A Trial of Aclaris Therapeutics, Inc. (ATI)-450 in Patients With Moderate-severe Novel Coronavirus Disease 2019 (COVID-19)

Study Overview
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Brief Summary
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COVID-19 morbidity and mortality has been associated with Cytokine Release Syndrome (CRS) and Acute Respiratory Distress Syndrome (ARDS). ATI-450 is an oral small molecule MAPKAPK2 (MK2) inhibitor that potently inhibits multiple inflammatory cytokines. The investigator hypothesizes that MK2 pathway blockade during active COVID-19 infection in hospitalized participants will result in improvement in respiratory-failure free survival.

Official Title
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A Double-blind, Randomized, Controlled Trial of ATI-450 in Patients With Moderate-severe COVID-19

Conditions
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Covid19

Intervention / Treatment
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* Drug: ATI-450
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to comprehend and be willing to sign the Institutional Review Board (IRB)-approved subject informed consent form (ICF) prior to administration of any study-related procedures, or consent from surrogate decision maker when the above criteria cannot be met Male or non-pregnant female adult ≥18 years of age at time of enrollment; female patients must have a negative serum pregnancy test at study enrollment Has laboratory-confirmed COVID-19 coronavirus infection as determined by polymerase chain reaction (PCR), or other commercial or public health assay in oropharyngeal or nasopharyngeal testing within 14 days of hospitalization. An additional 24-hour COVID-19 PCR test will be performed at KUMC. Patients outside of KUMC will have their samples sent to KUMC as a Central Lab for test processing Hospitalized as a result of symptoms and signs related to COVID-19 infection, and ≤14 days since positive test Evidence of hypoxic respiratory failure: SpO2≤93% on room air, or SpO2 >93% requiring ≥ 2 Liters (L) O2, or Pa02/Fi02 ratio <300 Millimeter of Mercury (mmHg), or tachypnea (respiratory rate > 30 breaths/min) Evidence of pulmonary involvement by: chest imaging or pulmonary exam Previous use of hydroxychloroquine or chloroquine is allowed in this study Adequate organ function per laboratory tests Females of child-bearing potential and males with partners of child-bearing potential must agree to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section for the duration of study participation and for 30 Days for females and 90 days for males following completion of therapy Exclusion Criteria: Known hypersensitivity to ATI-450 History or evidence of active or latent tuberculosis or recent exposure (within last 30d) to a person with active Tb Evidence of active, untreated bacterial infection. Patients who are treated with antibiotics for at least 72 hours, will become eligible for rescreening for trial enrollment Active use of immunosuppressant medication(s) (i.e. anti-rejection ,immunomodulators or immunosuppressant drugs, including but not limited to IL-6 inhibitors, TNF inhibitors, anti-IL-1 agents and Janus kinase (JAK) inhibitors within 5 half-lives or 30 days (whichever is longer) prior to randomization. (Use of hydroxychloroquine/chloroquine should be discontinued) Oncology patients who are on active chemotherapy or immunotherapy. However, oncology patients who come off active therapy prior to enrollment and have absolute neutrophil count (ANC) ≥1500/mmc are eligible for enrollment Active participation in a concurrent COVID-19 clinical trial with investigative medical drug therapies. However, co-enrollment for non-investigative drug therapies will be allowed; use or re-purposing of FDA approved treatments will be considered at the discretion of the medical monitor In the opinion of the investigator, unlikely to survive for at least 48 hours from screening or anticipate mechanical ventilation within 48 hours Pregnancy or breast feeding Prisoner Intubation and ventilation at time of enrollment Known history for HIV, hepatitis B or C infection. Patients with serologic evidence of hepatitis B vaccination (hepatitis B surface antibody without the presence of hepatitis B surface antigen) will be allowed to participate History of a past or current medical condition that in the opinion of the treating physician would compromise patient safety (e.g. uncontrolled HIV) by participation in the study

