A Study of RO7123520 to Evaluate the Safety and Efficacy in Participants With Moderately To Severely Active Rheumatoid Arthritis (RA) Who Are Inadequately Responding to Anti-Tumor Necrosis Factor (TNF)-Alpha Therapy

Study Overview
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Brief Summary
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This is a Phase IIa/b double-blind, placebo-controlled, randomized, parallel group, multicenter study to evaluate the safety and efficacy of RO7123520 as adjunctive therapy in participants with RA who are inadequately responding to standard-of-care (methotrexate and anti-TNF-alpha therapy). Part 1 of the study will evaluate safety. Part 2 will evaluate efficacy and safety. Part 3 will evaluate dose-ranging efficacy. Participants will have the option of continuing to the extension period of the study.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase II Study to Evaluate The Safety and Efficacy of RO7123520 as Adjunct Treatment in Patients With Moderately to Severely Active Rheumatoid Arthritis and an Inadequate Response to TNF-alpha Inhibitors

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Anti-TNF-alpha
* Drug: Methotrexate
* Drug: Placebo
* Drug: RO7123520


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of adult-onset RA as defined by the ACR 2010 criteria, for at least 6 months before screening Moderately to severely active RA as defined by at least 4/28 tender joints and at least 4/28 swollen joints, and a DAS28 greater than or equal to (≥) 3.2 For Part 2 only: Active synovitis and/or osteitis as determined by contrast-enhanced magnetic resonance imaging Participants must be taking stable dose of anti-TNF-alpha therapies Participants on stable oral glucocorticoids within 6 weeks of planned randomization Participants taking non-steroidal anti-inflammatory drugs (NSAIDs) intermittently (up to 2-3 times weekly) for short-term relief of pain and participants on regular NSAID use (on stable dose for ≥ 4 weeks) Exclusion Criteria: Parenteral glucocorticoids administration (intramuscular, IV) of ≥50 mg within 6 weeks or less than or equal to (≤) 50 milligrams (mg) within 4 weeks prior to planned randomization, or scheduled parenteral administrations during the study Joint(s) injected with intra-articular glucocorticoids or hyaluronic acid within 6 weeks prior to planned randomization Active inflammatory diseases of the joints not related to RA Systemic autoimmune disease other than RA Juvenile idiopathic arthritis or juvenile RA and/or RA developed before the age of 16 Active fibromyalgia that makes appropriate assessment of RA disease activity challenging in the opinion of the Investigator RA participants functional status class IV according to the ACR 1991 criteria Participants with severe chronic or recurrent viral, bacterial, parasitic, or fungal infections History of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection Any identified confirmed congenital or acquired immunodeficiency Abnormal laboratory values and liver function test Myocardial infarction within less than 6 months prior to participation in the study Severe central or peripheral nervous system diseases

