Clinical trial NCT04743011: Enriched Heparin Anti COVID-19 Trial
Official title: Nebulized Enriched Heparin to Treat no Critical Patients With Sars-Cov-2 - Triple Blind Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Covid19
Keywords: COVID-19
Heparin
Antiviral Agents
Blood Coagulation
Clinical Protocols
Lead sponsor: UPECLIN HC FM Botucatu Unesp
Sponsor class: OTHER
First posted: 2021-02-08
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change in Activated Partial Thromboplastin Time (APTT) > 1.5 Seconds
timeFrame: Immediately or up to 8 days after starting treatment
measure: Number of Participants With a Negative Viral Load in Nasal Swab Reverse Transcription Polymerase Chain Reaction (RT-PCR).
timeFrame: Immediately or up to 8 days after starting treatment
Secondary outcomes:
measure: Number of Participants That Develop Renal Failure
timeFrame: Immediately or up to 8 days after starting treatment
measure: Number of Participants That Develop Major Cardiovascular Events
timeFrame: Immediately or up to 8 days after starting treatment
measure: Number of Participants That Develop Deep Vein Thrombosis (DVT)
timeFrame: Immediately or up to 8 days after starting treatment
measure: Number of Participants That Develop Pancreatitis
timeFrame: Immediately or up to 8 days after starting treatment
measure: Number of Deaths Among Participants
timeFrame: Immediately or up to 8 days after starting treatment
measure: Number of Participants With Increased C Reactive Protein Test
timeFrame: Immediately or up to 8 days after starting treatment
measure: Number of Participants With Deterioration of Arterial Blood Gas paO2/pFiO2 Ratio
timeFrame: Immediately or up to 8 days after starting treatment
measure: Number of Participants With Increased Pulmonary Area Compromised (%)
timeFrame: Immediately or up to 8 days after starting treatment
Other outcomes:
Locations:
city: Botucatu
country: Brazil
facility: Hospital das Clinicas de Boucatu
state: Sao Paulo
city: Botucatu
country: Brazil
facility: School of Medicine at Botucatu- Paulista State University- UNESP, São Paulo, Brazil
state: SP
Study officials:
affiliation: São Paulo State University (Unesp)
name: Matheus Bertanha, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Phelps MK, Olson LM, Patel MAVB, Thompson MJ, Murphy CV. Nebulized Heparin for Adult Patients With Smoke Inhalation Injury: A Review of the Literature. J Pharm Technol. 2020 Aug;36(4):130-140. doi: 10.1177/8755122520925774. Epub 2020 Jun 1.