ACTT developed by the NIAID seems to be the outlin

ACTT developed by the NIAID seems to be the outline Brilacidin will be following for Brilacidin for Covid19 Phase2. Until the study guidelines are published on Clinicaltrials.gov it is useful to review the ACTT.

GLTA,Farrell

From todays PR:
" The trial’s primary endpoint is time to sustained recovery through Day 29, using a clinical status ordinal scale based on that used in the series of National Institute of Allergy and Infectious Diseases (NIAID) Adaptive COVID-19 Treatment Trials (ACTTs). Additional endpoints include: in-hospital outcomes (e.g., duration of hospitalization, time to discharge), all-cause mortality, measurement of disease biomarkers (e.g., CRP, ferritin) and inflammation-related biomarkers (e.g., IL-1ß, IL-6, IL-10, total IL-18, TNF-a), changes to SARS-CoV-2 viral load, as well as other key measures.

8 point ordinal scale:

The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Time to improvement by at least one category was determined for each participant


Brilacidin will follow some of the the NIAID Adaptive Treatment Trial guidelines for Covid 19 studies as outlined in the links below:

https://clinicaltrials.gov/ct2/show/NCT04280705 ACTT1}

https://clinicaltrials.gov/ct2/show/NCT04401579 {ACTT2}

https://clinicaltrials.gov/ct2/show/NCT04492475 {ACTT3}

In addition to the study parameters outlined in the PR the following are included in the ACTT 3 and most likely many of these will be incorporated in the Brilacidin for Covid19 protocol when it is released on clinicaltrials.gov:

1 "There will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. Because background standards of supportive care may evolve/improve over time as more is learned about successful management of COVID-19, comparisons of safety and efficacy will be based on data from concurrently randomized subjects. An independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data to make recommendations about early study closure or changes to study arms."

2 "Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. "

3. "All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized). OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and 29 (if the subject attends an in-person visit or are still hospitalized)."

4." The primary outcome is time to recovery by Day 29 for patients with baseline ordinal score 4, 5 and 6. A key secondary outcome evaluates treatment-related improvements in the 8-point ordinal scale at Day 15. Each stage may prioritize different secondary endpoints for the purpose of multiple comparison analyses."

5.Primary Outcome Measures :

" Time to recovery for patients with baseline ordinal score 4, 5, and 6 [ Time Frame: Day 1 through Day 29 ]
Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care."

6. Secondary Outcome Measures :

Change from baseline in alanine aminotransferase (ALT) [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Change from baseline in aspartate aminotransferase (AST) [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Change from baseline in C-reactive protein (CRP) [ Time Frame: Day 1 through Day 29 ]
Change from baseline in creatinine [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Change from baseline in d-dimer concentration [ Time Frame: Day 1 through Day 29 ]
Change from baseline in hemoglobin [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Change from baseline in international normalized ratio (INR) [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Change from baseline in platelets [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Change from baseline in total bilirubin [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Change from baseline in white blood cell count (WBC) with differential [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Change in National Early Warning Score (NEWS) from baseline [ Time Frame: Day 1 through Day 29 ]
The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.

Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events (AEs) [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6). Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening.

Cumulative incidence of serious adverse events (SAEs) [ Time Frame: Day 1 through Day 29 ]
Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6). An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.

Duration of hospitalization [ Time Frame: Day 1 through Day 29 ]
Measured in days.

Duration of invasive mechanical ventilation [ Time Frame: Day 1 through Day 29 ]
Measured in days.

Duration of new non-invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
Measured in days.

Duration of new oxygen use [ Time Frame: Day 1 through Day 29 ]
Measured in days.

Duration of new ventilator or extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
Measured in days.

Duration of non invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
Measured in days.

Duration of oxygen use [ Time Frame: Day 1 through Day 29 ]
Measured in days

Incidence of discontinuation or temporary suspension of study product administration [ Time Frame: Day 1 through Day 10 ]
For any reason. Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

Incidence of new non-invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
Incidence of new oxygen use [ Time Frame: Day 1 through Day 29 ]
Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
Mean change from baseline in the ordinal scale [ Time Frame: Day 1 through Day 29 ]
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Death.

Participant's clinical status at Day 15 by ordinal scale for patients with baseline ordinal score 4 and 5 [ Time Frame: Day 15 ]
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Death.

Percentage of subjects reporting each severity rating on an 8 point ordinal scale [ Time Frame: Days 3, 5, 8, 11, 22, and 29 ]
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Death.

Subject 14-day mortality [ Time Frame: Day 1 through Day 15 ]
Date and cause of death (if applicable).

Subject 28-day mortality [ Time Frame: Day 1 through Day 29 ]
Date and cause of death (if applicable).

Time to an improvement of one category using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Death.

Time to an improvement of two categories using an ordinal scale [ Time Frame: Day 1 through Day 29 ]
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Death.

Time to discharge or to a National Early Warning Score (NEWS) of </= 2 and maintained for 24 hours, whichever occurs first [ Time Frame: Day 1 through Day 29 ]
The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure.

Time to recovery for patients with a baseline ordinal score of 4 and 5 [ Time Frame: Day 1 through Day 29 ]
Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care