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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ATI-450 plus Methotrexate | Experimental | ATI-450 50mg oral tablet BID with a stable weekly dose of Methotrexate |
|
| Placebo plus Methotrexate | Placebo Comparator | Placebo oral tablet BID with a stable weekly dose of Methotrexate |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ATI-450 | Drug | Oral, small molecule MK2 inhibitor |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| David Gordon | Aclaris Therapeutics | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Aclaris Investigational Site | Anniston | Alabama | 36207 | United States | ||
| Aclaris Investigational Site |
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| ID | Title | Description |
|---|---|---|
| FG000 | ATI-450 Plus Methotrexate | ATI-450 50mg oral tablet BID with a stable weekly dose of Methotrexate ATI-450: Oral, small molecule MK2 inhibitor Methotrexate: 7.5 mg to 25 mg weekly |
| FG001 | Placebo Plus Methotrexate | Placebo oral tablet BID with a stable weekly dose of Methotrexate Placebo oral tablet: Placebo tablet manufactured to match ATI-450 in appearance Methotrexate: 7.5 mg to 25 mg weekly |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | ATI-450 Plus Methotrexate | ATI-450 50mg oral tablet BID with a stable weekly dose of Methotrexate ATI-450: Oral, small molecule MK2 inhibitor Methotrexate: 7.5 mg to 25 mg weekly |
| BG001 | Placebo Plus Methotrexate |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | The Safety population consisted of patients who receive at least 1 dose of study drug. This set was used for the safety data summaries and baseline characteristic summaries. This set was analyzed as treated. | Posted | Count of Participants | Participants | Baseline through Day 114 |
|
Baseline to Day 114
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | ATI-450 Plus Methotrexate | ATI-450 50mg oral tablet BID with a stable weekly dose of Methotrexate ATI-450: Oral, small molecule MK2 inhibitor Methotrexate: 7.5 mg to 25 mg weekly |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| COVID-19 pneumonia | Infections and infestations | MedDRA 23.0 | Non-systematic Assessment | SAE occurred during the follow-up period. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Palpitations | Cardiac disorders | MedDRA 23.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ajay Aggarwal | Aclaris Therapeutics, Inc. | 484-540-6296 | Clintrials@aclaristx.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 27, 2020 | Mar 3, 2023 | Prot_SAP_002.pdf |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| D001168 | Arthritis |
| ID | Term |
|---|---|
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D003240 | Connective Tissue Diseases |
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| ID | Term |
|---|---|
| D008727 | Methotrexate |
| ID | Term |
|---|---|
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
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Randomized, investigator and patient-blind, sponsor-unblinded, parallel group.
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The blinded placebo drug is packaged to match the active study drug and will be stored under the same conditions.
| Placebo oral tablet | Drug | Placebo tablet manufactured to match ATI-450 in appearance |
|
| Methotrexate | Drug | 7.5 mg to 25 mg weekly |
|
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:
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
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
| 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
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
| 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 |
| Tampa |
| Florida |
| 33613 |
| United States |
| Aclaris Investigational Site | Atlanta | Georgia | 30342 | United States |
| Aclaris Investigational Site | Duncansville | Pennsylvania | 16635 | United States |
| Aclaris Investigational Site | Mesquite | Texas | 75150 | United States |
| Protocol Violation |
|
Placebo oral tablet BID with a stable weekly dose of Methotrexate
Placebo oral tablet: Placebo tablet manufactured to match ATI-450 in appearance
Methotrexate: 7.5 mg to 25 mg weekly
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
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| Weight (kg) | Mean | Standard Deviation | kg |
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| Height (cm) | Mean | Standard Deviation | cm |
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| BMI (kg/m2) | Mean | Standard Deviation | kg/m2 |
|
| OG001 | Placebo Plus Methotrexate | Placebo oral tablet BID with a stable weekly dose of Methotrexate Placebo oral tablet: Placebo tablet manufactured to match ATI-450 in appearance Methotrexate: 7.5 mg to 25 mg weekly |
|
|
| Secondary | Percent Change in (hsCRP) Levels Over Time | Median percent change from baseline in high sensitivity C-reactive protein (hsCRP) levels over time | The Per-Protocol (PP) population consisted of all patients who completed their Day 84 visit and had valid hsCRP values for at least 6 of the 7 scheduled collection times. This set was analyzed as treated. | Posted | Median | Full Range | Percent Change from Baseline hsCRP | Baseline through Day 114 |
|
|
|
| Secondary | 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:
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. | The Per-Protocol (PP) population consisted of all patients who completed their Day 84 visit and had valid hsCRP values for at least 6 of the 7 scheduled collection times. This set was analyzed as treated. | Posted | Mean | Standard Deviation | score on a scale | Baseline through Day 114 |
|
|
|
| Secondary | Number and Percent of Patients Achieving DAS28-CRP <2.6 Over Time | Number and Percent of Patients Achieving DAS28-CRP <2.6 over time | The Per-Protocol (PP) population consisted of all patients who completed their Day 84 visit and had valid hsCRP values for at least 6 of the 7 scheduled collection times. This set was analyzed as treated. | Posted | Count of Participants | Participants | Baseline through Day 114 |
