Covid19
Conditions
Brief summary
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.
Interventions
DRUGATI-450
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.
DRUGPlacebo
Placebo pill will be taken twice daily preferably spaced 12 hours apart.
Sponsors
University of Kansas Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Respiratory Failure-free Survival in Participants With Moderate-severe COVID-19 Who Are Treated With ATI-450 | Study day 14 | Proportion of responders on Day 14 defined as all subjects who are alive, free of respiratory failure (do not require supplemental oxygen) and do not experience negative intercurrent events by Day 14 of the trial will be considered responders, as assessed by participant medical records. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Need for Advanced Respiratory Care | Baseline and continuous throughout hospitalization up to 14 days | Derived from medical record |
| All-cause Mortality | Baseline and through day 60 | Noted in participant medical record |
| Treatment-emergent Adverse Events | Up to Day 60 | Number of adverse events (AEs), as assessed by CTCAE v5.0. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL (Activities of Daily Living). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. |
| Treatment-emergent Serious Adverse Events | Up to Day 60 | Number of serious adverse events (SAEs), as assessed by CTCAE v5.0. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. |
| Number of Participants With Normalization of Fever for 24 Hours | Baseline through day 14 or at discharge <day 14 | Standard daily temperature measurement and obtained from participant medical record |
| Number of Participants Who Develop New Bacterial Infection | Continuous throughout hospitalization up to 14 days | Noted in participant medical record |
| Change in 7 Point-ordinal Scale | Baseline, Day 7, Day 14, Day 28 and follow-up up to 9 months | Using World Health Organization (WHO) COVID-19 Ordinal scale measuring: Participants were assessed on a 7-point categorical scale, and change in scores between timepoints is reported. 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). |
| Number of Adult Respiratory Distress Syndrome (ARDS2) | From day 1 though day 14 or at discharge <day 14 | Noted in participant medical record |
| Change in Serum Cytokine Interleukin (IL)-6 | Baseline to End of Treatment, or Day 14 | Plasma was assayed by Confluence Discovery Technologies using the MesoScale Discovery Platform from biobanked samples stored from the University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core, expressed in pg/mL. Change in biomarker was reported as a percent based on (EOT or D14)/baseline x100%. |
| Change in Serum Cytokine IL-8 | Baseline to End of Treatment, or Day 14 | Plasma was assayed by Confluence Discovery Technologies using the MesoScale Discovery Platform from biobanked samples stored from the University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core, expressed in pg/mL. Change in biomarker was reported as a percent based on (EOT or D14)/baseline x100%. |
| Change in Serum Cytokines IL-1β | Baseline to End of Treatment, or Day 14 | Plasma was assayed by Confluence Discovery Technologies using the MesoScale Discovery Platform from biobanked samples stored from the University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core, expressed in pg/mL. Change in biomarker was reported as a percent based on (EOT or D14)/baseline x100%. |
| Change in Serum Cytokine Tumor Necrosis Factor (TNF-α) | Baseline to End of Treatment, or Day 14 | Plasma was assayed by Confluence Discovery Technologies using the MesoScale Discovery Platform from biobanked samples stored from the University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core, expressed in pg/mL. Change in biomarker was reported as a percent based on (EOT or D14)/baseline x100%. |
| Number of Participants Who Develop New Fungal Infection | Continuous throughout hospitalization up to 14 days | Noted in participant medical record |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ATI-450 Treated with 50 mg dose of ATI-450, orally, twice daily for 14 days
ATI-450: 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. | 10 |
| Placebo Treated with matched placebo, orally, twice daily for 14 days
Placebo: Placebo pill will be taken twice daily preferably spaced 12 hours apart. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Placebo | Total | ATI-450 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 4 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 16 Participants | 6 Participants |
| Age, Continuous | 63 years | 63 years | 64 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 12 Participants | 6 Participants |
| Region of Enrollment United States | 10 participants | 20 participants | 10 participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 14 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 10 | 1 / 10 |
| other Total, other adverse events | 7 / 10 | 7 / 10 |
| serious Total, serious adverse events | 2 / 10 | 2 / 10 |
Outcome results
Primary
Respiratory Failure-free Survival in Participants With Moderate-severe COVID-19 Who Are Treated With ATI-450
Proportion of responders on Day 14 defined as all subjects who are alive, free of respiratory failure (do not require supplemental oxygen) and do not experience negative intercurrent events by Day 14 of the trial will be considered responders, as assessed by participant medical records.
