Epoprostenol Plus Conventional Therapy in COld and Frostbite Injury (ECCO)

NCT07424378 | Not Yet Recruiting Phase 4 DMC FDA Drug

• 2 other identifiers: 25-0256MT24001.345
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 2

Brief Summary

Severe frostbite injury can result in significant lifelong disability and amputation. Various medicines, including intravenous vasodilators (prostaglandins/iloprost, pentoxifylline, buflomedil) along with thrombolytics (alteplase), have been described to counter tissue ischemia after rewarming, with poor quality of evidence. An in-class prostacyclin, epoprostenol, has similar pharmacodynamic properties to iloprost including vasodilation and platelet inhibition and has been used in peripheral tissue ischemia such as Raynaud's and scleroderma. In this trial, we will evaluate the effectiveness and safety of epoprostenol treatment for severe frostbite injury in addition to standard of care.

Conditions

Frostbite

Keywords

Frostbite; Epoprostenol; Prostaglandin; Amputation

Outcome Measures

Primary Outcomes (1)

• Amputation Rate

  Amputation rate within 90 days of frostbite injury, defined as number of amputations per number of digits affected.

  from enrollment to the end of treatment when client returns for clinic visit at 90 days.

Secondary Outcomes (4)

• Hennepin frostbite score change

  from admission to final healing to day 90

• Preserved Digit Segments

  from admission to final healing to Day 90

• Change in Perfusion Imaging (fluorescence intravenous indocyanine green)

  from admission to final imaging at day 7

• Change in Technetium Bone Scans

  from admission to final imaging at day 7

Other Outcomes (12)

• Hospital Length of Stay

  from admission to day 90

• Mortality Rate

  from admission to day 90

• Need for Skin graft procedures

  from admission to 90 days of frostbite injury

Study Arms (2)

Epoprostenol

ACTIVE COMPARATOR

Standard of care plus epoprostenol intravenous infusion titrated based on tolerability for 8 hours per day and up to 5 days of treatment.

Drug: Standard of care plus Epoprostenol infusion for 8 hours (hrs) per day up to 5 days maximum

Placebo (Normal Saline)

PLACEBO COMPARATOR

Standard of care plus placebo infusion dosed and titrated to match epoprostenol infusion for 8 hours per day and up to 5 days of treatment.

Drug: Standard of Care + Placebo (Normal Saline)infusion for 8 hours per day up to 5 days maximum

Interventions

Standard of care plus Epoprostenol infusion for 8 hours (hrs) per day up to 5 days maximum DRUG

An in-class prostacyclin, epoprostenol (originally derived prostaglandin), has similar pharmacodynamic properties to Iloprost including vasodilation and platelet inhibition, is widely available and already stocked at most hospitals for already approved indications (pulmonary hypertension). Epoprostenol has advantageous pharmacokinetics including organ independent elimination, a shorter half-life allowing for a faster "off-set" of action, and decades of experience of use for other indications. This randomized controlled trial will assess the efficacy and safety of epoprostenol for frostbite in addition to our standard of care treatment for frostbite: rewarming and qualified early thrombolytic therapy.

Epoprostenol

Standard of Care + Placebo (Normal Saline)infusion for 8 hours per day up to 5 days maximum DRUG

The placebo or Normal saline will be given exactly the same as the intervention drug - via intravenous infusion for 8 hours a day up to 5 days maximum. Vital signs and monitoring will be the same. The packaging will be labeled "study medication" (epoprostenol or placebo) and neither the participant, treating clinicians, or study personnel will be able to tell the difference as both epoprostenol and normal saline have identical color, general appearance, and viscosity.

Placebo (Normal Saline)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged ≥ 18 years
• Admitted to University of Colorado Hospital (UCH) Burn and Frostbite Center
• Cauchy Grade 2-4 frostbite injury
• Admission within 72 hours post-rewarming

You may not qualify if:

• Patients unable to initiate therapy within 72 hours post-rewarming
• Unsalvageable frostbite as defined by obvious necrosis of tissue, wet gangrene, or other condition requiring amputation (within the first week)
• Anticipated death within 48 hours of admission
• Pregnant or breastfeeding patients
• Prisoners
• Inability to obtain consent from patient or legally authorized representative (LAR) or proxy
• Not a good candidate for treatment per treating physician or investigator
• Patients with known allergy/hypersensitivity to epoprostenol
• Current or planned receipt of other prostaglandin analog (iloprost and treprostinil)
• Known congestive heart failure due to severe left ventricular systolic dysfunction (New York Heart Association (NYHA) class III/IV)
• Known right heart failure (RHF)
• Hypotension unresponsive to fluids and discontinuation of concomitant anti-hypertensives (mean arterial pressure (MAP) \< 65 mmHg)
• Known pulmonary hypertension