|
|
|
| Secondary | 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
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
| The Per-Protocol (PP) population consisted of all patients who completed their Day 84 visit and had valid hsCRP values for at least 6 of the 7 scheduled collection times. This set was analyzed as treated. | Posted | Mean | Standard Deviation | Change in Osteitis average | Baseline through Day 84 |
|
|
|
| Secondary | 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
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
| The Per-Protocol (PP) population consisted of all patients who completed their Day 84 visit and had valid hsCRP values for at least 6 of the 7 scheduled collection times. This set was analyzed as treated. | Posted | Mean | Standard Deviation | Change in Synovitis average | Baseline through Day 84 |
|
|
|
| Secondary | 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. | The Per-Protocol (PP) population consisted of all patients who completed their Day 84 visit and had valid hsCRP values for at least 6 of the 7 scheduled collection times. This set was analyzed as treated. | Posted | Count of Participants | Participants | Baseline through Day 114 |
|
|
|
| Secondary | 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. | The Per-Protocol (PP) population consisted of all patients who completed their Day 84 visit and had valid hsCRP values for at least 6 of the 7 scheduled collection times. This set was analyzed as treated. | Posted | Count of Participants | Participants | Baseline through Day 114 |
|
|
|
| Secondary | 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. | The Per-Protocol (PP) population consisted of all patients who completed their Day 84 visit and had valid hsCRP values for at least 6 of the 7 scheduled collection times. This set was analyzed as treated. | Posted | Count of Participants | Participants | Baseline through Day 114 |
|
|
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| Secondary | Assessment of ATI-450 Concentration (ng/mL) | The PK population consisted of all patients who received at least 1 dose of study drug and provided at least 1 plasma concentration value. This set was analyzed as treated. | Posted | Mean | Standard Deviation | ATI-450 concentration (ng/mL) | Day 1 through Day Day 84 |
|
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|
| 0 |
| 16 |
| 1 |
| 16 |
| 8 |
| 16 |
| EG001 | Placebo Plus Methotrexate | Placebo oral tablet BID with a stable weekly dose of Methotrexate Placebo oral tablet: Placebo tablet manufactured to match ATI-450 in appearance Methotrexate: 7.5 mg to 25 mg weekly | 0 | 3 | 0 | 3 | 2 | 3 |
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| Ventricular extrasystoles | Cardiac disorders | MedDRA 23.0 | Non-systematic Assessment |
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| Dental caries | Gastrointestinal disorders | MedDRA 23.0 | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 23.0 | Non-systematic Assessment |
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| Mouth ulceration | Gastrointestinal disorders | MedDRA 23.0 | Non-systematic Assessment |
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| Urinary tract infection | Injury, poisoning and procedural complications | MedDRA 23.0 | Non-systematic Assessment |
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| Ear infection | Infections and infestations | MedDRA 23.0 | Non-systematic Assessment |
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| Sinusitis | Infections and infestations | MedDRA 23.0 | Non-systematic Assessment |
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| Ligament sprain | Injury, poisoning and procedural complications | MedDRA 23.0 | Non-systematic Assessment |
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| Muscle strain | Injury, poisoning and procedural complications | MedDRA 23.0 | Non-systematic Assessment |
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| Skin abrasion | Injury, poisoning and procedural complications | MedDRA 23.0 | Non-systematic Assessment |
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| Blood cholesterol increased | Investigations | MedDRA 23.0 | Non-systematic Assessment |
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| Blood creatine phosphokinase increased | Investigations | MedDRA 23.0 | Non-systematic Assessment |
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| Blood pressure increased | Investigations | MedDRA 23.0 | Non-systematic Assessment |
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| Electrocardiogram abnormal | Investigations | MedDRA 23.0 | Non-systematic Assessment |
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| Low density lipoprotein increased | Investigations | MedDRA 23.0 | Non-systematic Assessment |
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| White blood cell count increased | Investigations | MedDRA 23.0 | Non-systematic Assessment |
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| Hypokalemia | Metabolism and nutrition disorders | MedDRA 23.0 | Non-systematic Assessment |
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| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Non-systematic Assessment |
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| Essential hypertension | Vascular disorders | MedDRA 23.0 | Non-systematic Assessment |
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| COVID-19 pneumonia | Infections and infestations | MedDRA 23.0 | Non-systematic Assessment |
|
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| D017437 |
| Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D000072471 |
| Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Day 56 (Predose) |
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