SPECTRAL DIAGNOSTICS SDI-PMX-NA001 EUPHRATES TRIAL Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock This confidential document is the property of Spectral Diagnostics and it is provided for the use of the investigator and other designated personnel solely in connection with the conduct of the study described herein. No information contained herein may be disclosed, except as necessary to obtain consent from persons who are considering participation in the study, without prior written approval of Spectral Diagnostics. Current Version: 9.1 Date: 11Aug2015 Spectral Diagnostics (US) Inc. 20201 Century Boulevard, Germantown, MD 20874 Tel301. 528-7000. Fax: 301.528.2300 www.spectraldx.com Downloaded From: https://jamanetwork.com/ on 09/30/2021 EUPHRATES Trial: SDI-PMX-NA001 11Aug2015 Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock Protocol Number: SDI-PMX-NA001 Protocol Version: Version 9.1 Date: 11August2015 Medical Monitor: Shide Badri, MD Amarex, LLC 20201 Century Boulevard Germantown, MD USA 20874 Phone: 240-454-6825 Fax: 240-813-2868 Email: [email protected] Sponsor: Spectral Diagnostics (US), Inc. 20201 Century Boulevard, Ste 450 Germantown, MD USA 20874 Phone: 301-528-7000 Fax: 301-528-2300 Previous Protocol Versions: Version 1, July 30, 2009 Version 2, October 30, 2009 Version 3, December 30, 2009 Version 4, January 30, 2010 Version 5, July 1, 2011 Version 6, January 1, 2012 Version 7, April 27, 2012(not distributed to sites) Version 7.1, June 26, 2012 Version 8, August 8, 2012 Version 9, April 28, 2014 2 | Page CONFIDENTIAL Version 9.1 Downloaded From: https://jamanetwork.com/ on 09/30/2021 EUPHRATES Trial: SDI-PMX-NA001 11Aug2015 1 Protocol Synopsis Study Title: Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock. Study Number and Acronym: SDI-PMX-NA001 EUPHRATES Primary Objectives: To compare the safety and efficacy of the PMX cartridge based on mortality at 28-days in subjects with septic shock who have high levels of endotoxin and are treated with standard medical care plus use of the PMX cartridge, versus subjects who receive standard medical care alone. Secondary Objectives: 1. To compare mortality between the two groups at 90 days, 6 months and 12 months post-start of treatment 2. To compare the change in endotoxin levels between the PMX cartridge treated group and the control group at 12 hours after completion of a second PMX cartridge, with a treatment target of a > 15% reduction of EAA levels with PMX cartridge treatment 3. To compare the changes in vasopressor doses for the two groups from Day 0 to Day 3 4. To compare the number of days of need for vasopressors in each group from Day 0 to Day 28 (days alive and off vasopressors) 5. To compare changes in mean arterial blood pressure (MAP) for the two groups from Day 0 to Day 3 6. Comparison of the changes in renal function from day 0 to Day 3: i. Urine output ii. Serum creatinine 7. To compare the effects of two uses of the PMX cartridge on progression of, and recovery from, organ dysfunction using the Multiple Organ Dysfunction Score (MODS) from Day 0 to Day 3 8. To compare the number of days of need for renal replacement therapy (RRT) in each group from Day 0 to Day 28 (days alive and off RRT) 9. To compare the number of days of need for mechanical ventilation (MV) in each group from Day 0 to Day 28 (days alive and off MV) 3 | Page CONFIDENTIAL Version 9.1 Downloaded From: https://jamanetwork.com/ on 09/30/2021 EUPHRATES Trial: SDI-PMX-NA001 11Aug2015 10. To compare the mean number of days spent in the hospital by subjects in each group for survivors to Day 28 11. To compare survival time from baseline to death within 28 days and compare the risk of death between the two study arms 12. To compare survival time from baseline to death within 90 days and compare the risk of death between the two study arms Study Phase: Phase III Number of Centers: Approximately 60 in the USA and Canada Number of Subjects: Approximately 478 (239 per treatment arm) Study Design: Double-blinded, randomized, controlled trial of standard care plus the PMX cartridge versus standard of care alone. Investigational Device: The TORAYMYXIN PMX-20R (PMX cartridge) is a single use extracorporeal hemoperfusion device to remove endotoxin from patients’ blood through direct hemoperfusion (DHP). The PMX cartridge was approved for use in Japan in 1993, in the EU in 1998 and in Canada in 2003. Treatment Intervention: Two (2) PMX cartridges will be administered approximately 24 hours apart. Each treatment will target 2 hours with a minimum of 1 ½ hours, at a flow rate of approximately 100 ml/minute, (range of 80 to 120 ml/minute). The treatment and control arm of the study will include standard medical care for septic shock which will include fluid replacement, vasopressor infusion, antimicrobials and ventilator support or renal replacement therapy if necessary. Patient Population: Intensive Care Unit subjects with septic shock and endotoxemia. 