A Study to Evaluate the Long-Term Safety and Efficacy of GDC-0853 in Participants With Moderate to Severe Rheumatoid Arthritis Enrolled in Study GA29350

Study Overview
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Brief Summary
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A study to evaluate the long-term safety and efficacy of GDC-0853 in participants with moderate to severe active Rheumatoid Arthritis (RA) who have completed 12 weeks of study treatment in Study GA29350. Eligible participants from Study GA29350 who elect to participate will receive treatment with GDC-0853 twice daily (BID) in an open-label fashion for 52 weeks, followed by a safety follow-up period of 8 weeks.

Official Title
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A Phase II Open-Label Extension Study of Patients Previously Enrolled in Study GA29350 to Evaluate the Long-Term Safety and Efficacy of GDC-0853 in Patients With Moderate to Severe Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: GDC-0853


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completion of treatment as specified in Study GA29350, including completion of the Day 84 study visit assessments Acceptable safety and tolerability during Study GA29350 as determined by the investigator or Medical Monitor Have not received any prohibited medications in Study GA29350 While taking methotrexate, must be willing to receive oral folic acid (at least 5 milligrams per week [mg/week]) If receiving oral corticosteroids (less than or equal to [</=] 10 milligrams per day [mg/day] prednisone or equivalent) and/or non-steroidal anti-inflammatory drugs, doses have remained stable for the duration of Study GA29350 Exclusion Criteria: Met protocol defined treatment stopping criteria during Study GA29350 Treatment with any investigational agent (i.e., other than study drug) or live/attenuated vaccine or any other prohibited medication during Study GA29350 or since the last administration of study drug in Study GA29350 In the opinion of the investigator, any new (since initially enrolling in the Phase II Study GA29350), significant, uncontrolled comorbidity that would increase the risk to the participant in Study GA30067 Pregnant or lactating, or intending to become pregnant during the study Participants who experienced a de novo or reactivated serious viral infection such as hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) during the Phase II Study GA29350 Any major episode of infection requiring hospitalization or treatment with intravenous antibiotics during the Phase II Study GA29350 Participants who developed a malignancy during the Phase II Study GA29350 12-lead electrocardiogram (ECG) on Day 84 in Study GA29350 that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results Current treatment with medications that are well known to prolong the QT interval

