Preventive Strategies for Early and Late Complications of Leptospirosis

Official title

Decreasing Leptospirosis Emergence Through Prognosis and Treatment Optimization (DeLEPTO) Project 1: Preventive Strategies for Early and Late Complications of Leptospirosis

Overview

The goal of this clinical trial is to learn if complement factor I (CFI) works to predict development of complications in participants with leptospirosis. It will also learn if plasma transfusion, hemoperfusion, and extracorporeal membrane oxygenation works to treat participants with leptospirosis. The main questions it aims to answer are: * Does a low level of CFI predict the development of lung damage in participants with leptospirosis? * Does plasma tranfusion lower the chances of participants getting lung damage from leptospirosis? * Does hemoperfusion work to remove harmful materials from the blood of participants with leptospirosis? * Does extracorporeal membrane oxygenation increase the chance of survival in participants with lung damage? Researchers will compare plasma tranfusion and hemoperfusion to conventional therapy (standard of care for leptospirosis, including antibiotics, fluids, and other treatment that the doctor deems necessary) to see if these novel therapies work to treat leptospirosis. Participants will: * Give blood samples for the study of CFI * Receive conventional therapy and/or plasma transfusion for 4 times in 2 days, OR * Receive conventional therapy and/or hemoperfusion for at least 3 days, AND/OR * Receive extracorporeal membrane oxygenation if their condition worsens

Detailed description

This study aims to determine the clinical utility of complement factor I (CFI) as a prognosticator in patients with complicated leptospirosis without severe pulmonary complications and to determine if its guidance to preemptive measures can lead to a reduction in adverse clinical outcomes, specifically the occurrence of pulmonary bleeding and acute respiratory distress syndrome (ARDS), and mortality. Hence, the results of the study may lead to novel treatment approaches that can be readily applied in clinical practice. The decision to provide preemptive non-invasive therapies or early intensive care admission could lead to significant breakthroughs in managing the disease.

Within the Decreasing Leptospirosis Emergence through Prognosis and Treatment Optimization (DeLEPTO) program's vision of developing tools to increase the survival of leptospirosis patients, this project will explore the avenue of novel tertiary care. Specifically, the program will look into the possibility of CFI repletion using plasma transfusion, cytokine depletion strategies using hemoperfusion (HP), and extracorporeal membrane oxygenation (ECMO). It would be interesting to see how such interventions could work individually or in a pipeline with other proposed interventions. In addition to plasma therapy, ECMO was observed to improve outcomes in severe leptospirosis. As a secondary endpoint, it would also be interesting to know if CFI can prognosticate who will benefit the most from such interventions.

Interventions

• Biological Prophylactic Plasma Transfusion
  ABO/Rh-type compatible fresh frozen plasma (FPP) units will be thawed to 37° prior to administration. Plasma transfusion will be administered intravenously, 1 unit for 4 hours every 12 hours. There will be two consecutive days for the transfusion for a total of 4 units.
• Device Hemoperfusion
  The hemoperfusion (HP) procedure will follow the standard procedure of National Kidney and Transplant Institute (NKTI) using Jafron HA330 hemoperfusion cartridge. First, an internal jugular catheter is attached to the patient. Alternatively, an arteriovenous fistula or arteriovenous graft may be placed on the patient. The patient will then be hooked to a hemodialysis machine. Blood pump speed will be set to 150-200mL/min, and HP will last for 2 to 2.5 hours. Whole blood will flow through the sor
• Device Extracorporeal Membrane Oxygenation
  A veno-venous ECMO (VV ECMO) will be applied by aseptically inserting a venous cannula into the femoral veins. The patients will be hooked to an ECMO machine. Patients without significant bleeding or vascular intervention will be managed with an activated clotting time set at 140-180 sec by 800-1000 U/h of heparin. Otherwise, heparin will be titrated to maintain a partial thromboplastin time of 60-80 sec. ECMO settings are as follows: * Mean blood pressure of \>60 mm * SaO2 at \>90% with a flo
• Other Conventional therapy
  Conventional therapy for leptospirosis includes antibiotics, fluids, inotropes, renal replacement therapy, ventilator support, and other treatment that the attending physician deems necessary.

Primary outcome measures

• Determination of CFI levels via qPCR and via ELISA [Time frame: At baseline and Day 1 post-treatment, assessed up to study completion, an average of 3 years]
• Hospital Days [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]
• Occurrence of Mortality [Time frame: From admission to discharge from the hospital or date of death, assessed up to study completion, an average of 3 years]
• Presence of Significant Pulmonary Involvement [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]

Secondary outcome measures (8)

• Need for Renal Replacement Therapy [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]
• Need for Inotropic Support [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]
• Need for Emergent Invasive Respiratory Support [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]
• Presence of Refractory Hypotension [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]
• Presence of Significant Renal Involvement [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]
• Need for Extracorporeal Membrane Oxygenation (ECMO) assessed via Murray score [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]
• Need for Extracorporeal Membrane Oxygenation (ECMO) assessed via Horowitz Index for Lung Function (P/F Ratio) [Time frame: From admission to discharge from the hospital, assessed up to study completion, an average of 3 years]
• Intensive Care Unit (ICU) Days [Time frame: From admission into ICU to date out of ICU, assessed up to study completion, an average of 3 years]