Time frame: Study day 14
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATI-450 | Respiratory Failure-free Survival in Participants With Moderate-severe COVID-19 Who Are Treated With ATI-450 | 50 percentage of total patients |
| Placebo | Respiratory Failure-free Survival in Participants With Moderate-severe COVID-19 Who Are Treated With ATI-450 | 60 percentage of total patients |
Secondary
All-cause Mortality
Noted in participant medical record
Time frame: Baseline and through day 60
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATI-450 | All-cause Mortality | 1 participants |
| Placebo | All-cause Mortality | 1 participants |
Secondary
Change in 7 Point-ordinal Scale
Using World Health Organization (WHO) COVID-19 Ordinal scale measuring: Participants were assessed on a 7-point categorical scale, and change in scores between timepoints is reported. 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).
Time frame: Baseline, Day 7, Day 14, Day 28 and follow-up up to 9 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ATI-450 | Change in 7 Point-ordinal Scale | Baseline to Day 7 | 0 score on a scale | Standard Deviation 0.4714 |
| ATI-450 | Change in 7 Point-ordinal Scale | baseline to EoT | 0.7 score on a scale | Standard Deviation 1.2517 |
| ATI-450 | Change in 7 Point-ordinal Scale | baseline to Day 14 | 1.7 score on a scale | Standard Deviation 1.567 |
| ATI-450 | Change in 7 Point-ordinal Scale | baseline to Day 28 | 2.7 score on a scale | Standard Deviation 1.1738 |
| Placebo | Change in 7 Point-ordinal Scale | baseline to Day 28 | 2.2 score on a scale | Standard Deviation 0.9189 |
| Placebo | Change in 7 Point-ordinal Scale | Baseline to Day 7 | 0 score on a scale | Standard Deviation 0.4714 |
| Placebo | Change in 7 Point-ordinal Scale | baseline to Day 14 | 1.9 score on a scale | Standard Deviation 1.792 |
| Placebo | Change in 7 Point-ordinal Scale | baseline to EoT | 0.1 score on a scale | Standard Deviation 1.3703 |
Secondary
Change in Serum Cytokine IL-8
Plasma was assayed by Confluence Discovery Technologies using the MesoScale Discovery Platform from biobanked samples stored from the University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core, expressed in pg/mL. Change in biomarker was reported as a percent based on (EOT or D14)/baseline x100%.
Time frame: Baseline to End of Treatment, or Day 14
Population: baseline vs EoT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ATI-450 | Change in Serum Cytokine IL-8 | 40.1 percentage of baseline |
| Placebo | Change in Serum Cytokine IL-8 | 82.3 percentage of baseline |
Secondary
Change in Serum Cytokine Interleukin (IL)-6
Plasma was assayed by Confluence Discovery Technologies using the MesoScale Discovery Platform from biobanked samples stored from the University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core, expressed in pg/mL. Change in biomarker was reported as a percent based on (EOT or D14)/baseline x100%.
Time frame: Baseline to End of Treatment, or Day 14
Population: baseline vs EoT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ATI-450 | Change in Serum Cytokine Interleukin (IL)-6 | 34.8 percentage of baseline |
| Placebo | Change in Serum Cytokine Interleukin (IL)-6 | 137.6 percentage of baseline |
Secondary
Change in Serum Cytokines IL-1β
Plasma was assayed by Confluence Discovery Technologies using the MesoScale Discovery Platform from biobanked samples stored from the University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core, expressed in pg/mL. Change in biomarker was reported as a percent based on (EOT or D14)/baseline x100%.
Time frame: Baseline to End of Treatment, or Day 14
Population: Baseline vs EoT - this could not be measured because analyte could not be detected
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ATI-450 | Change in Serum Cytokines IL-1β | NA percentage of baseline |
| Placebo | Change in Serum Cytokines IL-1β | NA percentage of baseline |
Secondary
Change in Serum Cytokine Tumor Necrosis Factor (TNF-α)
Plasma was assayed by Confluence Discovery Technologies using the MesoScale Discovery Platform from biobanked samples stored from the University of Kansas Medical Center (KUMC) Biobanking and Biomarker Validation (BBV) Core, expressed in pg/mL. Change in biomarker was reported as a percent based on (EOT or D14)/baseline x100%.
