165)<br>* GSK3196165 solution in vial/pre-filled syringe (PFS) and auto injector (AI) to be administered SC.<br>Drug: csDMARD(s)<br>* Stable dose of csDMARD(s) as standard of care (SoC).<br>|
| Experimental: Participants receiving comparator in qualifying study<br>Participants receiving a comparator (e.g. tofacitinib or sarilumab) in their qualifying study will be re-randomized to receive either GSK3196165 90 mg or 150 mg weekly in this study. | Biological: Otilimab (GSK3196165)<br>* GSK3196165 solution in vial/pre-filled syringe (PFS) and auto injector (AI) to be administered SC.<br>Drug: csDMARD(s)<br>* Stable dose of csDMARD(s) as standard of care (SoC).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) , serious adverse events (SAEs) and adverse events of special interests (AESI) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or other important medical event that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. Protocol defined AESIs will be included. | Up to 4 years | 
| Change from Baseline in platelet count, neutrophils lymphocytes, monocytes, eosinophils, and basophils (Giga cells per liter [giga cells/L]) | Blood samples will be collected for the assessment of hematology parameters. | Baseline (Day 1) and up to 4 years | 
| Change from Baseline in hemoglobin level (Grams per liter) | Blood samples will be collected for the assessment of hemoglobin. | Baseline (Day 1) and up to 4 years | 
| Change from Baseline in total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein-cholesterol, triglycerides and other lipoprotein tests as needed (Millimoles per Liter) | Blood samples will be collected for the assessment of clinical chemistry parameters | Baseline (Day 1) and up to 4 years | 
| Change from Baseline in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP) gamma-glutamyl transferase (GGT) levels, lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) (International units per liter) | Blood samples will be collected for the assessment of clinical chemistry parameters. | Baseline (Day 1) and up to 4 years | 
| Change from Baseline in total and direct bilirubin (Micromoles per liter) | Blood samples will be collected for the assessment of clinical chemistry parameters | Baseline (Day 1) and up to 4 years | 
| Change from Baseline in albumin level (Grams per Liter) | Blood samples will be collected for the assessment of clinical chemistry parameters | Baseline (Day 1) and up to 4 years | 
| Proportion of participants with National Cancer Institute-Common terminology criteria for adverse events (NCI-CTCAE) more than or equal to (>=)Grade 3 hematological/clinical chemistry abnormalities | Hematological/clinical chemistry abnormalities will be evaluated using NCI-CTCAE grading. | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving Clinical disease activity index (CDAI) total score less than or equal to (<=10) (CDAI Low disease activity [LDA]) at Week 24 | CDAI for RA is a clinical composite score to determine disease severity using only clinical data. It will be calculated by the simple sum of the 4 following parameters: Tender joint count (28), Swollen joint count (28), Patient's global assessment of arthritis (PtGA) and Physician's global assessment of arthritis (PhGA) both transformed to a 0-10 scale. Total score approximate range 0-76, higher score indicates more severe disease. Proportion of participants achieving CDAI total score <=10 will be summarized. | Week 24 | 
| Proportion of participants achieving CDAI total score <=10 (CDAI LDA) at Week 48 and every 48 weeks thereafter | CDAI for RA is a clinical composite score to determine disease severity using only clinical data. It will be calculated by the simple sum of the 4 following parameters: Tender joint count (28), Swollen joint count (28), PtGA and PhGA both transformed to a 0-10 scale. Total score approximate range 0-76, higher score indicates more severe disease. Proportion of participants achieving CDAI total score <=10 will be summarized. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Proportion of participants achieving CDAI total score <=2.8 (CDAI Remission) at Week 24 | CDAI for RA is a clinical composite score to determine disease severity using only clinical data. It will be calculated by the simple sum of the 4 following parameters: Tender joint count (28), Swollen joint count (28), PtGA and PhGA. Proportion of participants achieving CDAI total score <=2.8 will be summarized. | Week 24 | 
| Proportion of participants achieving CDAI total score <=2.8 (CDAI Remission) at Week 48 and every 48 weeks thereafter | CDAI for RA is a clinical composite score to determine disease severity using only clinical data. It will be calculated by the simple sum of the 4 following parameters: Tender joint count (28), Swollen joint count (28), PtGA and PhGA. Proportion of participants achieving CDAI total score <=2.8 will be summarized. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Proportion of participants achieving Disease Activity Score using 28 joint count (DAS28)-C-reactive protein (CRP) <2.6 (DAS28-CRP Remission) at Week 24 | DAS28-CRP is a measure of RA disease activity calculated using the number of tender joints and swollen joints (28 joint count), high sensitivity (hs)CRP (mg/L) and PtGA (transformed to a 0-10 scale). Total score approximate range 0-9.4, higher score indicates more severe disease. Proportion of participants achieving DAS28-CRP <2.6 will be summarized. | Week 24 | 