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part 1: Placebo<br>Participants will receive placebo (matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. | Drug: Anti-TNF-alpha<br>* Participants will continue their pre-trial anti-TNF-alpha therapy at a stable dose.<br>Drug: Methotrexate<br>* Participants will continue their pre-trial methotrexate therapy at a stable dose.<br>Drug: Placebo<br>* Participants will receive intravenous infusion of placebo.<br>|
| Experimental: Part 1: RO7123520<br>Participants will receive RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. | Drug: Anti-TNF-alpha<br>* Participants will continue their pre-trial anti-TNF-alpha therapy at a stable dose.<br>Drug: Methotrexate<br>* Participants will continue their pre-trial methotrexate therapy at a stable dose.<br>Drug: RO7123520<br>* Participants will receive intravenous infusion of RO7123520.<br>|
| Placebo Comparator: Part 2: Placebo<br>Participants will receive placebo (matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. | Drug: Anti-TNF-alpha<br>* Participants will continue their pre-trial anti-TNF-alpha therapy at a stable dose.<br>Drug: Methotrexate<br>* Participants will continue their pre-trial methotrexate therapy at a stable dose.<br>Drug: Placebo<br>* Participants will receive intravenous infusion of placebo.<br>|
| Experimental: Part 2: RO7123520<br>Participants will receive RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. | Drug: Anti-TNF-alpha<br>* Participants will continue their pre-trial anti-TNF-alpha therapy at a stable dose.<br>Drug: Methotrexate<br>* Participants will continue their pre-trial methotrexate therapy at a stable dose.<br>Drug: RO7123520<br>* Participants will receive intravenous infusion of RO7123520.<br>|
| Placebo Comparator: Part 3: Placebo<br>Participants will receive placebo (matched to RO7123520) on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. NOTE: Part 3 was not conducted. | Drug: Anti-TNF-alpha<br>* Participants will continue their pre-trial anti-TNF-alpha therapy at a stable dose.<br>Drug: Methotrexate<br>* Participants will continue their pre-trial methotrexate therapy at a stable dose.<br>Drug: Placebo<br>* Participants will receive intravenous infusion of placebo.<br>|
| Experimental: Part 3: RO7123520<br>Participants will receive RO7123520 on Days 1, 14, 28, and 56 with pre-trial anti-TNF-alpha and methotrexate. NOTE: Part 3 was not conducted. | Drug: Anti-TNF-alpha<br>* Participants will continue their pre-trial anti-TNF-alpha therapy at a stable dose.<br>Drug: Methotrexate<br>* Participants will continue their pre-trial methotrexate therapy at a stable dose.<br>Drug: RO7123520<br>* Participants will receive intravenous infusion of RO7123520.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Baseline to last participant last visit (approximately 2 years) | 
| Proportion of Participants Achieving an American College of Rheumatology (ACR) 50 Response at Week 12 | The ACR50 is a composite measure defined as both improvement of 50% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points. | Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Percentage of Participants With Anti-Drug Antibodies |  | Baseline | 
| Change From Baseline in Bone Mineral Density Lumbar Spine L1-L4 as Assessed by Dual Energy X-ray Absorptiometry (DEXA) Scans |  | Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Disease Activity Index (CDAI) Score at Week 12 | The CDAI for Rheumatoid Arthritis (RA) assesses the severity of the disease using clinical data. It consists of the Patient Global disease Activity (PGA) estimate and the Evaluator Global disease Activity (EGA) estimate, each of which represent assessments of disease activity on a scale of 1-10, with 10 being maximum activity. | Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Change From Baseline in Disease Activity Score 28 (DAS28) at Week 12 | The DAS28 is a combined index for measuring disease activity in RA; the 28 refers to the number of joints included in the assessment. The index includes swollen and tender joint counts, acute phase response, and general arthritis disease activity status. An overall disease activity score of 5.1 or greater implies active disease, less than 3.2 implies low disease activity, and less that 2.6 implies disease remission. | Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Percentage of Participants Achieving DAS28 Remission at Week 12 | The DAS28 is a combined index for measuring disease activity in RA; the 28 refers to the number of joints included in the assessment. The index includes swollen and tender joint counts, acute phase response, and general arthritis disease activity status. An overall disease activity score of 5.1 or greater implies active disease, less than 3.2 implies low disease activity, and less that 2.6 implies disease remission. | Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Percentage of Participants Achieving CDAI Remission at Week 12 | The CDAI for Rheumatoid Arthritis (RA) assesses the severity of the disease using clinical data. It consists of the Patient Global disease Activity (PGA) estimate and the Evaluator Global disease Activity (EGA) estimate, each of which represent assessments of disease activity on a scale of 1-10, with 10 being maximum activity. CDAI remission is defined as a score of less than or equal to 2.8. | Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Percentage of Participants Achieving ACR20 Response at Week 12 | The ACR20 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points. | Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Percentage of Participants Achieving ACR70 Response at Week 12 | The ACR70 is a composite measure defined as both improvement of 70% in the number of tender and number of swollen joints, and a 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP). The ACR is reported as percent improvement at discrete time points. | Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Change From Baseline in Simple Disease Activity Index (SDAI) Score at Week 12 | The SDAI consists of 5 parameters used to assess RA disease activity: 28-joint count assessments of tenderness and swelling, participant and investigator global assessments, and CRP levels. A composite score is produced, with remission defined as an SDAI of <3.3, low disease activity as ≤11, moderate disease activity as ≤26 and high disease activity as >26. | Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Change From Baseline in the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 | The HAQ-DI is a 20-item, validated questionnaire used to assess 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. Subscale scores are combined and the mean value is reported for each arm per timepoint. | Baseline, Week 12 of PoC and Week 12 of Extension Period Analysis (overall study week 24) | 
| Serum RO7123520 Concentration |  | Pre-dose (0 hour), 1 hour post infusion (duration of infusion: approximately 1 hour) on Days 1, 14, 28, 56; Pre-dose (0 hour) on Days 84, 112 | 
| Synovial Fluid RO7123520 Concentration |  | Pre-dose (0 hour) on Days 1, 84 |