ATI-450 Plus Methotrexate (MTX) Versus Placebo Plus MTX in Participants With Moderate to Severe Active Rheumatoid Arthritis (RA)

September 2, 2026 updated by: Aclaris Therapeutics, Inc.

Phase 2b, Randomized, Multicenter, Double-blind, Parallel Group, Placebo Controlled, Dose Ranging Study to Investigate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ATI-450 Plus Methotrexate (MTX) Versus Placebo Plus MTX in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA) Who Have Had an Inadequate Response to MTX Alone

This study evaluates ATI-450 plus MTX versus placebo plus MTX in participants with moderate to severe active RA who have had an inadequate response to MTX alone.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a Phase 2b, randomized, multicenter, double-blind, parallel group, placebo controlled, dose ranging study to investigate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of ATI-450 plus MTX versus placebo plus MTX in participants with moderate to severe active RA who have had an inadequate response to MTX alone.

Study Type

Interventional

Enrollment (Actual)

251

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Bulgaria
      • Pleven, Bulgaria, 5800
        • Aclaris Investigational Site
      • Plovdiv, Bulgaria, 4000
        • Aclaris Investigational Site
      • Plovdiv, Bulgaria, 4001
        • Aclaris Investigational Site
      • Plovdiv, Bulgaria, 4002
        • Aclaris Investigational Site
      • Plovdiv, Bulgaria, 4004
        • Aclaris Investigational Site
      • Sofia, Bulgaria, 1336
        • Aclaris Investigational Site
      • Sofia, Bulgaria, 1431
        • Aclaris Investigational Site
      • Sofia, Bulgaria, 1606
        • Aclaris Investigational Site
      • Varna, Bulgaria, 9000
        • Aclaris Investigational Site
  • Czechia
      • Brno, Czechia, 615 00
        • Aclaris Investigational Site
      • Hlučín, Czechia, 748 01
        • Aclaris Investigational Site
      • Ostrava, Czechia, 702 00
        • Aclaris Investigational Site
      • Pardubice, Czechia, 530 02
        • Aclaris Investigational Site
      • Prague, Czechia, 128 50
        • Aclaris Investigational Site
      • Prague, Czechia, 140 00
        • Aclaris Investigational Site
      • Uherské Hradiště, Czechia, 686 01
        • Aclaris Investigational Site
  • Poland
      • Bialystok, Poland, 15-297
        • Aclaris Investigational Site
      • Bialystok, Poland, 15-879
        • Aclaris Investigational Site
      • Dąbrówka, Poland, 62-069
        • Aclaris Investigational Site
      • Krakow, Poland, 30-363
        • Aclaris Investigational Site
      • Lublin, Poland, 20-607
        • Aclaris Investigational Site
      • Nowa Sól, Poland, 67-100
        • Aclaris Investigational Site
      • Poznan, Poland, 60-218
        • Aclaris Investigational Site
      • Poznan, Poland, 60-446
        • Aclaris Investigational Site
      • Poznan, Poland, 61-397
        • Aclaris Investigational Site
      • Sochaczew, Poland, 96-500
        • Aclaris Investigational Site
      • Torun, Poland, 87-100
        • Aclaris Investigational Site
      • Warsaw, Poland, 04-141
        • Aclaris Investigational Site
      • Wroclaw, Poland, 52-442
        • Aclaris Investigational Site
    • Lesser Poland Voivodeship
      • Krakow, Lesser Poland Voivodeship, Poland, 30-002
        • Aclaris Investigational Site
    • Lubelski
      • Tomaszów Lubelski, Lubelski, Poland, 22-600
        • Aclaris Investigational Site
    • Lublin Voivodeship
      • Lublin, Lublin Voivodeship, Poland, 20-362
        • Aclaris Investigational Site
    • Masovian Voivodeship
      • Nadarzyn, Masovian Voivodeship, Poland, 05-830
        • Aclaris Investigational Site
    • Mzowieckie
      • Grodzisk Mazowiecki, Mzowieckie, Poland, 05-825
        • Aclaris Investigational Site
    • Podlaskie Voivodeship
      • Bialystok, Podlaskie Voivodeship, Poland, 15-351
        • Aclaris Investigational Site
    • Silesian Voivodeship
      • Katowice, Silesian Voivodeship, Poland, 40-282
        • Aclaris Investigational Site
    • Warm.Maz.
      • Elblag, Warm.Maz., Poland, 82-300
        • Aclaris Investigational Site
    • Warmińsko-Mazurskien
      • Olsztyn, Warmińsko-Mazurskien, Poland, 10-117
        • Aclaris Investigational Site
    • Wielkopolska
      • Poznan, Wielkopolska, Poland, 61-113
        • Aclaris Investigational Site
  • United States
    • California
      • El Cajon, California, United States, 92020
        • Aclaris Investigational Site
      • Encino, California, United States, 91436
        • Aclaris Investigational Site
      • La Jolla, California, United States, 92093
        • Aclaris Investigational Site
      • Palm Desert, California, United States, 92260
        • Aclaris Investigational Site
    • Florida
      • Tampa, Florida, United States, 33613
        • Aclaris Investigational Site
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73103
        • Aclaris Investigational Site
    • Pennsylvania
      • Duncansville, Pennsylvania, United States, 16635
        • Aclaris Investigational Site
    • Tennessee
      • Jackson, Tennessee, United States, 38305
        • Aclaris Investigational Site
    • Texas
      • Cypress, Texas, United States, 77429
        • Aclaris Investigational Site
      • Mesquite, Texas, United States, 75150
        • Aclaris Investigational Site
      • San Antonio, Texas, United States, 78229
        • Aclaris Investigational Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Able to comprehend and be willing to sign the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved participant ICF prior to administration of any study-related procedures.
  • Diagnosis of adult-onset RA as defined by the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria.
  • Have active moderate to severe RA at Screening.
  • A minimum of 12 weeks on MTX with a stable MTX dose.

