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

Phase 2

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: ATI-450
Drug: Placebo oral tablet
Drug: Methotrexate

Registration Number: NCT04247815

Lead Sponsor: Aclaris Therapeutics, Inc.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ATI-450 plus Methotrexate	ATI-450	ATI-450 50mg oral tablet BID with a stable weekly dose of Methotrexate
Placebo plus Methotrexate	Placebo oral tablet	Placebo oral tablet BID with a stable weekly dose of Methotrexate
ATI-450 plus Methotrexate	Methotrexate	ATI-450 50mg oral tablet BID with a stable weekly dose of Methotrexate
Placebo plus Methotrexate	Methotrexate	Placebo oral tablet BID with a stable weekly dose of Methotrexate

Primary Outcome Measures

Name	Time	Method
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)	Baseline through Day 114	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.

Secondary Outcome Measures

Name	Time	Method
Number and Percent of Patients Achieving ACR 70	Baseline through Day 114	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.
Percent Change in (hsCRP) Levels Over Time	Baseline through Day 114	Median percent change from baseline in high sensitivity C-reactive protein (hsCRP) levels over time
Change From Baseline in Disease Activity Score	Baseline through Day 114	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.
Number and Percent of Patients Achieving DAS28-CRP <2.6 Over Time	Baseline through Day 114	Number and Percent of Patients Achieving DAS28-CRP \<2.6 over time
Change From Baseline in RAMRIS Hand-Wrist Assessments (Osteitis Average)	Baseline through Day 84	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. 1-33% involvement of original articular bone 2. 34-67% involvement of original articular bone 3. 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. 1-33% volume enhancement 2. 34-67% volume enhancement 3. 68-100% volume enhancement
Change From Baseline in RAMRIS Hand-Wrist Assessments (Synovitis Average)	Baseline through Day 84	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. 1-33% involvement of original articular bone 2. 34-67% involvement of original articular bone 3. 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. 1-33% volume enhancement 2. 34-67% volume enhancement 3. 68-100% volume enhancement
Assessment of ATI-450 Concentration (ng/mL)	Day 1 through Day Day 84
Number and Percent of Patients Achieving ACR 20	Baseline through Day 114	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.
Number and Percent of Patients Achieving ACR 50	Baseline through Day 114	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.