Study of ATI-450 Plus Methotrexate (MTX) vs MTX Alone in Patients With Moderate to Severe RA

Study Overview
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Brief Summary
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This is a Phase 2 study to investigate the safety, tolerability, PK, and PD of ATI-450 plus methotrexate versus methotrexate alone in patients with moderate to severe RA.

Detailed Description
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This is a Phase 2, randomized, investigator and patient-blind, sponsor-unblinded, parallel group, placebo-controlled study to investigate the safety, tolerability, PK, and PD of ATI-450 plus methotrexate versus methotrexate alone in patients with moderate to severe RA with inadequate response to methotrexate. All subjects will be required to complete a safety follow up visit 30 days post last study medication administration.

Official Title
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A Phase 2a, Randomized, Investigator and Patient-blind, Sponsor-unblinded, Parallel Group, Placebo-controlled Study of ATI-450 Plus Methotrexate (MTX) vs MTX Alone in Patients With Moderate to Severe Active Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: ATI-450
* Drug: Placebo oral tablet
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of adult-onset RA as defined by the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria. DAS28-CRP ≥3.2 defined as moderate to high disease activity. Have moderately to severely active RA defined by at least 4/28 tender and 4/28 swollen joints. hsCRP ≥5 mg/L at screening. Patients must have definitive intra-articular synovitis or osteitis defined as a score of 1 or greater on a Hand-Wrist MRI as assessed by central imaging reader (using RAMRIS). On a stable MTX dose and a stable dose of folic or folinic acid prior to the screening visit. Exclusion Criteria: Patient has a current acute or chronic immunoinflammatory disease other than RA which may impact the course or assessment of RA. Patient has an uncontrolled non-immunoinflammatory disease that may place the patient at increased risk during the study or impact the interpretation of results. History or evidence of active or latent tuberculosis. Active infection requiring treatment with antibiotics. Blood pressure levels (in supine position after at least 5 minutes rest): <90 mmHg or >140 mmHg for systolic blood pressure or <40 mmHg or >90 mmHg for diastolic blood pressure. Are currently receiving corticosteroids at doses greater than 10 mg per day of prednisone (or equivalent) or have been receiving an unstable dosing regimen of corticosteroids within 2 weeks of the screening visit. Have started treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or have been receiving an unstable dosing regimen of NSAIDs within 2 weeks of the screening visit. Patients with history of stroke. Any joint procedure in the past 90 days prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Randomized, investigator and patient-blind, sponsor-unblinded, parallel group.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATI-450 plus Methotrexate<br>ATI-450 50mg oral tablet BID with a stable weekly dose of Methotrexate | Drug: ATI-450<br>* Oral, small molecule MK2 inhibitor<br>* Other names: CDD-450;Drug: Methotrexate<br>* 7.5 mg to 25 mg weekly<br>|
| Placebo Comparator: Placebo plus Methotrexate<br>Placebo oral tablet BID with a stable weekly dose of Methotrexate | Drug: Placebo oral tablet<br>* Placebo tablet manufactured to match ATI-450 in appearance<br>Drug: Methotrexate<br>* 7.5 mg to 25 mg weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Outcome Measure is the Determination of the Safety and Tolerability of ATI-450 Plus Methotrexate in Patients With Moderate to Severe Rheumatoid Arthritis: Adverse Events (AEs) | Safety and tolerability reported as Adverse Events (AEs). AEs will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0. AEs will be presented by system organ class and preferred term in frequency tables. | Baseline through Day 114 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in (hsCRP) Levels Over Time | Median percent change from baseline in high sensitivity C-reactive protein (hsCRP) levels over time | Baseline through Day 114 | 
