Precision Medicine Adaptive Network Platform Trial in Hypoxemic Acute Respiratory Failure (US-PANTHER)

The goal of this trial is to accelerate the development of pharmacological therapies for critical illness by identifying biological sub phenotypes in patients with acute respiratory distress syndrome (ARDS). The trial will stratify participants by biological markers into different sub phenotypes, then randomized 1:1:1 to active treatment 1, active treatment 2, or usual care. Initial stratification will be into hyperinflammatory and hypoinflammatory sub phenotypes in ARDS based on plasma biomarker profiles. Regular adaptive analyses will enable efficient identification of treatment effects within each sub phenotype, stopping interventions where there is evidence of efficacy or futility, and bringing in new interventions and potentially new sub phenotypes.

Study Overview

• Status: Not yet recruiting
• Conditions: ARDS (Acute Respiratory Distress Syndrome); Acute Hypoxic Respiratory Failure
• Intervention / Treatment: Drug: Simvastatin; Drug: Baricitinib

Detailed Description

The primary objective of this trial is to accelerate the development of pharmacological therapies for critical illness by establishing an adaptive platform trial to test the efficacy of prioritized pharmacological interventions in patients with acute respiratory distress syndrome (ARDS). Participants will be recruited from multiple sites within the United States.

ARDS is defined by:

A known acute clinical insult or new or worsening respiratory dysfunction, and Receipt of respiratory support via invasive mechanical ventilation or non-invasive ventilation including continuous positive airway pressure, or high-flow nasal oxygen ≥30L/min, and

Within the same 24-hour time period:

Bilateral opacities on chest imaging not fully explained by effusions, lobar/lung collapse/atelectasis, or nodules, and Respiratory failure not fully explained by cardiac failure, fluid overload, pulmonary embolism, acute airways disease, or interstitial lung disease and Pa02/Fi02 ration <40 kPa from arterial blood gases, or Sp02/Fi02 <315 from pulse oximetry where Sp02 <97.

The time of onset of ARDS is when the last criterion in 3 is met.

Developing effective pharmacological therapies for ARDS will improve patient outcomes in an area of significant unmet need as well as reduce health care costs. Survivors of ARDS experience reduced health-related quality of life, with substantial health care and societal costs. Secondary analyses of prior randomized clinical trials have suggested different treatment responses between biological sub phenotypes in patients with ARDS.

A new paradigm in critical care suggests that de-emphasizing clinical syndromic definitions and focusing instead on sub phenotypes more closely linked to the host biological response is the key to identifying effective therapeutics. Using syndromic definitions does not provide information on which subgroups of patients are likely to respond effectively and safely to a given pharmacological treatment.

Initially, the platform will use the hyper and hypoinflammatory sub phenotypes in ARDS that are characterized by differing levels of systemic inflammation, clinical features, and treatment responses. Hyper and hypoinflammatory phenotyping will be determined using validated assays for IL-6 and sTNFR1. These measurements will be combined with measurement of the lowest bicarbonate level within the proceeding 24 hours from a plasma or an arterial blood gas and the data used to determine phenotype in real time at the bedside using a validated algorithm. Thus, sub phenotyping will occur via collection and real-time processing of plasma biomarkers after inclusion criteria are met and prior to randomization.

The ELLA Device (Bio-Techne) is a fully automated immune-analyzer that enables on-site simultaneous detection of analytes from a single sample of blood. As a minimal risk procedure for the participant and user, a sample of less than 1 mL of fresh blood from the consented participant is required. The results are generated typically within 60-80 minutes, and biomarker values for IL-6 and sTNFR1, along with the lowest blood bicarbonate level in the previous 24 hours, are entered into a logistic regression model to identify the probability of belonging to the hyperinflammatory sub phenotype. Participants and clinical teams will not be aware of the participant's real-time sub phenotype.