Sponsors & Collaborators

• University of Colorado, Denver: lead
• United States Department of Defense: collaborator

Study Sites (2)

University of Colorado, Denver

Aurora, Colorado, 80045, United States

Location

University of Colorado, Denver

Aurora, Colorado, 80045, United States

Location

Related Publications (21)

• Endorf FW, Nygaard RM. Social Determinants of Poor Outcomes Following Frostbite Injury: A Study of the National Inpatient Sample. J Burn Care Res. 2021 Nov 24;42(6):1261-1265. doi: 10.1093/jbcr/irab115.

  PMID: 34139760 BACKGROUND

• Update: Cold weather injuries, active and reserve components, U.S. Armed Forces, July 2016-June 2021. MSMR. 2021 Oct 1;28(10):2-10.

  PMID: 34964583 BACKGROUND

• Nygaard RM, Endorf FW. Frostbite in the United States: An Examination of the National Burn Repository and National Trauma Data Bank. J Burn Care Res. 2018 Aug 17;39(5):780-785. doi: 10.1093/jbcr/irx048.

  PMID: 29931369 BACKGROUND

• Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, Rich S, Barst RJ, Barrett PS, Kral KM, Jobsis MM, Loyd JE, Murali S, Frost A, Girgis R, Bourge RC, Ralph DD, Elliott CG, Hill NS, Langleben D, Schilz RJ, McLaughlin VV, Robbins IM, Groves BM, Shapiro S, Medsger TA Jr. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000 Mar 21;132(6):425-34. doi: 10.7326/0003-4819-132-6-200003210-00002.

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• Young A, Namas R, Dodge C, Khanna D. Hand Impairment in Systemic Sclerosis: Various Manifestations and Currently Available Treatment. Curr Treatm Opt Rheumatol. 2016 Sep;2(3):252-269. doi: 10.1007/s40674-016-0052-9. Epub 2016 Jul 19.

  PMID: 28018840 BACKGROUND

• Kowal-Bielecka O, Landewe R, Avouac J, Chwiesko S, Miniati I, Czirjak L, Clements P, Denton C, Farge D, Fligelstone K, Foldvari I, Furst DE, Muller-Ladner U, Seibold J, Silver RM, Takehara K, Toth BG, Tyndall A, Valentini G, van den Hoogen F, Wigley F, Zulian F, Matucci-Cerinic M; EUSTAR Co-Authors. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009 May;68(5):620-8. doi: 10.1136/ard.2008.096677. Epub 2009 Jan 15.

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  PMID: 39874231 BACKGROUND

• Sitbon O, Vonk Noordegraaf A. Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience. Eur Respir Rev. 2017 Jan 17;26(143):160055. doi: 10.1183/16000617.0055-2016. Print 2017 Jan.

  PMID: 28096285 BACKGROUND

• McIntosh SE, Freer L, Grissom CK, Auerbach PS, Rodway GW, Cochran A, Giesbrecht GG, McDevitt M, Imray CH, Johnson EL, Pandey P, Dow J, Hackett PH. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2019 Update. Wilderness Environ Med. 2019 Dec;30(4S):S19-S32. doi: 10.1016/j.wem.2019.05.002. Epub 2019 Jul 17.

  PMID: 31326282 BACKGROUND

• Bello JW, Rickrode GA, Harlan NP, Buckey JC. Systemic Prostacyclin Analogues for Frostbite Require Careful Monitoring. J Burn Care Res. 2023 Mar 2;44(2):487-488. doi: 10.1093/jbcr/irac178. No abstract available.

  PMID: 36444642 BACKGROUND

• Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J, Cunin G, Fermanian J, Ginies P, Grun-Overdyking A, Jafari-Schluep H, Lanteri-Minet M, Laurent B, Mick G, Serrie A, Valade D, Vicaut E. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain. 2005 Mar;114(1-2):29-36. doi: 10.1016/j.pain.2004.12.010. Epub 2005 Jan 26.