Eligibility criteria

Inclusion criteria

• Subjects with acute fever (38ºC for at least two days) and at least one of the following: myalgia, jaundice, headache, meningeal irritation, oliguria, conjunctival suffusion
• Who have a microscopic agglutination test (MAT) that indicates a single serum sample MAT titer greater than or equal to 1:400
• Or a positive result for the latex agglutination test or a repeat test after seven days
• Or a positive result for Leptospira IgG/IgM lateral flow immunochromatographic test (ICT) or a repeat test within 3-14 days after the baseline test
• Or a positive result for Leptospira polymerase chain reaction (PCR)
• Or a positive blood culture of leptospira WITHOUT the complication specified in a subgroup of interest
• PPTTRT/PPTCONV: Not requiring ventilator support
• HPTRT/HPCONV: Dialysis Requiring Acute Kidney Injury. Defined as KDIGO Acute Kidney Injury Stage 3 or requiring renal replacement therapy to correct intractable acidosis, electrolyte abnormality, or over uremic encephalopathy or pericarditis
• HPTRT/HPCONV: Vasopressor Requiring - The subject must have received intravenous fluid resuscitation of a minimum of 30ml/kg within 24 hours of eligibility and still with hypotension (blood pressure less than 90/60, MAP less than 65) requiring vasopressor support
• HPTRT/HPCONV: SOFA SCORE less than 15
• ECMO: A Murray score of greater than or equal to 2.75

Exclusion criteria

• Previous diagnosis of chronic kidney disease or on maintenance dialysis
• Previous diagnoses of diseases associated with hemoptysis, such as bronchiectasis
• Blood dyscrasias, malignancy, severe heart disease, HIV, cavitary PTB, Cirrhosis by ultrasound, severe malnutrition (Weight of less than 35kg)
• Post cardiac arrest or those with GCS less than 8 at present. Participant has had chest compressions or CPR
• Pregnancy
• PPTTRT/PPTCONV: Requiring emergent dialyses
• PPTTRT/PPTCONV: Significant lung pathology as defined by P/F ratio less than 300, or obvious respiratory distress
• PPTTRT/PPTCONV: Presence of severe neurological symptoms
• PPTTRT/PPTCONV: Hypotension (or need for vasopressor support)
• PPTTRT/PPTCONV: Ongoing hemodynamic instability

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

Open label

Primary purpose

Treatment

Study locations

Philippines · 3 centers

• Institute of Human Genetics, National Institutes of Health - University of the Philippines — Manila
• San Lazaro Hospital — Manila
• National Kidney and Transplant Institute — Quezon City

Publications

• Milhem MM, Knutson T, Yang S, Zhu D, Wang X, Leslie KK, Meng X. Correlation of MTDH/AEG-1 and HOTAIR Expression with Metastasis and Response to Treatment in Sarcoma Patients. J Cancer Sci Ther. 2011 Dec 29;S5(4):004. PMID 23543869
• Popugaev KA, Bakharev SA, Kiselev KV, Samoylov AS, Kruglykov NM, Abudeev SA, Zhuravel SV, Shabanov AK, Mueller T, Mayer SA, Petrikov SS. Clinical and pathophysiologic aspects of ECMO-associated hemorrhagic complications. PLoS One. 2020 Oct 13;15(10):e0240117. doi: 10.1371/journal.pone.0240117. eCollection 2020. PMID 33048966
• Na SJ, Chung CR, Choi HJ, Cho YH, Sung K, Yang JH, Suh GY, Jeon K. The effect of multidisciplinary extracorporeal membrane oxygenation team on clinical outcomes in patients with severe acute respiratory failure. Ann Intensive Care. 2018 Feb 27;8(1):31. doi: 10.1186/s13613-018-0375-9. PMID 29484504
• Combes A, Brodie D, Bartlett R, Brochard L, Brower R, Conrad S, De Backer D, Fan E, Ferguson N, Fortenberry J, Fraser J, Gattinoni L, Lynch W, MacLaren G, Mercat A, Mueller T, Ogino M, Peek G, Pellegrino V, Pesenti A, Ranieri M, Slutsky A, Vuylsteke A; International ECMO Network (ECMONet). Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory fai PMID 25062496
• Cheng R, Hachamovitch R, Kittleson M, Patel J, Arabia F, Moriguchi J, Esmailian F, Azarbal B. Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: a meta-analysis of 1,866 adult patients. Ann Thorac Surg. 2014 Feb;97(2):610-6. doi: 10.1016/j.athoracsur.2013.09.008. Epub 2013 Nov 8. PMID 24210621
• Khalid N, Javed H, Ahmad SA, Edelman JJ, Shlofmitz E, Chen Y, Musallam A, Rogers T, Hashim H, Bernardo NL, Waksman R. Analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience Database for Patient- and Circuit-Related Adverse Events Involving Extracorporeal Membrane Oxygenation. Cardiovasc Revasc Med. 2020 Feb;21(2):230-234. doi: 10.1016/j.carrev.2019.11.011. Ep PMID 31767523
• Xu L, Wu X, Zou Y. Clinical efficacy comparison of HA280 and DNA280 immunoadsorption column in treating systemic lupus erythematosus. Mod Rheumatol. 2016;26(1):94-8. doi: 10.3109/14397595.2015.1056955. Epub 2015 Aug 19. PMID 26025438
• Pomare Montin D, Ankawi G, Lorenzin A, Neri M, Caprara C, Ronco C. Biocompatibility and Cytotoxic Evaluation of New Sorbent Cartridges for Blood Hemoperfusion. Blood Purif. 2018;46(3):187-195. doi: 10.1159/000489921. Epub 2018 Jun 8. PMID 29886501

Identifiers

NCT: NCT07127718 · SJREB 2024-70

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