4 | Page CONFIDENTIAL Version 9.1 Downloaded From: https://jamanetwork.com/ on 09/30/2021 EUPHRATES Trial: SDI-PMX-NA001 11Aug2015 Inclusion Criteria: Subjects who meet the following criteria (and have a signed informed consent) will be allowed into the study: 1. Age ≥18 years of age 2. Hypotension requiring vasopressor support: Requirement for at least one of the vasopressors listed below, at the dose shown below, for at least 2 continuous hours and no more than 30 hours* a. Norepinephrine > 0.05mcg/kg/min b. Dopamine > 10 mcg/kg/min c. Phenylephrine > 0.4 mcg/kg/min d. Epinephrine > 0.05 mcg/kg/min e. Vasopressin > 0.03 units/min f. Vasopressin (any dose) in combination with another vasopressor listed above 3. The subject must have received intravenous fluid resuscitation of a minimum of 30mL/kg administered within 24 hours of eligibility 4. Documented or suspected infection defined as definitive or empiric intravenous antibiotic administration 5. Endotoxin Activity Assay ≥ 0.60 EAA units 6. Evidence of at least 1 of the following criteria for new onset organ dysfunction that is considered to be due to the acute illness a. Requirement for positive pressure ventilation via an endotracheal tube or tracheostomy tube b. Thrombocytopenia defined as acute onset of platelet count < 150,000 μ/L or a reduction of 50% from prior known levels c. Acute oliguria defined as urine output < 0.5 ml/kg/hr for at least 6 hours despite adequate fluid resuscitation Exclusion Criteria: 1. Inability to obtain an informed consent from the subject, family member or an authorized surrogate * When determining the eligible dose of vasopressors for a subject whose measured body weight is >100 kg, the maximum weight of 100 kg (220 lbs) will be used. This maximum weight applies to both males and females. 5 | Page CONFIDENTIAL Version 9.1 Downloaded From: https://jamanetwork.com/ on 09/30/2021 EUPHRATES Trial: SDI-PMX-NA001 11Aug2015 2. Lack of commitment for full medical support 3. Inability to achieve or maintain a minimum mean arterial pressure (MAP) of ≥ 65mmHg despite vasopressor therapy and fluid resuscitation 4. Subject has end stage renal disease and requires chronic dialysis 5. There is clinical support for non-septic shock such as a. Acute pulmonary embolus b. Transfusion reaction c. Severe congestive heart failure (e.g. NYHA Class IV, ejection fraction < 35%) * 6. Subject has had chest compressions as part of CPR this hospitalization without immediate return to communicative state 7. Subject has had an acute myocardial infarction (AMI) within the past 4 weeks 8. Subject has uncontrolled hemorrhage (acute blood loss requiring > 3 UPC in the past 24 hours) 9. Major trauma within 36 hours of screening 10. Subject has severe granulocytopenia (leukocyte count less than 500 cells/mm3) or severe thrombocytopenia (platelet count less than 30,000 cells/mm3) 11. HIV infection in association with a last known or suspected CD4 count of <50/mm3 12. Subject’s baseline state is non-communicative 13. Subject has sustained extensive third-degree burns within the past 7 days 14. Body weight < 35 kg (77 pounds) 15. Known hypersensitivity to Polymyxin B 16. Subject has known sensitivity or allergy to heparin or has a history of heparin associated thrombocytopenia (H.I.T.) 17. Subject is currently enrolled in an investigational drug or device trial 18. Subject has been previously enrolled in the current trial 19. Any other condition, that in the opinion of the investigator, would preclude the subject from being a suitable candidate for enrollment, such as end stage chronic illness with no reasonable expectation of survival to hospital discharge 20. Subject has a screening MOD score ≤9 * Please note that an ejection fraction of <35% does not automatically exclude the subject. This ejection fraction example is intended to describe chronic severe congestive heart failure NYHA Class IV only. 6 | Page CONFIDENTIAL Version 9.1 Downloaded From: https://jamanetwork.com/ on 09/30/2021 EUPHRATES Trial: SDI-PMX-NA001 11Aug2015 Study Procedures: This is a double-blind, randomized, controlled trial of standard medical care plus the PMX cartridge versus standard medical care alone in subjects with endotoxemia and septic shock. Subjects in ICUs will be assessed for septic shock using known or suspected infection and hypotension requiring vasopressor support as primary criteria. Subjects will meet all entry criteria for study except EAA activity ≥ 0.60. Subjects (or surrogate decision maker) will then be consented to a blood draw to determine the presence of an elevated endotoxin level (≥ 0.60 EAA units) using the Endotoxin Activity Assay (EAA™).