This trial is open-label whereby participants, the clinical team and study team will not be masked to the intervention. Randomization will be balanced with equal ratios between usual care and each intervention participants are eligible for, i.e. a 1:1:1 ratio (usual care versus intervention (where eligible) by sub phenotype). There is no fixed sample size, but we have capped the sample size for the initial treatments and sub phenotype, and will stop enrollment when results indicate efficacy or futility. Every participant will have additional blood collected at trial enrollment (day 0), day 2, and day 6.

Participants will be followed by the clinical research team daily whilst in the ICU.

Once the participants have left ICU and been discharged to acute care, they will be followed prior to hospital discharge. They will also be followed up by telephone or electronically 90 days and 180 days after randomization (+14 days). Survival status will be entered at 365 days.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Carrie B Higgins, BSN; Phone Number: 3037240961; Email: carrie.higgins@cuanschutz.edu
• Study Contact Backup: Name: Jeffrey McKeehan, MSN AC-AGNP; Phone Number: 3037246080; Email: jeffrey.mckeehan@cuanschutz.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Critically ill patients in hospital and at least 1 of the following:

1. Acute respiratory distress syndrome (ARDS). ARDS as defined by:

   1. a known acute clinical insult or new or worsening respiratory dysfunction
   2. receiving respiratory support via invasive mechanical ventilation or non- invasive mechanical ventilation including continuous positive airway pressure, or high flow nasal oxygen greater than or equal to 30L/min
   3. within the same 24-hour time period:

   i. bilateral opacities on chest imaging not fully explained by effusion, lobar/lung collapse/atelectasis, or nodules ii. respiratory failure not fully explained by cardiac failure, fluid overload, pulmonary embolism, acute airway disease iii. Pa02/Fi02 ration <40 kPa from arterial blood gases, or Sp02 <315 from pulse oximetry where Sp02 <97

2. A pandemic associated syndrome

Exclusion criteria:

Simvastatin:

1. More than 48 hours from the diagnosis of AHRF
2. Patient is known to be pregnant
3. Liver transaminases >8 times the upper limit of the normal range
4. Creatine kinase >10 times the upper limit of the normal range
5. Currently receiving ongoing treatment with any of the following: itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, cyclosporine, amiodarone, verapamil, or diltiazem.
6. Severe renal impairment (eGFR < 30mL/min and not receiving renal replacement therapy).
7. Current or recent treatment (within 2 weeks) with statins
8. Physician decision that a statin is required for proven indication
9. Contraindication to enteral drug administration, e.g., patients with mechanical bowel obstruction. Patients with high gastric aspirates due to an ileus are not excluded.
10. Known hypersensitivity to simvastatin

Baricitinib

1. More than 48 hours from the diagnosis of AHRF
2. Patient is known to be pregnant
3. Liver transaminases >8 times the upper limit of the normal range
4. Absolute neutrophil count less than 0.5x10 9/L
5. Currently receiving ongoing immunosuppressants (high dose corticosteroids, B and T cell targeted therapies, interferon, or JAK inhibitors)
6. Severe renal impairment (eGFR < 15mL/min) or receiving renal replacement therapy
7. Known active tuberculosis infection or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines.
8. Contraindication to enteral drug administration, e.g., patients with mechanical bowel obstruction. Patients with high gastric aspirates due to an ileus are not excluded.
9. Known hypersensitivity to baricitinib

