Study of ATI-450 in Patients With Cryopyrin-Associated Periodic Syndrome (CAPS)

• ClinicalTrials.gov Identifier: NCT04524858
• Recruitment Status: Terminated
• First Posted: August 24, 2020
• Last Update Posted: April 1, 2021
• Sponsor: Aclaris Therapeutics, Inc.
• Information provided by (Responsible Party): Aclaris Therapeutics, Inc.

Tracking Information

• First Submitted Date: August 19, 2020
• First Posted Date: August 24, 2020
• Last Update Posted Date: April 1, 2021
• Actual Study Start Date: October 23, 2020
• Actual Primary Completion Date: February 25, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 21, 2020)

Assess the safety and tolerability of ATI-450 to maintain remission in patients with CAPS previously managed with anti-IL-1 therapy: Adverse Events (AEs) [ Time Frame: Baseline to week 12 ]

Adverse Events (AEs) will be coded with the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be presented by system organ class and preferred term in frequency tables.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 25, 2020)

• Total Number of participants who maintain disease remission (hsCRP) [ Time Frame: Baseline to week 12 ]
  Remission is defined as a high sensitivity C-reactive protein (hsCRP) within normal range (≤10 mg/L).
• Total Number of participants who maintain disease remission (SAA) [ Time Frame: Baseline to week 12 ]
  Remission is defined as a serum amyloid A (SAA) value within the normal range (≤10 mg/L).
• Total number of participants who maintain disease remission (PGA) [ Time Frame: Baseline to week 12 ]
  Remission is defined as a Physician Global Assessment (PGA) score of absent or minimal. The Physician's Global Assessment of Autoinflammatory Disease Activity (PGA) is a measure to be completed by the investigator or designee. The PGA uses a 5-point rating scale: absent, minimal, mild, moderate, and severe. The investigator will select a rating based on the patient's current disease activity at the time of the visit. Lower PGA scores represent better outcomes.
• Time to relapse [ Time Frame: Baseline to week 12 ]
  Relapse is defined as a two-point worsening on the PGA scale. The Physician's Global Assessment of Autoinflammatory Disease Activity (PGA) is a measure to be completed by the investigator or designee. The PGA uses a 5-point rating scale: absent, minimal, mild, moderate, and severe. The investigator will select a rating based on the patient's current disease activity at the time of the visit. Lower PGA scores represent better outcomes.
• Total number of participants who experience re-emergence of disease symptoms after discontinuation of ATI-450 [ Time Frame: Follow-up day 1 to follow-up day 7 ]
  Re-emergence is defined as a daily Key Symptom Score (KSS) ≥ 3 points higher than baseline for at least 2 consecutive days. The KSS is derived from the patient-administered DHAF, and is the average on a 0 to 10 scale (0 = None, 10 = Very Severe) of 5 separate scales - rash, feeling of fever and chills, joint pain, eye redness and pain, and fatigue. Lower KSS scores represent better outcomes.
• Total number of participants with a mean KSS no more than 2 points higher than baseline for at least 6 out of 8 weeks during the treatment period [ Time Frame: Baseline to week 12 ]
  Key Symptom Score (KSS). The KSS is derived from the patient-administered DHAF, and is the average on a 0 to 10 scale (0 = None, 10 = Very Severe) of 5 separate scales - rash, feeling of fever and chills, joint pain, eye redness and pain, and fatigue. Lower KSS scores represent better outcomes.
• Change from baseline in PGA [ Time Frame: Baseline to week 12 ]
  Physician Global Assessment (PGA). The Physician's Global Assessment of Autoinflammatory Disease Activity (PGA) is a measure to be completed by the investigator or designee. The PGA uses a 5-point rating scale: absent, minimal, mild, moderate, and severe. The investigator will select a rating based on the patient's current disease activity at the time of the visit. Lower PGA scores represent better outcomes.
• Change from baseline in KSS [ Time Frame: Baseline to week 12 ]
  Key Symptom Score (KSS). The KSS is derived from the patient-administered DHAF, and is the average on a 0 to 10 scale (0 = None, 10 = Very Severe) of 5 separate scales - rash, feeling of fever and chills, joint pain, eye redness and pain, and fatigue. Lower KSS scores represent better outcomes.
• Change from baseline in CRP [ Time Frame: Baseline to week 12 ]
  C-reactive protein (CRP). CRP values ≤10 mg/L are considered normal range.
• Change from baseline in SAA [ Time Frame: Baseline to week 12 ]
  serum amyloid A (SAA). SAA values ≤10 mg/L are considered normal range.

