Enriched Heparin Anti COVID-19 Trial

Study Overview
=================
Brief Summary
-----------------
Coronavirus 19 (COVID-19) is a viral respiratory disease that was identified in December 2019 after the first cases in China, spreading rapidly until reaching pandemic status, causing the collapse of numerous health systems and strong economic and social impact. By the end of April 2020, 3.08 million cases, and more than 214 thousand deaths were already recorded. The treatment so far has not been established and there are several clinical trials testing known drugs that have antiviral activity in vitro, due to the urgency that the global situation imposes. Medicines with specific actions can take years to be discovered, while a vaccine also takes a long time. Recently, it has been shown that the worsening of Coronavirus infection may be related to the formation of micro clots in blood vessels and anticoagulants have been used as adjuvants in the treatment. This study is justified by conducting a pilot study that showed an in vitro antiviral action (anti-COVID-19) of high molecular weight heparin. Methods: A phase I / II clinical trial will be conducted. 40 participants will be included in two arms. Participants allocated to Group 1 (control) will receive inhalation with 0.9% saline applied 4/4 hours, for 7 days. Participants allocated to Group 2 (intervention) will receive high molecular weight inhaled heparin (250ug / mL 0.9% SF), at a 4/4 hour dose, for 7 days. The outcomes of interest will be safety (absence of moderate or serious adverse events) and effectiveness (measured in a score of 7 points, with 1 absence of limitations and 7, death). Expected results: The development of a new therapeutic option for COVID-19 is expected, with the possibility of use in other serious coronavirus diseases, to be subsequently tested in phase III studies.

Detailed Description
-----------------
In view of the enormous health, financial and social crisis resulting of the pandemic caused by SARS-Cov-2, it is justified to urgently conduct tests with possible antiviral drugs. The high molecular weight heparin (HMWH) (heparin enriched by ultrafiltration process) proposed by this study, has a potential inhibition activity over viral replication, demonstrated by preliminary in vitro tests, carried out in a model established in partnership with the Laboratory of Clinical and Molecular Virology (LVCM) of the Institute of Biomedical Sciences of the University of São Paulo (ICB-USP). Along with the findings in the literature, such as the study carried out by Phelps, M.K. et al (2020), among others, the use of inhaled heparin presents adequate levels of safety to be used in a clinical trial. Taking into account that the dose of high molecular weight heparin (enriched by this study team) with antiviral activity in vitro is much lower than the doses currently presented in published clinical trials using inhaled UFH, we have the safety premise to carry out this study. The intentions of this study differ from what has been presented in the world literature so far, as it does not aim to induce anticoagulation, nor to effectively inhibit the formation of pulmonary fibrin, but rather, to act as an inhibitor of viral replication. Also, as characteristics of the product to be tested, this heparin (HMWH) is presented in a buffered solution free of low-sulfated low-weight molecules, which is obtained in a sterile environment through ultrafiltration of the unfractionated solution of porcine origin available in Brazil (Hemofol - Cristália) using Centriprep-10kDa® centrifuge filter (Millipore ™) used as recommended by the manufacturer. The high molecular weight heparin (HMWH) - enriched heparin - had two process patents filed, one under the description HIGH MOLECULAR WEIGHT DEFINITION HEPARINE DEVELOPMENT PROCESS, BR 102014027804-4 A2 - granted by the Instituto Nacional de Propriedade Industrial (INPI) and another with the description COMPOSITION OF HIGH MOLECULAR WEIGHT NON-FRACTIONAL HEPARINE FOR ANTIVIRAL ACTION , BR 102020 011964-8 - deposited at INPI.

Official Title
-----------------
Nebulized Enriched Heparin to Treat no Critical Patients With Sars-Cov-2 - Triple Blind Clinical Trial