| Proportion of participants achieving DAS28-CRP <2.6 (DAS28-CRP Remission) at Week 48 and every 48 weeks thereafter | DAS28-CRP is a measure of RA disease activity calculated using the number of tender joints and swollen joints (28 joint count), hsCRP (mg/L) and PtGA (transformed to a 0-10 scale). Total score approximate range 0-9.4, higher score indicates more severe disease. Proportion of participants achieving DAS28-CRP <2.6 will be summarized. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Proportion of participants with DAS28- Erythrocyte sedimentation rate (ESR)<2.6 (DAS28-ESR Remission) at Week 24 | DAS28-ESR is a measure of RA disease activity calculated using the number of tender joints and swollen joints (28 joint count), ESR (millimeters per hour [mm/hour]) and PtGA (transformed to a 0-10 scale). Total score approximate range 0-9.4, higher score indicates more severe disease. Proportion of participants achieving DAS28-ESR <2.6 will be summarized. | Week 24 | 
| Proportion of participants with DAS28-ESR<2.6 (DAS28-ESR Remission) at Week 48 and every 48 weeks thereafter | DAS28-ESR is a measure of RA disease activity calculated using the number of tender joints and swollen joints (28 joint count), ESR (mm/hour) and PtGA (transformed to a 0-10 scale). Total score approximate range 0-9.4, higher score indicates more severe disease. Proportion of participants achieving DAS28-ESR <2.6 will be summarized. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Proportion of participants achieving American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) remission (Boolean and simplified disease activity index [SDAI]) at Week 24 | ACR/EULAR remission in RA clinical trials will be assessed using both Boolean and SDAI definitions. For the Boolean definition, this includes: Tender/Painful Joint Count (28), Swollen Joint Count (28), hsCRP, PtGA For the SDAI definition, this includes: Tender/Painful Joint Count (28), Swollen Joint Count (28), hsCRP, PtGA, and PhGA. | Week 24 | 
| Proportion of participants achieving ACR and EULAR remission (Boolean and SDAI) at Week 48 and every 48 weeks thereafter | ACR/EULAR remission in RA clinical trials will be assessed using both Boolean and SDAI definitions. For the Boolean definition, this includes: Tender/Painful Joint Count (28), Swollen Joint Count (28), hsCRP, PtGA For the SDAI definition, this includes: Tender/Painful Joint Count (28), Swollen Joint Count (28), hsCRP, PtGA, and PhGA. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of CDAI total score at Week 24 | CDAI is a clinical composite score to determine disease severity using only clinical data. It will be calculated by the simple sum of the 4 following parameters: Tender joint count (28), Swollen joint count (28), PtGA and PhGA both transformed to a 0-10 scale. Total score approximate range 0-76, higher score indicates severe disease. | Week 24 | 
| Absolute values of CDAI total score at Week 48 and every 48 weeks thereafter | CDAI is a clinical composite score to determine disease severity using only clinical data. It will be calculated by the simple sum of the 4 following parameters: Tender joint count (28), Swollen joint count (28), PtGA and PhGA both transformed to a 0-10 scale. Total score approximate range 0-76, higher score indicates severe disease. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of DAS28-CRP at Week 24 | DAS28-CRP will be calculated using number of tender joints and swollen joints (28 joint count), hsCRP (mg/L) and PtGA (transformed to a 0-10 scale). Total score approximate range 0-9.4, higher score indicates severe disease. | Week 24 | 
| Absolute values of DAS28-CRP at Week 48 and every 48 weeks thereafter | DAS28-CRP will be calculated using number of tender joints and swollen joints (28 joint count), hsCRP (mg/L) and PtGA (transformed to a 0-10 scale). Total score approximate range 0-9.4, higher score indicates severe disease. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of DAS28-ESR at Week 24 | DAS28-ESR will be calculated using number of tender joints and swollen joints (28 joint count), ESR (mm/hour) and PtGA (transformed to a 0-10 scale). Total score approximate range 0-9.4, higher score indicates severe disease. | Week 24 | 
| Absolute values of DAS28-ESR at Week 48 and every 48 weeks thereafter | DAS28-ESR will be calculated using number of tender joints and swollen joints (28 joint count), ESR (mm/hour) and PtGA (transformed to a 0-10 scale). Total score approximate range 0-9.4, higher score indicates severe disease. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of van der Heijde modified total sharp score (mTSS) (in participants from 201790 [NCT03980483] and 201791 [NCT03970837] only) at Week 24 | Van der Heijde mTSS is a measure of the level of joint damage. Radiographs of the hands and feet will be obtained. Joints will be scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores will be added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). | Week 24 | 