Original Secondary Outcome Measures (submitted: August 21, 2020)

• Total Number of participants who maintain disease remission (hsCRP) [ Time Frame: Baseline to week 12 ]
  Remission is defined as a high sensitivity C-reactive protein (hsCRP) within normal range (≤10 mg/L).
• Total Number of participants who maintain disease remission (SAA) [ Time Frame: Baseline to week 12 ]
  Remission is defined as a serum amyloid A (SAA) value within the normal range (≤10 mg/L).
• Total number of participants who maintain disease remission (PGA) [ Time Frame: Baseline to week 12 ]
  Remission is defined as a Physician Global Assessment (PGA) score of absent or minimal. Lower PGA scores represent better outcomes.
• Time to relapse [ Time Frame: Baseline to week 12 ]
  Relapse is defined as a two-point worsening on the PGA scale. Lower PGA scores represent better outcomes.
• Total number of participants who experience re-emergence of disease symptoms after discontinuation of ATI-450 [ Time Frame: Follow-up day 1 to follow-up day 7 ]
  Re-emergence is defined as a daily Key Symptom Score (KSS) ≥ 3 points higher than baseline for at least 2 consecutive days. KSS is derived from the patient-administered daily health assessment form (DHAF). Lower KSS scores represent better outcomes.
• Total number of participants with a mean KSS no more than 2 points higher than baseline for at least 6 out of 8 weeks during the treatment period [ Time Frame: Baseline to week 12 ]
  Key Symptom Score (KSS). Lower KSS scores represent better outcomes.
• Change from baseline in PGA [ Time Frame: Baseline to week 12 ]
  Physician Global Assessment (PGA). Lower PGA scores represent better outcomes.
• Change from baseline in KSS [ Time Frame: Baseline to week 12 ]
  Key Symptom Score (KSS). Lower KSS scores represent better outcomes.
• Change from baseline in CRP [ Time Frame: Baseline to week 12 ]
  C-reactive protein (CRP). CRP values ≤10 mg/L are considered normal range.
• Change from baseline in SAA [ Time Frame: Baseline to week 12 ]
  serum amyloid A (SAA). SAA values ≤10 mg/L are considered normal range.

Current Other Pre-specified Outcome Measures (submitted: August 21, 2020)

• Change from baseline in serum cytokines IL-1β [ Time Frame: Baseline to week 12 ]
  Exploratory endpoint to assess the change from baseline in serum cytokines IL-1β ATI-450 in patients with CAPS.
• Change from baseline in serum cytokines IL-1α [ Time Frame: Baseline to week 12 ]
  Exploratory endpoint to assess the change from baseline in serum cytokines IL-1α of ATI-450 in patients with CAPS.
• Change from baseline in serum cytokines IL-6 [ Time Frame: Baseline to week 12 ]
  Exploratory endpoint to assess the change from baseline in serum cytokines IL-6 of ATI-450 in patients with CAPS.
• Change from baseline in serum cytokines IL-18 [ Time Frame: Baseline to week 12 ]
  Exploratory endpoint to assess the change from baseline in serum cytokines IL-18 of ATI-450 in patients with CAPS.
• Change from baseline in serum cytokines TNF-α [ Time Frame: Baseline to week 12 ]
  Exploratory endpoint to assess the change from baseline in serum cytokines TNF-α of ATI-450 in patients with CAPS.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Study of ATI-450 in Patients With Cryopyrin-Associated Periodic Syndrome (CAPS)
• Official Title: A Phase 2a, Open-Label, Single-Arm Study to Investigate the Safety and Efficacy of ATI-450 for the Maintenance of Remission in Patients With Cryopyrin-Associated Periodic Syndrome (CAPS) Previously Managed With Anti-IL-1 Therapy
• Brief Summary: This is a Phase 2 study to investigate the safety and efficacy of ATI-450 for the Maintenance of Remission in Patients with Cryopyrin-Associated Periodic Syndrome (CAPS) Previously Managed with Anti-IL-1 Therapy.
• Detailed Description: This is a Phase 2a, Open-Label, Single-Arm Study to Investigate the Safety and Efficacy of ATI-450 for the Maintenance of Remission in Patients with Cryopyrin-Associated Periodic Syndrome (CAPS) Previously Managed with Anti-IL-1 Therapy. The study will consist of up to an 8-week screening period, a 12-week treatment period, and a 4-week safety follow-up period. The total duration of the study for patients remaining until their final follow-up assessment will be up to 24 weeks.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Open-label, single-arm study

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Cryopyrin-Associated Periodic Syndrome

Intervention

Drug: ATI-450

Oral, small molecule MK2 inhibitor

Study Arms

Experimental: ATI-450

Oral, small molecule MK2 inhibitor will be administered twice daily (BID) at a dose of 50 mg

Intervention: Drug: ATI-450

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: March 26, 2021): 1
• Original Estimated Enrollment (submitted: August 21, 2020): 10
• Actual Study Completion Date: February 25, 2021
• Actual Primary Completion Date: February 25, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease. Prior agreement between the Investigator and Aclaris for study eligibility is required for patients who do not have a molecular diagnosis of NALP3 mutations available (either testing not performed, or testing performed, but negative) upon study entry. For those patients who have not been molecularly tested for NALP3 mutations, molecular testing should be performed during the study.
• Patients with a PGA score of "minimal" or less and hsCRP and SAA values within the normal range (≤10mg/L), and who are considered to have achieved that response as a result of successful anti-IL-1 therapy.
• Continuous Treatment with anti-IL1 therapy for at least 6 months.
• Able to understand and comply with study procedures and able to provide informed consent.