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 76 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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GDC-0853 (200mg BID) Cohort 1<br>Participants received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 1 of Study GA29350. Cohort 1 participants in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to previous methotrexate (MTX) therapy and then randomized to 12 weeks of GDC-0853 (50 mg daily, 150 mg daily, or 200 mg BID), adalimumab, or placebo. | Drug: GDC-0853<br>* GDC-0853 was administered orally at a dose of 200mg, as per the dosing schedules described above.<br>* Other names: RO7010939;|
| Experimental: GDC-0853 (200mg BID) Cohort 2<br>Participants received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 2 of Study GA29350. Cohort 2 participants in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to one or two tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) therapy, and then randomized to 12 weeks of GDC-0853 (200 mg BID) or placebo. | Drug: GDC-0853<br>* GDC-0853 was administered orally at a dose of 200mg, as per the dosing schedules described above.<br>* Other names: RO7010939;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) | An Adverse Event (AE) was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. | Day 1 up until 8 weeks after the last dose of study drug (up to 1 year, 2 months) | 
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 52 | ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate]. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving ACR50 Response up to Week 12 | ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate]. | Weeks 4, 8 and 12 | 
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response | ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate] | Weeks 4, 8, 12, 24, 36 and 52 | 
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response | ACR70 response is defined as a ≥ 70% improvement (reduction) compared with Baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate]. | Weeks 4, 8, 12, 24, 36 and 52 | 
| Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (3 Variables) (DAS28-3 CRP) | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. | Baseline, Weeks 4, 8, 12, 24, 36 and 52 | 
| Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (4 Variables) (DAS28-4 CRP) | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. | Baseline, Weeks 4, 8, 12, 24, 36 and 52 | 
| Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (3 Variables) (DAS28-3 ESR) | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. | Baseline, Weeks 4, 8, 12, 24, 36 and 52 | 
| Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 ESR) | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. | Baseline, Weeks 4, 8, 12, 24, 36 and 52 | 
| Percentage of Participants With Remission Based on Disease Activity Score Based on 28-Joints Count (DAS28) | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. | Weeks 4, 8, 12, 24, 36 and 52 | 
| Percentage of Participants With Low Disease Activity (LDA) Based on DAS28 | The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. LDAS is defined as DAS28 ≤ 3.2 | Weeks 4, 8, 12, 24, 36 and 52 | 
| Percentage of Participants With ACR/EULAR Remission | Assessed according to the Boolean based definition (tender joint count =<1, swollen joint count =<1, C-reactive Protein (CRP) =<1, and patient global assessment =<1) | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in Simplified Disease Activity Index (SDAI) | Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =< 3.3 indicates disease remission, > 3.4 to 11 indicates low disease activity, > 11 to 26 indicates moderate disease activity, and > 26 indicates high disease activity | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in Clinical Disease Activity Index (CDAI) | CDAI was derived as the sum of the following: tender joint count (TJC), swollen joint count (SJC), participant global assessment (PGA) of disease activity, and physician assessment of disease activity. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 millimeters (mm) and rounded to the nearest centimeter (cm) on a visual analog scale (VAS), where higher scores indicate greater perceived disease activity. The total CDAI score range was 0-76, where higher scores indicate increased disease activity. Change from baseline at a particular time point was calculated among patients with data available at both baseline and the time point of interest. Negative values indicate improvement/reduction in RA disease activity. | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in Tender/Painful Joint Count Based on 68 Joints | Tender Joint Count: a total of 68 joints will be assessed for tenderness. Each joint is assessed for the presence/absence of tenderness. 68 joints are assessed for tenderness and joints are classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from Baseline indicated improvement. | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in Swollen Joint Count Based on 66 Joints | Swollen Joint Count: a total of 66 joints will be assessed for swelling. Each joint is assessed for the presence/absence of swelling. 66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from Baseline indicated improvement. | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in Patient's Assessment of Arthritis Pain, Using Visual Analog Scale (VAS) Score | Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in Patient's Global Assessment of Arthritis, Using VAS Score | Participant-assessed arthritis pain was scored on a 100-mm VAS, where the distance from 0 mm represented the participant's self evaluation of arthritis pain (0 mm=none; 100 mm=very severe). Change from baseline at a particular time point was calculated among patients with data available at both baseline and the time point of interest, where negative change indicated a decrease in participant-assessed arthritis pain. | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in Physician's Global Assessment of Arthritis, Using VAS Score | Physician's assessment of participant's disease activity was scored on a 100-mm VAS, where the distance from 0 mm represented the physician's assessment of the participant's disease activity (0 mm=very good; 100 mm=very poor). Change from baseline at a particular time point was calculated among patients with data available at both baseline and the time point of interest, where negative change from baseline indicated an improvement in physician-assessed disease activity. | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in C-Reactive Protein (CRP) Levels | C-reactive protein is a biological marker of inflammation and is measured in milligrams per decilitre (mg/dL) | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score | The Stanford Health Assessment Questionnaire disability index is a patient-reported outcome used to assess difficulty in performing activities of daily living. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. To respond to each question, a four-level response with higher scores showing larger functional limitations, was chosen. Scoring is as follows with respect to performance of participant's everyday activities: 0 (equals)=without difficulties; 1= with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. The composite HAQ-DI score is the mean of the eight domain scores and the score ranges from 0 (no functional impairment) to 3 (maximum functional impairment). A negative change from baseline indicates improvement. | Weeks 4, 8, 12, 24, 36 and 52 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Version 2.0 (V2) Scores for Physical and Mental Components | The 36-Item Short Form Health Survey (SF-36v2) is a questionnaire used to assess functional health and well-being and consists of eight domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. The SF-36v2 is summarized into Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. The PCS and MCS scores range from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. | Weeks 12, 24 and 52 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score | The FACIT-Fatigue Scale consists of 13 items designed to measure the degree of fatigue experienced by the patient in the previous 7 days. For each question, there are five possible responses: 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit), 4 (very much). A total fatigue score is calculated by summing all items, and possible total scores range from 0 (maximum fatigue) to 52 (no fatigue). A positive change from baseline indicates an improvement in the patient's fatigue (less fatigue). | Weeks 12, 24 and 52 | 
| Area Under the Concentration Time Curve (AUC) of GDC-0853 at Steady State (AUC,ss) | Population PK model estimated AUC of GDC-0853 at steady-state. AUC was measured in Nanograms (ng) per millilitre(mL)*hour (hr). | Pre-dose (0 hour) on Weeks 0 (Day 1), 4, 12, 24, 36, and 52/early termination | 
| Minimum Plasma Concentration of GDC-0853 at Steady State (Ctrough,ss) | Population PK model estimated minimal plasma concentration (Ctrough) of GDC-0853 at steady-state (ss). | Pre-dose (0 hour) on Weeks 0 (Day 1), 4, 12, 24, 36, and 52/early termination | 
| Plasma Decay Half-Life of GDC-0853 at Steady State (t1/2,ss) | Population PK model estimated plasma decay half life of GDC-0853 at steady-state. | Pre-dose (0 hour) on Weeks 0 (Day 1), 4, 12, 24, 36, and 52/early termination | 
| Apparent Oral Clearance of GDC-0853 at Steady State (CL/F,ss) | Population PK model estimated apparent oral clearance of GDC-0853 at steady-state. | Pre-dose (0 hour) on Weeks 0 (Day 1), 4, 12, 24, 36, and 52/early termination |