| Absolute values of van der Heijde mTSS (in participants from 201790 [NCT03980483] and 201791 [NCT03970837] only) at Week 48 and every 48 weeks thereafter | Van der Heijde mTSS is a measure of the level of joint damage. Radiographs of the hands and feet will be obtained. Joints will be scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores will be added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of Health assessment questionnaire-disability index (HAQ-DI) at Week 24 | The HAQ-DI includes 20 questions which assesses difficulty in performing activities of daily living. The questionnaire assesses eight domains of physical functioning: Dressing and Grooming (2 items), Hygiene (3 items), Arising (2 items), Reach (2 items), Eating (3 items), Grip (3 items), Walking (2 items), Common Daily Activities (3 items). The questions assess usual abilities ranging from 0 without any difficulty to 3 unable to do. A lower HAQ-DI score indicates better quality of life. | Week 24 | 
| Absolute values of HAQ-DI at Week 48 and every 48 weeks thereafter | The HAQ-DI includes 20 questions which assesses difficulty in performing activities of daily living. The questionnaire assesses eight domains of physical functioning: Dressing and Grooming (2 items), Hygiene (3 items), Arising (2 items), Reach (2 items), Eating (3 items), Grip (3 items), Walking (2 items), Common Daily Activities (3 items). The questions assess usual abilities ranging from 0 without any difficulty to 3 unable to do. A lower HAQ-DI score indicates better quality of life. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of Arthritis pain visual analogue scale (VAS) at Week 24 | Participant's assessment of the severity of their arthritis pain over the past week, using a 100 unit VAS, with anchors 0 (no pain) and 100 (most severe pain). | Week 24 | 
| Absolute values of Arthritis pain VAS at Week 48 and every 48 weeks thereafter | Participant's assessment of the severity of their arthritis pain over the past week, using a 100 unit VAS, with anchors 0 (no pain) and 100 (most severe pain). | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of the physical component scores of short form (SF)-36 at Week 24 | SF-36 is a generic health survey that contains 36 questions covering eight domains of health: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue and general health perceptions. Scores on each item will be summed and averaged (range = 0 [poorer health] to 100 [better health]). | Week 24 | 
| Absolute values of the mental component scores of SF-36 at Week 24 | SF-36 is a generic health survey that contains 36 questions covering eight domains of health: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue and general health perceptions. Scores on each item will be summed and averaged (range = 0 [poorer health] to 100 [better health]). | Week 24 | 
| Absolute values of domain scores of SF-36 at Week 24 | SF-36 is a generic health survey that contains 36 questions covering eight domains of health: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue and general health perceptions. Scores on each item will be summed and averaged (range = 0 [poorer health] to 100 [better health]). | Week 24 | 
| Absolute values of the physical component scores of SF-36 at Week 48 and every 48 weeks thereafter | SF-36 is a generic health survey that contains 36 questions covering eight domains of health: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue and general health perceptions. Scores on each item will be summed and averaged (range = 0 [poorer health] to 100 [better health]). | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of the mental component scores of SF-36 at Week 48 and every 48 weeks thereafter | SF-36 is a generic health survey that contains 36 questions covering eight domains of health: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue and general health perceptions. Scores on each item will be summed and averaged (range = 0 [poorer health] to 100 [better health]). | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of domain scores of SF-36 at Week 48 and every 48 weeks thereafter | SF-36 is a generic health survey that contains 36 questions covering eight domains of health: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue and general health perceptions. Scores on each item will be summed and averaged (range = 0 [poorer health] to 100 [better health]). | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Absolute values of Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue at Week 24 | FACIT-fatigue questionnaire is a validated participant-reported measure developed originally to assess fatigue in individuals with cancer and has been subsequently used and validated in numerous chronic conditions, including RA. | Week 24 | 
| Absolute values of FACIT-Fatigue at Week 48 and every 48 weeks thereafter | FACIT-fatigue questionnaire is a validated participant-reported measure developed originally to assess fatigue in individuals with cancer and has been subsequently used and validated in numerous chronic conditions, including RA. | Week 48 and every 48 weeks thereafter, up to 4 years | 
| Proportion of participants with anti-GSK3196165 antibodies | Presence of anti-GSK3196165 antibodies will be determined. | Up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, GSK3196165, Otilimab, Long-term safety, Long-term efficacy