Exclusion Criteria:

  • Current acute or chronic immunoinflammatory disease other than RA which may impact the course or assessment of RA.
  • Uncontrolled non-immunoinflammatory disease that may place the participant at increased risk during the study or impact the interpretation of results (eg, previous malignancy, recurrent infection, previous venous thromboembolism).
  • Participant has experience with > 2 biologics, > 1 JAK inhibitor, or a combination of 1 biologic experience and 1 JAK inhibitor.
  • Currently receiving corticosteroids at doses > 10 mg/day of prednisone (or equivalent) or have been receiving an unstable dosing regimen of corticosteroids within 2 weeks of screening.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ATI-450 20 mg BID plus Methotrexate

ATI-450 20 mg oral tablet twice daily (BID) with a stable weekly dose of methotrexate for 12 weeks
Drug: Methotrexate

15 mg to 25 mg weekly

Drug: ATI-450 20 mg oral tablet BID

Oral, small molecule MK2 inhibitor

Other Names:
  • zunsemetinib
Experimental: ATI-450 50 mg BID plus Methotrexate

ATI-450 50 mg oral tablet BID with a stable weekly dose of methotrexate for 12 weeks
Drug: Methotrexate

15 mg to 25 mg weekly

Drug: ATI-450 50 mg oral tablet BID

Oral, small molecule MK2 inhibitor

Other Names:
  • zunsemetinib
Placebo Comparator: Placebo plus Methotrexate

Placebo oral tablet BID with a stable weekly dose of methotrexate for 12 weeks
Drug: Methotrexate

15 mg to 25 mg weekly

Drug: Placebo oral tablet

Placebo tablet manufactured to match ATI-450 in appearance

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Achieving ACR20 at Week 12
Time Frame: Week 12

Participants achieving American College of Rheumatology (ACR) 20 (responders) were defined as having ≥20% improvement in both the number of swollen and tender joints (66/68 joint counts) and ≥20% improvement in ≥3 of the following 5 measures: Patient's Global Assessment of Disease Activity (VAS), Patient's Assessment of Arthritis Pain (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), Physician's Global Assessment of Disease Activity (VAS), and acute phase reactant as measured by hsCRP.

