Treatment of ARDS With Instilled T3

Study Overview
=================
Brief Summary
-----------------
It is hypothesized that instillation of Liothyronine Sodium (T3) into the airspace will be safe, well tolerated, and will increase alveolar fluid clearance and decrease inflammation in patients with ARDS, reflected in improved oxygenation index (OI) and oxygenation saturation index (OSI).

Detailed Description
-----------------
T3 Therapy in ARDS- Phase 2 Randomized, Unblinded, Intervention versus Non- Intervention Trial. Enrollment 68 participants (50 treatment + 18 control). Purpose- To determine the safety and tolerability of T3 delivery into the lungs of ARDS patients, and to measure the effect of T3 on Oxygenation in ARDS patients. Study Drug- Liothyronine Sodium (T3), 50 mcg will be instilled twice daily via a catheter through the ETT into the airway in a total volume of 10 mL (T3+0.9% sodium chloride), over 5 days (10 total doses), or until extubation, whichever comes first.

Official Title
-----------------
PHASE II RANDOMIZED, INTERVENTION VERSUS NON- INTERVENTION, MULTI- CENTER STUDY OF THE EFFECTS OF THYROID HORMONE (T3) ON SAFETY/TOLERABILITY AND OXYGENATION IN SUBJECTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)

Conditions
-----------------
ARDS, Human, Lung, Wet, Thyroid, Pulmonary Edema, Lung Inflammation