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Usual Care; Usual care of ICU patients with ARDS. Patients randomized to the control arm or usual care will not receive simvastatin or baricitinib for 28 days or discharge from the ICU.
Active Comparator: Simvastatin; Simvastatin will be administered at a dose of 80 mg once daily by the enteral route for up to 28 days	Drug: Simvastatin; Simvastatin will be administered at a dose of 80 mg once daily by the enteral route for up to 28 days
Active Comparator: Baricitinib; Baricitinib will be administered at a dose of 4 mg once daily by the enteral route for up to 10 days.Baricitinib will be prescribed on the participants' in-patient drug administration chart (or equivalent) and administered to the participant by appropriately trained clinical staff with appropriate competencies in accordance with local practice. These staff do not need to be on the study delegation log. The dosing regimen below will be used in the setting of renal impairment: eGFR 30 to <60 mL/min Baricitinib Dose: 2mg eGFR15 to <30 mL/min Baricitinib Dose:1mg eGFR <15 mL/min (or receiving RRT) Baricitinib Dose withheld	Drug: Baricitinib; Baricitinib will be administered at a dose of 4 mg once daily by the enteral route for up to 10 days.Baricitinib will be prescribed on the participants' in-patient drug administration chart (or equivalent) and administered to the participant by appropriately trained clinical staff with appropriate competencies in accordance with local practice. These staff do not need to be on the study delegation log. The dosing regimen below will be used in the setting of renal impairment: eGFR 30 to <60 mL/min Baricitinib Dose: 2mg eGFR15 to <30 mL/min Baricitinib Dose:1mg eGFR <15 mL/min (or receiving RRT) Baricitinib Dose withheld

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28 day organ support free days	Number of days alive and free of organ support, which is defined as needing either respiratory or cardiovascular support. Respiratory support is defined as invasive mechanical ventilation or non-invasive ventilation including continuous positive airway pressure or high-flow nasal oxygen with a Fraction of inspired oxygen (FiO2) ≥ 0.4 and a flow rate ≥30L/min. Cardiovascular support is defined as the continuous infusion of any vasopressor or inotrope medication	in- hospital through day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28 day vasopressor free days	Number of days alive and free of vasopressor use	in-hospital through day 28
28-day respiratory support free days	Days alive and free of invasive mechanical ventilation or non-invasive ventilation including continuous positive airway pressure or high-flow nasal oxygen with an FiO2 ≥ 0.4 and a flow rate ≥30L/min	28 days
Receiving new renal replacement therapy	Initiation of hemodialysis, peritoneal dialysis, or continuous renal replacement therapy	in-hospital through day 28
ICU length of stay	Number of days alive and requiring ICU-level of care	in-hospital through day 90
Hospital length of stay	Number of days alive and in the hospitalized	In-hospital through day 90
All-cause mortality	The total number of deaths from any reason	In-hospital through Day 28 and day 90
Elevated Creatine Kinase more than 10 times the upper limit of normal	Number of occurrences in which creatinine kinase is elevated more than 10 times the upper limit of normal.	28 days
Alanine Transaminase or Aspartate Transaminase more than 8 times the upper limit of normal	Number of occurrences in which alanine transaminase (ALT) or aspartate transaminase (AST) more than 8 times the upper limit of normal.	28 days
Severe thrombocytopenia, out of keeping with clinical disease	Number of occurrences where the platelet count is lower than expected trajectory for a known clinical disease course.	28 days
Severe neutropenia, out of keeping with clinical disease	Number of occurrences in which low neutrophil count is lower than expected trajectory for a known clinical disease course.	28 days
Serious infection defined as a positive blood cultures requiring treatment.	Number of occurrences of a serious infection, defined as a positive blood culture that requires treatment, and pulmonary aspergillosis that requires treatment	28 days
Venous thromboembolism	Number of occurrences of a venous thromboembolism defined as a condition where a blood clot forms in a non-superficial vein	28 days
Stroke	number of occurrences of a stroke, defined as a sudden interruption of blood flow to the brain, either ischemic or hemorrhagic	28 days
Myocardial infarction	Number of occurrences of a myocardial infarction, defined interruption or blockage of blood flow to the heart.	28 days
Ischemic bowel	number of occurrences of an ischemic bowel, defined as blood flow to the intestines that has slowed or stopped.	28 days
Gastrointestinal perforation	number of occurrences of gastrointestinal (GI) perforation, defined as a hole that has formed all the way through the wall of the stomach, small intestine, or large intestine.	28 days
Clinically important gastrointestinal bleeding.	Number of occurrences of clinically important GI bleeding, defined as overt bleeding on GI endoscopy, developing as a complication in the ICU and accompanied by 1 or more of the following features within 24 hours: Spontaneous drop of systolic, mean arterial pressure or diastolic blood pressure of 20mmHg or more Start of vasopressor or a 20% increase in vasopressor dose Decrease in hemoglobin of at least 2 g/dl Transfusion of 2 units of packed red blood cells (PRBCs) or more	28 days
Serious adverse events	Number of occurrences of a serious adverse event (SAE), defined as any event that; Results in death;; Is life-threatening; Requires hospitalization or prolongation of existing inpatient's hospitalization; Results in persistent or significant disability or incapacity; Is a congenital abnormality or birth defect	90 days
Physical function (SPPB) at hospital discharge	The Short Physical Performance Battery (SPPB) is an objective assessment tool for evaluating lower extremity functioning.	Hospital discharge
Cognitive function Montreal Cognitive Assessment (MoCA)	Completion of the mini-Montreal Cognitive Assessment (mini-MoCA), a tool for early detection of mild cognitive impairment. MoCA accurately and quickly assesses short term memory, visuospatial abilities, executive functions, attention, concentration and working memory, language, and orientation to time and place	Hospital discharge, day 90, day 180
Progression to invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) or death among those not receiving that support at baseline	New initiation of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), or death	In-hospital through day 90