Model-based estimates and 95% confidence intervals (CIs) were produced.
Week 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
ATI-450 and Metabolite (CDD-2164) Concentrations
Time Frame: 2 hours postdose on Days 1, 8, and 85
2 hours postdose on Days 1, 8, and 85
Percentage of Participants Achieving ACR50 at Week 12
Time Frame: Week 12

Participant achieving ACR50 (responders) were defined as having ≥50% improvement in both the number of swollen and tender joints (66/68 joint counts) and ≥50% improvement in ≥3 of the following 5 measures: Patient's Global Assessment of Disease Activity (VAS), Patient's Assessment of Arthritis Pain (VAS), HAQ-DI, Physician's Global Assessment of Disease Activity (VAS), Acute phase reactant as measured by hsCRP.

Model-based estimates and 95% CIs were produced.
Week 12
Percentage of Participants Achieving ACR70 at Week 12
Time Frame: Week 12

Participants achieving ACR70 (responders) were defined as having ≥70% improvement in both the number of swollen and tender joints (66/68 joint counts) and ≥70% improvement in ≥3 of the following 5 measures: Patient's Global Assessment of Disease Activity (VAS), Patient's Assessment of Arthritis Pain (VAS), HAQ-DI, Physician's Global Assessment of Disease Activity (VAS), Acute phase reactant as measured by hsCRP.

Model-based estimates and 95% CIs were produced.
Week 12
Change From Baseline in DAS28-CRP at Week 12
Time Frame: Baseline, Week 12

The DAS28-CRP consists of a composite score of the following variables: TJC28, SJC28, CRP (hsCRP was used for the purposes of this study), and Patient's Global Assessment of Disease Activity. Interpretation of the DAS28-CRP is on a scale of 0 to 9.4, where <2.6 is considered remission, ≥2.6 to <3.2 is considered low/minimal disease activity, ≥3.2 to ≤5.1 is considered moderate disease activity, and >5.1 is considered high/severe disease activity.

The least square (LS) mean change from baseline in DAS28-CRP at Week 12 was estimated from the Mixed Model Repeated Measures (MMRM) model.
Baseline, Week 12
Percentage of Participants Achieving DAS28-CRP Remission (Score <2.6) at Week 12
Time Frame: Week 12

The Disease Activity Score using 28 Joint Count-C-reactive protein (DAS28-CRP) consists of a composite score of the following variables: TJC28, SJC28, CRP (hsCRP is used for the purposes of this study), and Patient's Global Assessment of Disease Activity. Interpretation of the DAS28-CRP is on a scale of 0 to 9.4, where <2.6 is considered remission, ≥2.6 to <3.2 is considered low/minimal disease activity, ≥3.2 to ≤5.1 is considered moderate disease activity, and >5.1 is considered high/severe disease activity.

Model-based estimates and 95% CIs were produced.
Week 12
Percentage of Participants Achieving DAS28-CRP Low Disease Activity (Score ≤ 3.2) at Week 12
Time Frame: Week 12

The DAS28-CRP consists of a composite score of the following variables: TJC28, SJC28, CRP (hsCRP is used for the purposes of this study), and Patient's Global Assessment of Disease Activity. Interpretation of the DAS28-CRP is on a scale of 0 to 9.4, where <2.6 is considered remission, ≥2.6 to <3.2 is considered low/minimal disease activity, ≥3.2 to ≤5.1 is considered moderate disease activity, and >5.1 is considered high/severe disease activity.

