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

Official title

Randomized Controlled Trial of Epoprostenol Versus Placebo in Addition to Standard Therapy for Severe Frostbite Injury

Overview

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.

Detailed description

Prospective single center placebo controlled randomized trial comparing epoprostenol versus placebo in patients already receiving the standard of care for frostbite, including alteplase. Hypothesis: treatment effect of epoprostenol will be greater than placebo, independent of prior alteplase administration. Standard of care in both groups includes immediate warm water rewarming, thrombolysis with alteplase if they are a thrombolytic candidate per our usual care, immediate therapeutic anticoagulation if received thrombolysis, and ibuprofen at the attending physician's discretion.

Study Aim: To determine the efficacy and safety of treatment with epoprostenol versus placebo in adult patients with severe frostbite injury.

Intervention Group: Standard of care plus epoprostenol intravenous infusion titrated based on tolerability for 5 days.

Control Group: Standard of care plus placebo (normal saline) infusion dosed and titrated to match epoprostenol infusion for 5 days.

Interventions

• Drug Standard of care plus Epoprostenol infusion for 8 hours (hrs) per day up to 5 days maximum
  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. Th
• Drug Standard of Care + Placebo (Normal Saline)infusion for 8 hours per day up to 5 days maximum
  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.

Primary outcome measures

• Amputation Rate [Time frame: from enrollment to the end of treatment when client returns for clinic visit at 90 days.]

Secondary outcome measures (4)

• Hennepin frostbite score change [Time frame: from admission to final healing to day 90]
• Preserved Digit Segments [Time frame: from admission to final healing to Day 90]
• Change in Perfusion Imaging (fluorescence intravenous indocyanine green) [Time frame: from admission to final imaging at day 7]
• Change in Technetium Bone Scans [Time frame: from admission to final imaging at day 7]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 2 centers

• University of Colorado, Denver — Aurora
• University of Colorado, Denver — Aurora

Publications

• 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
• 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
• 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
• 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 rando PMID 10733441
• 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
• 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 PMID 19147617
• Del Galdo F, Lescoat A, Conaghan PG, Bertoldo E, Colic J, Santiago T, Suliman YA, Matucci-Cerinic M, Gabrielli A, Distler O, Hoffmann-Vold AM, Castellvi I, Balbir-Gurman A, Vonk M, Ananyeva L, Rednic S, Tarasova A, Ostojic P, Boyadzhieva V, El Aoufy K, Farrington S, Galetti I, Denton CP, Kowal-Bielecka O, Mueller-Ladner U, Allanore Y. EULAR recommendations for the treatment of systemic sclerosis: PMID 39874231
• 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

Identifiers

NCT: NCT07424378 · 25-0256 · MT24001.345

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