Time frame: Baseline to End of Treatment, or Day 14
Population: baseline vs EoT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ATI-450 | Change in Serum Cytokine Tumor Necrosis Factor (TNF-α) | 56.6 percentage of baseline |
| Placebo | Change in Serum Cytokine Tumor Necrosis Factor (TNF-α) | 104.1 percentage of baseline |
Secondary
Number of Adult Respiratory Distress Syndrome (ARDS2)
Noted in participant medical record
Time frame: From day 1 though day 14 or at discharge <day 14
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATI-450 | Number of Adult Respiratory Distress Syndrome (ARDS2) | 1 Participants |
| Placebo | Number of Adult Respiratory Distress Syndrome (ARDS2) | 1 Participants |
Secondary
Number of Participants Who Develop New Bacterial Infection
Noted in participant medical record
Time frame: Continuous throughout hospitalization up to 14 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATI-450 | Number of Participants Who Develop New Bacterial Infection | 0 participants |
| Placebo | Number of Participants Who Develop New Bacterial Infection | 0 participants |
Secondary
Number of Participants Who Develop New Fungal Infection
Noted in participant medical record
Time frame: Continuous throughout hospitalization up to 14 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATI-450 | Number of Participants Who Develop New Fungal Infection | 1 participants |
| Placebo | Number of Participants Who Develop New Fungal Infection | 0 participants |
Secondary
Number of Participants With a Need for Advanced Respiratory Care
Derived from medical record
Time frame: Baseline and continuous throughout hospitalization up to 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ATI-450 | Number of Participants With a Need for Advanced Respiratory Care | 2 Participants |
| Placebo | Number of Participants With a Need for Advanced Respiratory Care | 1 Participants |
Secondary
Number of Participants With Normalization of Fever for 24 Hours
Standard daily temperature measurement and obtained from participant medical record
Time frame: Baseline through day 14 or at discharge <day 14
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATI-450 | Number of Participants With Normalization of Fever for 24 Hours | 9 participants |
| Placebo | Number of Participants With Normalization of Fever for 24 Hours | 9 participants |
Secondary
Treatment-emergent Adverse Events
Number of adverse events (AEs), as assessed by CTCAE v5.0. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL (Activities of Daily Living). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time frame: Up to Day 60
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATI-450 | Treatment-emergent Adverse Events | Grade 5 | 0 adverse events |
| ATI-450 | Treatment-emergent Adverse Events | Grade 1-2 | 12 adverse events |
| ATI-450 | Treatment-emergent Adverse Events | Grade 3 | 2 adverse events |
| ATI-450 | Treatment-emergent Adverse Events | Grade 4 | 0 adverse events |
| ATI-450 | Treatment-emergent Adverse Events | Any Grade | 14 adverse events |
| Placebo | Treatment-emergent Adverse Events | Grade 4 | 0 adverse events |
| Placebo | Treatment-emergent Adverse Events | Any Grade | 6 adverse events |
| Placebo | Treatment-emergent Adverse Events | Grade 3 | 0 adverse events |
| Placebo | Treatment-emergent Adverse Events | Grade 1-2 | 6 adverse events |
| Placebo | Treatment-emergent Adverse Events | Grade 5 | 0 adverse events |
Secondary
Treatment-emergent Serious Adverse Events
Number of serious adverse events (SAEs), as assessed by CTCAE v5.0. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time frame: Up to Day 60
Population: Report of any treatment-emergent Serious adverse events (TeSAE)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATI-450 | Treatment-emergent Serious Adverse Events | Grade 1 or 2 | 0 serious adverse events |
| ATI-450 | Treatment-emergent Serious Adverse Events | Grade 4 | 0 serious adverse events |
| ATI-450 | Treatment-emergent Serious Adverse Events | Grade 3 | 1 serious adverse events |
| ATI-450 | Treatment-emergent Serious Adverse Events | Grade 5 | 1 serious adverse events |
| ATI-450 | Treatment-emergent Serious Adverse Events | Any Grade | 2 serious adverse events |
| Placebo | Treatment-emergent Serious Adverse Events | Grade 5 | 1 serious adverse events |
| Placebo | Treatment-emergent Serious Adverse Events | Any Grade | 2 serious adverse events |
| Placebo | Treatment-emergent Serious Adverse Events | Grade 1 or 2 | 1 serious adverse events |
| Placebo | Treatment-emergent Serious Adverse Events | Grade 3 | 0 serious adverse events |
| Placebo | Treatment-emergent Serious Adverse Events | Grade 4 | 0 serious adverse events |