• Male or non-pregnant, non-nursing female patients at least 18 years of age, inclusive.

  • Female patients who are of childbearing potential must use 2 methods of highly effective contraception* - one of which must be a physical barrier- for the duration of the study and for 30 days after the last dose.
  • Male patients of childbearing potential with a female partner of childbearing potential must agree to use a condom plus another highly effective form of birth control for the duration of the study and for 90 days after the last dose.
• Female patients must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to dosing on Day 1.
• Willing and capable of taking appropriate Covid-19 risk mitigation precautions (e.g. wearing a mask in public, adhering to social distancing, etc.) as required by local, state, or federal guidelines during participation in the study.

Exclusion Criteria:

• Participation in any clinical study with an investigative agent within 12 weeks prior to entry or within 5 half-lives of the investigational agent.
• Being treated with another immuno-suppressive agent (i.e., in addition to an anti-IL-1 product) for CAPS syndrome (anti- IL-1 therapy will have been used for at least 6 months and will be stopped at study entry).

• Use of any of the following treatments within the indicated washout period prior to the baseline visit:

  • Systemic immunosuppressant or immunomodulatory therapy (e.g., etanercept, alefacept, infliximab, methotrexate) within 16 weeks prior to Visit 2 (excluding anti- IL-1 therapy for CAPS).
  • Janus Kinase (JAK) inhibitors (systemic or topical) within 4 weeks prior to Visit 2.
  • Systemic corticosteroids within 4 weeks prior to Visit 2 (Intranasal, inhaled, and topical ocular corticosteroids are allowed).
• History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot) test result. [Previous treatment with anti-IL1 therapy is not an exclusion]
• A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody test result.
• Live vaccinations within 3 months prior to the start of the trial, or during the trial.
• History of recurrent and/or evidence of active bacterial, fungal, or viral infections.
• History or evidence of active or latent tuberculosis (TB).

• Tests performed at a central laboratory at screening that meet any of the criteria below (out of range labs may be rechecked one time, after consultation with sponsor or designee, before patient is considered a screen failure):

  • White blood cell (WBC) count <3.0×103 cells/mm3
  • Absolute neutrophil count (ANC) <1.5×103 cells/mm3
  • Lymphocyte count <0.5×103 cells/mm3
  • Platelet count <100×103 cells/mm3
  • Hemoglobin <10 g/dL
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2×upper limit of normal (ULN)
  • Total bilirubin level >2×ULN, unless patient has been diagnosed with Gilberts' disease and this is clearly documented
  • Estimated glomerular filtration rate Estimated glomerular filtration rate (eGFR), <40 mL/min/1.73m2 based on Modification of Diet and Renal Disease formula
• Any clinically significant laboratory abnormality that would affect interpretation of study data or safety of the patient's participation in the study, per the judgment of the investigator.
• Patient has clinically significant abnormal findings other than CAPS from physical examination that may affect the interpretation of study data or the safety of the patient's participation in the study, per the judgment of the investigator.
• Patient has a clinically important history of a medical disorder that would compromise patient safety or data quality, per the judgement of the investigator.
• Blood pressure (BP) levels (in supine position after at least 5 minutes rest): <90 mmHg or >140 mmHg for systolic BP or <40 mmHg or >90 mmHg for diastolic blood pressure.
• Patients with history of stroke.
• Significant cardiac disease that would affect interpretation of study data or the safety of the patient's participation in the study, per the judgment of the investigator, including recent myocardial infarction or unstable angina, or heart failure with New York Heart Association Class III or IV symptoms.

• Patients with the following screening or pre-dose ECG findings, specifically:

  • Evidence of atrial fibrillation, atrial flutter, complete right or left bundle branch block, Wolff-Parkinson-White Syndrome, or other significant rhythm disturbance
  • Evidence of acute ischemia
  • Screening or pre-dose baseline mean QTcF >450 msec for males or >470 msec for females (use of the ECG algorithm is acceptable for this purpose)
  • Personal or family history of congenital long QT syndrome or sudden death
  • Any other finding that is considered clinically significant
• A confirmed diagnosis of Covid-19 at baseline or at any time during the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04524858
• Other Study ID Numbers: ATI-450-CAPS-201
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Aclaris Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Aclaris Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: David Gordon; Aclaris Therapeutics

• PRS Account: Aclaris Therapeutics, Inc.
• Verification Date: March 2021