Enriched Heparin Anti COVID-19 Trial

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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04743011

Acronym

EnHanCed

Enrollment

Registered

2021-02-08

Start date

2021-06-01

Completion date

2021-12-31

Last updated

2024-10-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Covid19

Keywords

COVID-19, Heparin, Antiviral Agents, Blood Coagulation, Clinical Protocols

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.

Interventions

DRUGHeparin sodium

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)

DRUGPlacebo

Nebulized inhalation of 5 mL of 0.9% saline solution, every 4 hours for 7 days, except during the nighttime (5 doses/day)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

The clinical trial will be triple-blind. Participants, researchers, and the data/statistical analysis team will not have access to the research data. Only one member of the team will produce the test product and assist a external physician (not part of the research team), with the adverse events that may occur with the participants during the execution of the research.

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.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in Activated Partial Thromboplastin Time (APTT) > 1.5 Seconds	Immediately or up to 8 days after starting treatment	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 APTT ratio \> 1.5 or heparin-induced thrombocytopenia. In Brazilian standards, the APTT is measured in seconds and compared to a laboratory control for a ratio, which is used as a measurement.
Number of Participants With a Negative Viral Load in Nasal Swab Reverse Transcription Polymerase Chain Reaction (RT-PCR).	Immediately or up to 8 days after starting treatment	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. The measurement consists in patients that tested negative for any viral load at the end of the treatment.

Secondary

Measure	Time frame	Description
Number of Participants That Develop Deep Vein Thrombosis (DVT)	Immediately or up to 8 days after starting treatment	Worsening of clinical parameters characterized by deep vein thrombosis (DVT);
Number of Participants That Develop Pancreatitis	Immediately or up to 8 days after starting treatment	Worsening of clinical parameters characterized by pancreatitis through measurement of amylase (\> 200 U/L);
Number of Deaths Among Participants	Immediately or up to 8 days after starting treatment	Worsening of clinical parameters characterized by death;
Number of Participants That Develop Renal Failure	Immediately or up to 8 days after starting treatment	Worsening of clinical parameters characterized by renal failure through measurement of urea and creatinine;
Number of Participants With Deterioration of Arterial Blood Gas paO2/pFiO2 Ratio	Immediately or up to 8 days after starting treatment	Worsening of laboratory parameters measured by alterations in arterial blood gas measured by paO2/pFiO2 \< 200;
Number of Participants With Increased Pulmonary Area Compromised (%)	Immediately or up to 8 days after starting treatment	Worsening of tomographic parameters measured by the pulmonary area compromised by the infection and/or inflammation.
Number of Participants With Increased C Reactive Protein Test	Immediately or up to 8 days after starting treatment	Worsening of laboratory parameters measured by increase in C reactive protein test (\>3.00mg/L);
Number of Participants That Develop Major Cardiovascular Events	Immediately or up to 8 days after starting treatment	Worsening of clinical parameters characterized by major cardiovascular events (pulmonary embolism, acute myocardial infarction)

Countries

Brazil

Participant flow

Participants by arm

Arm	Count
Placebo Participants will receive inhalation with 5mL 0.9% saline solution (placebo), 4/4h, during the day period (5 doses). Placebo: Nebulized inhalation of 5 mL of 0.9% saline solution, every 4 hours for 7 days, except during the nighttime (5 doses/day)	14
Heparin Sodium 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). Heparin sodium: 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)	13
Total	27

Baseline characteristics

Characteristic	Placebo	Heparin Sodium	Total
Age, Continuous	52 years	53 years	53 years
Alcoholism	0 Participants	2 Participants	2 Participants
Anxiety or Depression Disorders	2 Participants	0 Participants	2 Participants
Autoimmune Disease	0 Participants	1 Participants	1 Participants
Body Mass Index	33 kg/m²	29.4 kg/m²	31.3 kg/m²
Coronary Disease	3 Participants	1 Participants	4 Participants
Dyslipidemia	6 Participants	9 Participants	15 Participants
Height	168 centimeters	162 centimeters	165 centimeters
Hypertension	10 Participants	5 Participants	15 Participants
Hypothyroidism	0 Participants	2 Participants	2 Participants
Previous Cancer	0 Participants	0 Participants	0 Participants
Previous Stroke	1 Participants	1 Participants	2 Participants
Previous Tabagism (Ceased)	2 Participants	4 Participants	6 Participants
Previous Transplantation or Immunosuppression	3 Participants	3 Participants	6 Participants
Pulmonary Emphysema or Asthma	2 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized Black	2 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized White	12 Participants	13 Participants	25 Participants
Sedentarism	12 Participants	10 Participants	22 Participants
Sex: Female, Male Female	6 Participants	8 Participants	14 Participants
Sex: Female, Male Male	8 Participants	5 Participants	13 Participants
Tabagism	2 Participants	1 Participants	3 Participants
Weight	92 kilograms	79 kilograms	85 kilograms

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 14	0 / 13
other Total, other adverse events	0 / 14	0 / 13
serious Total, serious adverse events	0 / 14	0 / 13

Outcome results

Primary

Change in Activated Partial Thromboplastin Time (APTT) > 1.5 Seconds

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 APTT ratio \> 1.5 or heparin-induced thrombocytopenia. In Brazilian standards, the APTT is measured in seconds and compared to a laboratory control for a ratio, which is used as a measurement.