| Change From Baseline in Disease Activity Score | The Disease Activity Score using 28 joint count C-reactive protein DAS28 (CRP) consists of a composite score of the following variables: tender joint count, swollen joint count, CRP, and Patient's Global Assessment of Disease Activity score. The following equation will be used to calculate the DAS28 (CRP): DAS28 (CRP) = 0.56 √TJC28 + 0.28√SJC28 + 0.36ln(CRP +1) + 0.014×(Patient's Global Assessment of Disease Activity) + 0.96, where: TJC28 = number of joints tender out of 28 SJC28 = number of joints swollen out of 28 CRP = C-reactive protein Patient's Global Assessment of Disease Activity on a 100 mm visual analog scale (VAS) recorded by the patient Interpretation of the DAS28 (CRP) disease activity measure is on a scale of 0 to 9.4, where: <2.6 is considered remission, ≥2.6 to <3.2 is considered low/minimal, ≥3.2 to ≤5.1 is considered moderate, and >5.1 is considered high/severe. | Baseline through Day 114 | 
| Number and Percent of Patients Achieving DAS28-CRP <2.6 Over Time | Number and Percent of Patients Achieving DAS28-CRP <2.6 over time | Baseline through Day 114 | 
| Change From Baseline in RAMRIS Hand-Wrist Assessments (Osteitis Average) | Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) uses integer scales to measure the severity of disease at each bone or joint of interest in the hand and wrist, with separate scores given for osteitis and synovitis. Osteitis was scored at 25 bone locations: distal radius and ulna, 8 carpal bones (trapezium, trapezoid, capitate, hamate, pisiform, scaphoid, lunate, and triquetrum, as well as the 5 metacarpal bases), 5 metacarpal heads, and 5 proximal phalangeal bases. Score Definition 0 No osteitis 1-33% involvement of original articular bone 34-67% involvement of original articular bone 68-100% involvement of original articular bone Synovitis was scored at the following 8 joint locations: distal radioulnar joint, radiocarpal joint, intercarpal / carpometacarpal joints 2-5, and 5 metacarpophalangeal (MCP) joints. Score Definition 0 No synovitis 1-33% volume enhancement 34-67% volume enhancement 68-100% volume enhancement | Baseline through Day 84 | 
| Change From Baseline in RAMRIS Hand-Wrist Assessments (Synovitis Average) | Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) uses integer scales to measure the severity of disease at each bone or joint of interest in the hand and wrist, with separate scores given for osteitis and synovitis. Osteitis was scored at 25 bone locations: distal radius and ulna, 8 carpal bones (trapezium, trapezoid, capitate, hamate, pisiform, scaphoid, lunate, and triquetrum, as well as the 5 metacarpal bases), 5 metacarpal heads, and 5 proximal phalangeal bases. Score Definition 0 No osteitis 1-33% involvement of original articular bone 34-67% involvement of original articular bone 68-100% involvement of original articular bone Synovitis was scored at the following 8 joint locations: distal radioulnar joint, radiocarpal joint, intercarpal / carpometacarpal joints 2-5, and 5 metacarpophalangeal (MCP) joints. Score Definition 0 No synovitis 1-33% volume enhancement 34-67% volume enhancement 68-100% volume enhancement | Baseline through Day 84 | 
| Number and Percent of Patients Achieving ACR 20 | American College of Rheumatology (ACR) 20 will be calculated at each treatment visit and the number and percent of subjects with a 20% improvement will be tabulated at each scheduled visit. | Baseline through Day 114 | 
| Number and Percent of Patients Achieving ACR 50 | American College of Rheumatology (ACR) 50 will be calculated at each treatment visit and the number and percent of subjects with a 50% improvement will be tabulated at each scheduled visit. | Baseline through Day 114 | 
| Number and Percent of Patients Achieving ACR 70 | American College of Rheumatology (ACR) 70 will be calculated at each treatment visit and the number and percent of subjects with a 70% improvement will be tabulated at each scheduled visit. | Baseline through Day 114 | 
| Assessment of ATI-450 Concentration (ng/mL) |  | Day 1 through Day Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arthritis, Rheumatoid