Model-based estimates and 95% CIs were produced.
Week 12
Change From Baseline in HAQ-DI Score at Week12
Time Frame: Baseline, Week 12

The HAQ-DI (standard disability method calculation) was utilized to assess the participant's physical function or disability according to the participant. The HAQ-DI is a 20-item, validated questionnaire used to assess the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities [errands and chores]). Responses in each functional area are scored from 0 (no difficulty) to 3 (inability to perform a ask in that area). Overall score was computed as the sum of category scores and divided by the number of categories answered, ranging from 0 to 3. A lower score demonstrated less disability.

LS mean change from baseline in HAQ-DI score at Week 12 was estimated from the MMRM model.
Baseline, Week 12
Change From Baseline in CDAI Score at Week 12
Time Frame: Baseline, Week 12

The Clinical Disease Activity Index (CDAI) was the sum of 4 outcome parameters:

  • Tender joint count out of 28 joints (TJC28)
  • Swollen joint count out of 28 joints (SJC28)
  • Patient's Global Assessment of Disease Activity; and
  • Physician's Global Assessment of Disease Activity.

Interpretation of the CDAI disease activity was measured on a scale of 0 to 76, where ≤2.8 was considered remission, >2.8 to ≤10 was considered low/minimal disease activity, >10 to ≤22 was considered moderate disease activity, and >22.0 was considered high/severe disease activity.

LS mean change from baseline in CDAI score at Week 12 was estimated from the MMRM model.
Baseline, Week 12
Percentage of Participants Achieving CDAI Remission (Score ≤ 2.8)
Time Frame: Week 12

The CDAI was the sum of 4 outcome parameters:

  • Tender joint count out of 28 joints (TJC28)
  • Swollen joint count out of 28 joints (SJC28)
  • Patient's Global Assessment of Disease Activity; and
  • Physician's Global Assessment of Disease Activity.

Interpretation of the CDAI disease activity was measured on a scale of 0 to 76, where ≤2.8 was considered remission, >2.8 to ≤10 was considered low/minimal disease activity, >10 to ≤22 was considered moderate disease activity, and >22.0 was considered high/severe disease activity.

Model-based estimates and 95% CIs were produced.
Week 12
Percent Change From Baseline in hsCRP Level at Week 12
Time Frame: Baseline, Week 12

Blood samples were evaluated to measure levels of hsCRP.
Baseline, Week 12
Change From Baseline in Short Form Health Survey SF-36 Physical Component Summary (PCS) Score at Week 12
Time Frame: Baseline, Week 12

The PCS is composed of 4 scales of the Short Form-36 Health Status Survey Questionnaire (SF-36) version 2 assessing physical function, role limitations caused by physical problems, bodily pain, and general health. The range of the SF-36 PCS is between 0 and 100, where higher scores represent better physical functioning.

A 2.5 to 5-point change from baseline is established as the minimum clinically-important difference for the PCS in RA participants.

LS mean change from baseline in SF-36 PCS score at Week 12 was estimated from the MMRM model.
Baseline, Week 12
Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) Score at Week 12
Time Frame: Baseline, Week 12

The FACIT-Fatigue is a 13-item questionnaire that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a 4 point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The total score range is from 0 to 52. The higher the score, the lower the fatigue level.

LS mean change from baseline in FACIT-Fatigue score at Week 12 was estimated from the MMRM model.
Baseline, Week 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Aclaris Therapeutics, Inc.

Investigators

  • Study Director: Ajay Aggarwal, Aclaris Therapeutics, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2022

Primary Completion (Actual)

September 5, 2023

Study Completion (Actual)

October 11, 2023

Study Registration Dates

First Submitted

February 18, 2022

First Submitted That Met QC Criteria

March 4, 2022

First Posted (Actual)

March 15, 2022

Study Record Updates

Last Update Posted (Actual)

September 28, 2026

Last Update Submitted That Met QC Criteria

September 2, 2026

Last Verified

September 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ATI-450-RA-202
  • 2021-002860-31 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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