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Drug: Heparin sodium
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signature and agreement to the Free Consent Form; Both sexes, of any ethnic origin, aged between 18 and 90 years; COVID-19 infected patients diagnosed by RT-PCR (reverse-transcriptase polymerase chain reaction) or with a strong suspicion of COVID-19 by clinical evaluation through compatible clinical and radiological findings; Time of disease evolution less than 10 days; Radiological diagnosis of grade 2A pneumonia, with gas exchange ratio > 200 on blood gas analysis (paO2 / pFiO2), characterizing mild hypoxemia; Indication of hospital treatment regime, provided that the period of hospitalization before inclusion is not more than 24 hours; Need for supplemental oxygen therapy (O2) less than 5L / min. Exclusion Criteria: No agreement to the terms of this study; Moderate or severe respiratory failure requiring admission to the ICU and the need for invasive mechanical ventilation or non-invasive ventilation (NIV) with positive pressure; Pregnancy or puerperium; Patients with hematological diseases, coagulation disorders, use of anticoagulants, previous heparin-induced allergy or thrombocytopenia, thrombocytopenia with a count of fewer than 50,000 platelets / mm3; COVID-19 not confirmed by RT-PCR within 72 hours of inclusion in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants allocated to Group 1 (control) will receive inhalation with 0.9% saline solution applied 4/4 hours, for 7 days. Participants allocated to Group 2 (intervention) will receive high molecular weight inhaled heparin (2,5mg / mL 0.9% SF), at a 4/4 hour dose, for 7 days.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive inhalation with 5mL 0.9% saline solution (placebo), 4/4h, during the day period (5 doses). | Drug: Placebo<br>* Nebulized inhalation of 5 mL of 0.9% saline solution, every 4 hours for 7 days, except during the nighttime (5 doses/day)<br>* Other names: Physiological solution 0.9%;|
| Active Comparator: Heparin sodium<br>Participants will receive inhalation with 5mL 0.9% saline solution + 2,5mg of high molecular weight heparin - enriched heparin, 4/4h, during the day period (5 doses). | Drug: Heparin sodium<br>* Nebulized inhalation of 5 mL of a solution containing high molecular weight heparin - enriched heparin - 2.5mg/mL and 0.9% saline solution, every 4 hours for 7 days, except during the nighttime (5 doses/day)<br>* Other names: Hepamax S BLAU;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in activated partial thromboplastin time (APTT) > 1.5 | Safety-related to the use of high molecular weight heparin inhaled in patients with SARS-COV-2 through the assessment of hemorrhagic events of any nature, alteration of the coagulogram that indicates an increase in APTT> 1.5, heparin-induced thrombocytopenia. | Immediately or up to 8 days after starting treatment | 
| Viral load in nasal swab reverse transcription polymerase chain reaction (RT-PCR). | Effectiveness related to the proposed treatment, based on the analysis of the viral load of SARS-COV-2 virus in the participants through a sequential assessment of the viral load in nasal swab RT-PCR. | Immediately or up to 8 days after starting treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants needing supplemental oxygen therapy | Worsening of respiratory parameters measured by the need for supplemental oxygen therapy at greater doses than 5L/min; | Immediately or up to 8 days after starting treatment | 
| Number of participants needing mechanical pulmonary ventilation | Worsening of respiratory parameters measured by the need of definitive airway assisted pulmonary ventilation; | Immediately or up to 8 days after starting treatment | 
| Number of hospitalization days | Worsening of clinical parameters characterized by a prolonged hospital stay; | Immediately or up to 8 days after starting treatment | 
| Number of participants that develop renal failure | Worsening of clinical parameters characterized by renal failure through measurement of urea and creatinine; | Immediately or up to 8 days after starting treatment | 
| Number of participants that develop major cardiovascular events | Worsening of clinical parameters characterized by major cardiovascular events (pulmonary embolism, acute myocardial infarction) | Immediately or up to 8 days after starting treatment | 
| Number of participants transferred to the intensive care unit (ICU) | Worsening of clinical parameters characterized by need for Intensive Care Unit (ICU) treatment; | Immediately or up to 8 days after starting treatment | 
| Number of participants presenting secondary pulmonary bacterial infections | Worsening of clinical parameters characterized by presentation of secondary pulmonary bacterial infections (pneumonia); | Immediately or up to 8 days after starting treatment | 
| Number of participants that develop deep vein thrombosis (DVT) | Worsening of clinical parameters characterized by deep vein thrombosis (DVT); | Immediately or up to 8 days after starting treatment | 
| Number of participants that develop pancreatitis | Worsening of clinical parameters characterized by pancreatitis through measurement of amylase (> 200 U/L); | Immediately or up to 8 days after starting treatment | 
| Number of participants that need corticosteroid therapy | Worsening of clinical parameters characterized by need for hydrocortisone, dexamethasone or other corticosteroids due to inflammatory pulmonary disease; | Immediately or up to 8 days after starting treatment | 
| Number of deaths among participants | Worsening of clinical parameters characterized by death; | Immediately or up to 8 days after starting treatment | 
| Number of participants with increased white blood cell count | Worsening of laboratory parameters measured by increased white blood cell count (>10.000 cells/mm³); | Immediately or up to 8 days after starting treatment | 
| Number of participants with increased C reactive protein test | Worsening of laboratory parameters measured by increase in C reactive protein test (>3.00mg/L); | Immediately or up to 8 days after starting treatment | 
| Number of participants with deterioration of arterial blood gas paO2/pFiO2 ratio | Worsening of laboratory parameters measured by alterations in arterial blood gas measured by paO2/pFiO2 < 200; | Immediately or up to 8 days after starting treatment | 
| Number of participants with altered sodium | Worsening of laboratory parameters measured by alterations in sodium (< 135mEq/L or > 145mEq/L) | Immediately or up to 8 days after starting treatment | 
| Number of participants with altered potassium | Worsening of laboratory parameters measured by alterations in potassium (< 3,5mEq/L or > 5,5mEq/L); | Immediately or up to 8 days after starting treatment | 
| Number of participants with increased pulmonary area compromised (%) | Worsening of tomographic parameters measured by the pulmonary area compromised by the infection and/or inflammation. | Immediately or up to 8 days after starting treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, Heparin, Antiviral Agents, Blood Coagulation, Clinical Protocols