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
14-day Delirium and Coma-Free Days	Days alive and free of delirium, assessed by the Confusion Assessment Method for the Instensive Care Unit (CAM-ICU), and delirium, assessed by the Richmond Agitation Sedation Scale (RASS score)	14 days
Incidence of ICU acquired weakness.	Evaluated using the Manual Muscle Strength Testing (MMST) and handgrip strength. The MMST is a standardized, hands-on clinical assessment to measure strength and function of individual muscles or muscle groups. Handgrip strength by dynamometer measures the maximum isometric hand and forearm strength.	Day 7 or ICU discharge and hospital discharge
Health-related quality of life	The EQ-5D-5L is a survey tool to measure health-related quality of life, whereby a score of 100 indicates the best possible health state and a score 0 is the worst possible health state.	90 days and 180 days
Hospital Anxiety and Depression Scale (HADS)	HADS is a 14-item scale with 7 items each for anxiety and depression subscales. Scoring for each item ranges from 0 to 3, whereby a subscale score >8 denotes anxiety or depression.	90 days and 180 days
Social and Wellbeing	Social and wellbeing as measured by the 36-Item Short Form Health Survey (SF-36): a patient-reported survey that measures general health and quality of life.	90 days and 180 days
Impact of events scale (6 item) at 90 days and 180 days	The Impact of Event Scale-6 (IES-6) is a short, 6-item version of the IES-R, which is used to quickly screen for post-traumatic stress disorder (PTSD) symptoms.	90 days and 180 days

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: University of Pennsylvania; New York University; Emory University; Montefiore Medical Center; University of California, San Francisco; Intermountain Health Care, Inc.; Vanderbilt University School of Medicine; Wake Forest University
• Investigators: Principal Investigator: Neil Aggarwal, MD, University of Colorado, Denver