Intervention / Treatment
-----------------
* Drug: Liothyronine Sodium (T3+0.9% sodium chloride) modified formulation specifically for airway instillation.
* Other: Non-intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Study population is critically ill patients requiring mechanical ventilatory support for ARDS in an intensive care unit. Adults (≥18 years of age). Male or female (non-pregnant). Clinical diagnosis of ARDS (all are required): Onset: <= 7 days. Chest x-ray: Bilateral Patchy Opacities, Infiltrates. Mechanical Vent Support: PEEP or CPAP Support >= 5 cm H2O. Pulmonary Edema: Not fully explained by cardiogenic etiology. Hypoxia: PaO2/FIO2 Ratio <300, or O2Sat/FIO2 Ratio <315. On mechanical ventilatory support. Capable of giving informed consent directly or from the subject's legally authorized representative (LAR) as determined by the site Principal Investigator and/or Sub- Investigators. Exclusion Criteria: Patients with any of the following conditions will be excluded from this trial: Inadequate medical history for determining inclusion/exclusion criteria, as determined by the Principal Investigator and/or Sub- Investigators. Unlikely to complete the protocol with clinic follow-up after discharge, as determined by the Principal Investigator and/or Sub- Investigators or hospice status. Prior history of thyroid cancer or hyperthyroidism, per thorough patient/family interviews, review of past medical history, medication list, laboratory test. Prior history of cardiovascular disease defined as: Hypertensive crisis in the past 3 months (systolic >200, or diastolic >120 mmHg), Sustained ventricular arrhythmia in the past 3 months (duration >30 seconds) Coronary artery disease (documented >=70% occlusion untreated in any coronary vessel), as per the 2021 ACC/AHA/SCAI Guidelines for Coronary Artery Revascularization. Cardiac-related angina pectoris (>=2 episodes in the past 3 months) Myocardial infarction with ischemia on ECG (i.e.,new ST- elevation/depression of >1mm in contiguous leads). Peripheral vascular disease (documented >=70% occlusion untreated in any peripheral vessel), as per the 2018 ACC/AHA/SCAI/SIR/SVM Guidelines for Appropriate Use Criteria for Peripheral Artery Intervention. Decompensated or symptomatic heart failure (i.e., hospitalized for CHF exacerbation, or a change in CHF medications within two weeks prior) Currently pregnant or breastfeeding. Known allergy to study drug.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, unblinded, intervention versus non-intervention trial. 68 [50 treatment + 18 controls]
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>Liothyronine Sodium (T3+0.9% sodium chloride) modified formulation specifically for airway instillation. | Drug: Liothyronine Sodium (T3+0.9% sodium chloride) modified formulation specifically for airway instillation.<br>* Study Drug Administration: Dose/Volume- Liothyronine Sodium 50 mcg / 10 mL Frequency/Duration: Twice daily over 5 days (10 total doses), or until extubation, whichever comes first. Method: Instilled via a catheter through the ETT directly into the airway.<br>|
| Other: Control arm<br>Standard of Care | Other: Non-intervention<br>* Standard of Care (SOC)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygenation: Oxygenation Index (OI), and/or Oxygenation Saturation Index (OSI). | To assess the efficacy of airway instilled T3 improving oxygenation by reducing OI and OSI in ARDS patients. OI will be measured by mechanical ventilator (FIO2 and Mean Airway Pressure, MAP), and ABG (PaO2). OSI will be measured by mechanical ventilator (FIO2, SpO2 and MAP): OI = (FIO2 x MAP / PaO2). OSI = (FIO2 x MAP / SpO2). | baseline | 
| Oxygenation: Oxygenation Index (OI), and/or Oxygenation Saturation Index (OSI). | To assess the efficacy of airway instilled T3 improving oxygenation by reducing OI and OSI in ARDS patients. OI will be measured by mechanical ventilator (FIO2 and Mean Airway Pressure, MAP), and ABG (PaO2). OSI will be measured by mechanical ventilator (FIO2, SpO2 and MAP): OI = (FIO2 x MAP / PaO2). OSI = (FIO2 x MAP / SpO2). | 6 hours post-dose | 
| Oxygenation: Oxygenation Index (OI), and/or Oxygenation Saturation Index (OSI). | To assess the efficacy of airway instilled T3 improving oxygenation by reducing OI and OSI in ARDS patients. OI will be measured by mechanical ventilator (FIO2 and Mean Airway Pressure, MAP), and ABG (PaO2). OSI will be measured by mechanical ventilator (FIO2, SpO2 and MAP): OI = (FIO2 x MAP / PaO2). OSI = (FIO2 x MAP / SpO2). | 12 hours post-dose | 
| Oxygenation: Oxygenation Index (OI), and/or Oxygenation Saturation Index (OSI). | To assess the efficacy of airway instilled T3 improving oxygenation by reducing OI and OSI in ARDS patients. OI will be measured by mechanical ventilator (FIO2 and Mean Airway Pressure, MAP), and ABG (PaO2). OSI will be measured by mechanical ventilator (FIO2, SpO2 and MAP): OI = (FIO2 x MAP / PaO2). OSI = (FIO2 x MAP / SpO2). | 24 hours post-dose | 
| Oxygenation: Oxygenation Index (OI), and/or Oxygenation Saturation Index (OSI). | To assess the efficacy of airway instilled T3 improving oxygenation by reducing OI and OSI in ARDS patients. OI will be measured by mechanical ventilator (FIO2 and Mean Airway Pressure, MAP), and ABG (PaO2). OSI will be measured by mechanical ventilator (FIO2, SpO2 and MAP): OI = (FIO2 x MAP / PaO2). OSI = (FIO2 x MAP / SpO2). | 48 hours post-dose | 
| Oxygenation: Oxygenation Index (OI), and/or Oxygenation Saturation Index (OSI). | To assess the efficacy of airway instilled T3 improving oxygenation by reducing OI and OSI in ARDS patients. OI will be measured by mechanical ventilator (FIO2 and Mean Airway Pressure, MAP), and ABG (PaO2). OSI will be measured by mechanical ventilator (FIO2, SpO2 and MAP): OI = (FIO2 x MAP / PaO2). OSI = (FIO2 x MAP / SpO2). | 72 hours post-dose | 
| Oxygenation: Oxygenation Index (OI), and/or Oxygenation Saturation Index (OSI). | To assess the efficacy of airway instilled T3 improving oxygenation by reducing OI and OSI in ARDS patients. OI will be measured by mechanical ventilator (FIO2 and Mean Airway Pressure, MAP), and ABG (PaO2). OSI will be measured by mechanical ventilator (FIO2, SpO2 and MAP): OI = (FIO2 x MAP / PaO2). OSI = (FIO2 x MAP / SpO2). | 96 hours post-dose | 
| Oxygenation: Oxygenation Index (OI), and/or Oxygenation Saturation Index (OSI). | To assess the efficacy of airway instilled T3 improving oxygenation by reducing OI and OSI in ARDS patients. OI will be measured by mechanical ventilator (FIO2 and Mean Airway Pressure, MAP), and ABG (PaO2). OSI will be measured by mechanical ventilator (FIO2, SpO2 and MAP): OI = (FIO2 x MAP / PaO2). OSI = (FIO2 x MAP / SpO2). | 120 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary events | Progressive hemoptysis: bright, red blood in streaks, mixed or clots within sputum on suctioning of greater than 30 mL accumulation anytime following the initial and subsequent intratracheal dosing administrations. | baseline and 120 hours post-dose | 
| Cardiovascular event 1 | New sustained ventricular arrhythmia (>30 secs) | baseline to 120hours post-dose | 
| Cardiovascular event 2 | New sustained accelerated junctional arrhythmia (rate >80 bpm) with worsened hypotension (decrease in mean arterial pressure to less than 65mmHg). | baseline to 120hours post-dose | 
| Cardiovascular event 3 | New sustained atrial fibrillation with rapid ventricular response (ventricular rate >160 bpm) with worsened hypotension (decrease in mean arterial pressure to less than 65mmHg). | baseline to 120hours post-dose | 
| Cardiovascular event 4 | Cardiac arrest (pulseless electrical activity, or asystole). | baseline to 120hours post-dose | 
| Cardiovascular event 5 | Hypertensive crisis (systolic pressure of 180 mmHg (or higher), or diastolic pressure of 120 mmHg (or higher) or change in MAP > 20 mmHg with three consecutive measurements over 30 minutes). | baseline to 120hours post-dose | 
| SOC pulmonary vasodilator | yes or no | baseline and 5 days | 
| SOC pressor(s) dose(s) |  | baseline and 5 days | 
| SOC diurectic(s) dose(s) |  | baseline and 5 days | 
| Ventilator Free Days |  | baseline and 5 days | 
| ICU Free Days |  | baseline and 5 days | 
| Oxygen Free Days |  | baseline and 5 days | 
| All-Cause Mortality |  | baseline and 5 days | 
| Tracheostomy placement requirement |  | baseline and 5 days | 
| Supplemental oxygen on discharge | yes or no | baseline and 5 days | 
| Discharge disposition | home, inpatient rehabilitation, long-term acute care hospital (LTACH) | baseline and 5 days | 
| TSH, Total T3, Free T3, Free T4 |  | baseline and 156-hrs post-dose | 
| Free T3, Free T4 |  | baseline and 5 days |