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ATI-450<br>Treated with 50 mg dose of ATI-450, orally, twice daily for 14 days | Drug: ATI-450<br>* 50 mg (as determined from Phase I study) per dose. (100 mg per day). Up to a maximum of 14 days while inpatient. Patients discharged home or transferred to the intensive care unit (ICU) will be discontinued off drug permanently.<br>|
| Placebo Comparator: Placebo<br>Treated with matched placebo, orally, twice daily for 14 days | Drug: Placebo<br>* Placebo pill will be taken twice daily preferably spaced 12 hours apart.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory failure-free survival in participants with moderate-severe COVID-19 who are treated with ATI-450 | Participants medical record | Study day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 7 point-ordinal scale | Using World Health Organization (WHO) COVID-19 Ordinal scale measuring: Proportion and time to participants with greater than 2 point improvement on the 7 point categorical scale. This scale measures illness severity over time and has a range of 0-7. 0- Uninfected: No clinical or virological evidence of infection. 1- Ambulatory: No limitation of activities. 2- Ambulatory: Limitation of activities. 3- Hospitalized, mild disease: Hospitalized, no oxygen. 4- Hospitalized, mild disease: Oxygen by mask or nasal prongs. 5- Hospitalized, severe disease: Non- invasive ventilation or high- flow oxygen. 6- Hospitalized, severe disease: Intubation and mechanical ventilation. 7- Hospitalized, severe disease: Ventilation + organ support; pressors, Renal Replacement Therapy (RRT), Extracorporeal Membrane Oxygenation (ECMO). | Baseline, Day 7, Day 14, Day 28 and follow-up up to 9 months | 
| Change in oxygen saturation-normalization | Peripheral capillary pulse oximeter to measure: Oxygen Saturation (SpO2)/Fraction of Inspired Oxygen (FiO2) ratio over time, sustainment of normalization in 24 hours, and relative shifts in SpO2/FiO2 categories (<235, between 235 and 315, greater than 315) over time | Baseline and continuous throughout hospitalization up to 14 days | 
| Need for advanced respiratory care | Derived from medical record | Baseline and continuous throughout hospitalization up to 14 days | 
| All-cause mortality | Noted in participant medical record | Baseline and through day 60 | 
| Percentage of adverse events (AEs) | CTCAE v5.0 | Baseline through day 14 or at discharge <day 14, at day 28, day 45 and day 60 | 
| Percentage of serious adverse events (SAEs) | CTCAE v5.0 | Baseline through day 14 or at discharge <day 14, at day 28, day 45 and day 60 | 
| Proportion of participants with normalization of fever for 24 hours | Standard daily temperature measurement and obtained from participant medical record | Baseline through day 14 or at discharge <day 14 | 
| Number of participants who develop new bacterial infection | Noted in participant medical record | Continuous throughout hospitalization up to 14 days | 
| Number of participants who develop new fungal infection | Noted in participant medical record | Continuous throughout hospitalization up to 14 days | 
| Incidence of Adult Respiratory distress Syndrome (ARDS2) | Noted in participant medical record | From day 1 though day 14 or at discharge <day 14 | 
| Change in serum cytokine Interleukin (IL)-6 | Serum collected from blood and assayed on Luminex panel performed by University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core | Baseline, day 3, day 7 (or discharge <day 7), day 14 (or discharge >day 7 and <day 14) | 
| Change in serum cytokine IL-8 | Serum collected from blood and assayed on Luminex panel performed by KUMC BBV Core | Baseline, day 3, day 7 (or discharge <day 7), day 14 (or discharge >day 7 and <day 14) | 
| Change in serum cytokines IL-1β | Serum collected from blood and assayed on Luminex panel performed by KUMC BBV Core | Baseline, day 3, day 7 (or discharge <day 7), day 14 (or discharge >day 7 and <day 14) | 
| Change in serum cytokine Tumor Necrosis Factor (TNF-α) | Serum collected from blood and assayed on Luminex panel performed by KUMC BBV Core | Baseline, day 3, day 7 (or discharge <day 7), day 14 (or discharge >day 7 and <day 14) |