Publications and helpful links

General Publications

• Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011 Apr 7;364(14):1293-304. doi: 10.1056/NEJMoa1011802.
• Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA; NHLBI ARDS Network. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014 Aug;2(8):611-20. doi: 10.1016/S2213-2600(14)70097-9. Epub 2014 May 19.
• Maslove DM, Tang B, Shankar-Hari M, Lawler PR, Angus DC, Baillie JK, Baron RM, Bauer M, Buchman TG, Calfee CS, Dos Santos CC, Giamarellos-Bourboulis EJ, Gordon AC, Kellum JA, Knight JC, Leligdowicz A, McAuley DF, McLean AS, Menon DK, Meyer NJ, Moldawer LL, Reddy K, Reilly JP, Russell JA, Sevransky JE, Seymour CW, Shapiro NI, Singer M, Summers C, Sweeney TE, Thompson BT, van der Poll T, Venkatesh B, Walley KR, Walsh TS, Ware LB, Wong HR, Zador ZE, Marshall JC. Redefining critical illness. Nat Med. 2022 Jun;28(6):1141-1148. doi: 10.1038/s41591-022-01843-x. Epub 2022 Jun 17.
• Dowdy DW, Eid MP, Dennison CR, Mendez-Tellez PA, Herridge MS, Guallar E, Pronovost PJ, Needham DM. Quality of life after acute respiratory distress syndrome: a meta-analysis. Intensive Care Med. 2006 Aug;32(8):1115-24. doi: 10.1007/s00134-006-0217-3. Epub 2006 Jun 17.
• Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291.
• Famous KR, Delucchi K, Ware LB, Kangelaris KN, Liu KD, Thompson BT, Calfee CS; ARDS Network. Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med. 2017 Feb 1;195(3):331-338. doi: 10.1164/rccm.201603-0645OC.
• McNamee JJ, Gillies MA, Barrett NA, Perkins GD, Tunnicliffe W, Young D, Bentley A, Harrison DA, Brodie D, Boyle AJ, Millar JE, Szakmany T, Bannard-Smith J, Tully RP, Agus A, McDowell C, Jackson C, McAuley DF; REST Investigators. Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial. JAMA. 2021 Sep 21;326(11):1013-1023. doi: 10.1001/jama.2021.13374.
• Calfee CS, Delucchi KL, Sinha P, Matthay MA, Hackett J, Shankar-Hari M, McDowell C, Laffey JG, O'Kane CM, McAuley DF; Irish Critical Care Trials Group. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med. 2018 Sep;6(9):691-698. doi: 10.1016/S2213-2600(18)30177-2. Epub 2018 Aug 2.
• Dimairo M, Pallmann P, Wason J, Todd S, Jaki T, Julious SA, Mander AP, Weir CJ, Koenig F, Walton MK, Nicholl JP, Coates E, Biggs K, Hamasaki T, Proschan MA, Scott JA, Ando Y, Hind D, Altman DG; ACE Consensus Group. The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. Trials. 2020 Jun 17;21(1):528. doi: 10.1186/s13063-020-04334-x.
• McAuley DF, Laffey JG, O'Kane CM, Perkins GD, Mullan B, Trinder TJ, Johnston P, Hopkins PA, Johnston AJ, McDowell C, McNally C; HARP-2 Investigators; Irish Critical Care Trials Group. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014 Oct 30;371(18):1695-703. doi: 10.1056/NEJMoa1403285. Epub 2014 Sep 30.
• Boyle AJ, McDowell C, Agus A, Logan D, Stewart JD, Jackson C, Mills J, McNamee JJ, McAuley DF. Acute hypoxaemic respiratory failure after treatment with lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal: long-term outcomes from the REST randomised trial. Thorax. 2023 Aug;78(8):767-774. doi: 10.1136/thorax-2022-218874. Epub 2022 Oct 5.
• Gorman EA, O'Kane CM, McAuley DF. Acute respiratory distress syndrome in adults: diagnosis, outcomes, long-term sequelae, and management. Lancet. 2022 Oct 1;400(10358):1157-1170. doi: 10.1016/S0140-6736(22)01439-8. Epub 2022 Sep 4.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): September 1, 2030

Study Registration Dates

• First Submitted: August 18, 2026
• First Submitted That Met QC Criteria: August 18, 2026
• First Posted (Actual): August 21, 2026

Study Record Updates

• Last Update Posted (Actual): August 31, 2026
• Last Update Submitted That Met QC Criteria: August 27, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: ARDS; acute hypoxic respiratory failure
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Injury; Acute Lung Injury; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Lovastatin; Simvastatin; baricitinib
• Other Study ID Numbers: 26-0523; HT94252510958 (Other Grant/Funding Number: US Army Medical Research Acquisition Activity as a Department of Defense Awarding Office)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No