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• Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the Brief Pain Inventory for chronic nonmalignant pain. J Pain. 2004 Mar;5(2):133-7. doi: 10.1016/j.jpain.2003.12.005.

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• Kamstra RJM, Boorsma A, Krone T, van Stokkum RM, Eggink HM, Peters T, Pasman WJ. Validation of the Mobile App Version of the EQ-5D-5L Quality of Life Questionnaire Against the Gold Standard Paper-Based Version: Randomized Crossover Study. JMIR Form Res. 2022 Aug 11;6(8):e37303. doi: 10.2196/37303.

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• Ogawa A, Matsubara H, Fujio H, Miyaji K, Nakamura K, Morita H, Saito H, Kusano KF, Emori T, Date H, Ohe T. Risk of alveolar hemorrhage in patients with primary pulmonary hypertension--anticoagulation and epoprostenol therapy. Circ J. 2005 Feb;69(2):216-20. doi: 10.1253/circj.69.216.

  PMID: 15671616 BACKGROUND

• Lindford A, Valtonen J, Hult M, Kavola H, Lappalainen K, Lassila R, Aho P, Vuola J. The evolution of the Helsinki frostbite management protocol. Burns. 2017 Nov;43(7):1455-1463. doi: 10.1016/j.burns.2017.04.016. Epub 2017 Aug 1.

  PMID: 28778759 BACKGROUND

• Murphy J, Endorf FW, Winters MK, Rogers C, Walter E, Neumann N, Weber L, Lacey AM, Punjabi G, Nygaard RM. Bleeding Complications in Patients With Severe Frostbite Injury. J Burn Care Res. 2023 Jul 5;44(4):745-750. doi: 10.1093/jbcr/irac180.

  PMID: 36482743 BACKGROUND

• Poole A, Gauthier J, MacLennan M. Management of severe frostbite with iloprost, alteplase and heparin: a Yukon case series. CMAJ Open. 2021 May 21;9(2):E585-E591. doi: 10.9778/cmajo.20200214. Print 2021 Apr-Jun.

  PMID: 34021017 BACKGROUND

• Crooks S, Shaw BH, Andruchow JE, Lee CH, Walker I. Effectiveness of intravenous prostaglandin to reduce digital amputations from frostbite: an observational study. CJEM. 2022 Sep;24(6):622-629. doi: 10.1007/s43678-022-00342-9. Epub 2022 Jul 23.

  PMID: 35870081 BACKGROUND

• Cauchy E, Cheguillaume B, Chetaille E. A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite. N Engl J Med. 2011 Jan 13;364(2):189-90. doi: 10.1056/NEJMc1000538. No abstract available.

  PMID: 21226604 BACKGROUND

• Cauchy E, Davis CB, Pasquier M, Meyer EF, Hackett PH. A New Proposal for Management of Severe Frostbite in the Austere Environment. Wilderness Environ Med. 2016 Mar;27(1):92-9. doi: 10.1016/j.wem.2015.11.014.

  PMID: 26948558 BACKGROUND

• Wibbenmeyer L, Lacey AM, Endorf FW, Logsetty S, Wagner ALL, Gibson ALF, Nygaard RM. American Burn Association Clinical Practice Guidelines on the Treatment of Severe Frostbite. J Burn Care Res. 2024 May 6;45(3):541-556. doi: 10.1093/jbcr/irad022.

  PMID: 37045447 BACKGROUND

Related Links

• Veletri (epoprostenol). Package insert. Actelion Pharmaceuticals US, Inc.; 2020

MeSH Terms

Conditions

Frostbite

Interventions

Standard of Care; Histidine-tRNA Ligase

Condition Hierarchy (Ancestors)

Cold Injury; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Amino Acyl-tRNA Synthetases; Carbon-Oxygen Ligases; Ligases; Enzymes; Enzymes and Coenzymes

Study Officials

• Arek J Wiktor, MD, FACS

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Beth A Strimpel, MA, BSN, RN

CONTACT

203-980-2209; beth.a.strimpel@cuanschutz.edu

Arek J Wiktor, MD, FACS

CONTACT

303-724-1055; arek.wiktor@cuanschutz.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Research Coordinators
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participant will be randomized to either intervention or placebo

Study Record Dates

• First Submitted: January 28, 2026
• First Posted: February 20, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)