Local Thermotherapy for Patients With Mild-to-moderate COVID-19

Study Overview
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Brief Summary
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The etiological agent of the current pandemic is a (+)ssRNA virus. SARS-CoV-2 is infecting thousands of people in the world with a fatality rate that varies from 0.1 to 5% in affected countries, thereby causing enormous economic losses. Few antibiotics have shown any efficacy in their combat, but have not yet proven adequate to stop the spread of the disease, nor are there any approved vaccines at the moment. From experiments in plants ongoing infections by RNA viruses, using thermotherapy, which is the application of heat at a temperature between 35-43 °C, the investigators know that raising the temperature affects the transcription of viral proteins due to the formation of small RNA molecules that interrupt the replication process by grouping in specific regions of the RNA molecule, preventing and inhibiting transcription. These small molecules are called small interfering RNAs (siRNAs). This feature has been used through thermotherapy in humans to combat the rapid replication of cells (i.e. cancer cells), attack cells infected by RNA viruses, and in the treatment of some parasitic infections.There are various commercially available devices for thermotherapy use in humans; they are mainly being used to ease muscle pain. They work by increasing the temperature in the range recommended for thermotherapy in humans 39-43 ° C. Therefore, the investigators consider this treatment modality can be used to aid in the elimination of SARS-CoV-2 from the human body, decreasing viral load, which could allow the immune system time for its control and elimination.

Detailed Description
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Considering the nature of the causative agent of COVID-19, a (+)ssRNA virus, the investigators propose the use of thermotherapy as a modality for viral containment, thereby preventing the progression of the infection to severe cases. The investigators consider applying the intervention with thermotherapy mainly as an adjuvant therapy in high-risk patients. The most accessible thermotherapy delivery method the investigators have identified is the use of an electric chest pad for its wide and known clinical use, including its recommended use for patients with arthritis. The intensity of temperature delivered by the electric cushion should be placed on the first level (lowest level), to avoid discomfort to the patient. The electric cushion provides a continuous hour of regulated heat, with enough penetration to raise the external temperature of the area to 40-42 ° C, a temperature range at which facilitation of elimination of the virus is expected.

Official Title
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A Multicenter, Open-label, Parallel-group, Randomized, Adaptive Trial to Evaluate Local Thermotherapy in Patients With Mild-to-moderate COVID-19, to Prevent Disease Progression

Conditions
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COVID-19, Thermotherapy

Intervention / Treatment
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* Device: Electric pad for human external pain therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with symptoms of COVID-19 (fever, headache, cough, sore throat, myalgias, arthralgias, shortness of breath, anosmia, fatigue, diarrhea, vomit, or conjunctivitis) meeting criteria for mild or moderate COVID-19 according to the following criteria: Mild COVID-19: With or without mild pneumonia. Peripheral oxygen arterial saturation (SaO2) greater than or equal to 94% (90% in Mexico City and Guadalajara) at room air. Does not meet criteria of moderate, severe, or critical COVID-19. Moderate COVID-19: Patient with pneumonia and risk factors for disease progression; meeting all the following: Shortness of breath, peripheral oxygen arterial saturation (SaO2) greater than or equal to 94% (90% in Mexico City and Guadalajara) with a maximum 3 L/min of supplementary oxygen, does not meet criteria for severe, or critical COVID-19. Patient with less than or equal to 5 days from symptom onset Participant understands the intervention and procedures and accepts randomization. Exclusion Criteria: Suspected or confirmed pregnancy at evaluation Severe decompensation of any of the patient's underlying diseases Previous diagnosis of COVID-19 with complete resolution of symptoms for at least 2 days. Patients meeting criteria for severe or critical COVID-19 at evaluation: Severe COVID-19 - Patient with ≥1 of the following: tachypnea (≥30 breaths per minute), peripheral oxygen arterial saturation (SaO2) less than or equal to 93% (89% in Mexico City and Guadalajara) with a maximum 3 L/min of supplementary oxygen (patients requiring ≥4 L/min will be considered to have progressed to severe COVID-19), or PaO2/FiO2 ratio <300. Critical COVID-19 - Patient with ARDS, shock, multiorgan failure, or any other condition requiring admission to an intensive care unit. Elimination Criteria: Participant retires consent to participate in the study Patient requiring ≥4 L/min of supplementary oxygen in the 24 hours of hospitalization (in the case that randomization occurred in the first 24 hours of hospitalization) Two negative tests against SARS-CoV-2 (a sequential diagnostic strategy will be implemented to reduce losses due to false negative tests). Patient that do not tolerate thermotherapy and requests to stop receiving the intervention. Transfer to another medical unit in the first 5 days of inclusion in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The application of an electric chest pad. The use of an electric cushion was chosen because it is designed to be used in human thermal therapy. The electric cushion provides continuous 90 minutes of regulated heat, with enough penetration to raise the external temperature of the area to 40-42 ° C. It is a therapy designed to detain disease progression. It is not expected to have an effect on concomitant microorganisms such as bacteria or opportunists such as Candida albicans, so that when the concomitant infection is suspected, the antibiotic of choice should be given or continued, depending on the nature of the infection.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Thermotherapy<br>Electric heat pad applied in the thorax for 90 minutes, twice daily, for 5 days. + Usual in-hospital care | Device: Electric pad for human external pain therapy<br>* An electric pad for local heat production will be put on the back of the patient for two hours<br>|
| No Intervention: Control<br>Usual in-hospital care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of disease (composite outcome) | Progression to any of the following: Severe COVID-19 - Patient with ≥1 of the following: tachypnea (≥30 breaths per minute), peripheral oxygen arterial saturation (SaO2) less than or equal to 93% (89% in Mexico City and Guadalajara) with a maximum 3 L/min of supplementary oxygen (patients requiring ≥4 L/min will be considered to have progressed to severe COVID-19), or PaO2/FiO2 ratio <300. Critical COVID-19 - Patient with ARDS, shock, multiorgan failure, or any other condition requiring admission to an intensive care unit. Death | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality at day 15 | Proportion of participants deceased by day 15 after enrollment | 15 days | 
| Mortality at day 28 | Proportion of participants deceased by day 28 after enrollment | 28 days | 
| Time to progression to severe COVID-19 | Days from symptom onset to progression to severe COVID-19 | Up to 33 days | 
| Time to progression to critical COVID-19 | Days from symptom onset to progression to critical COVID-19 | Up to 33 days | 
| Hospitalization time | In-hospital stay in days | Up to 33 days | 
| Percentage of participants at each clinical status in the Ordinal Scale at Day 15 | Ordinal scale of 7 categories: 1) Not hospitalized, without limitations on daily activities; 2) Not hospitalized, with limitations on daily activities; 3) Hospitalized, not requiring supplementary oxygen; 4) Hospitalized, requiring low-flow supplementary oxygen; 5) Hospitalized, requiring supplementary oxygen with high-flow nasal cannula or non-invasive ventilation; 6) Hospitalized, under invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 7) Death | 15 days | 
| Percentage of participants at each clinical status in the Ordinal Scale at Day 28 | Ordinal scale of 7 categories: 1) Not hospitalized, without limitations on daily activities; 2) Not hospitalized, with limitations on daily activities; 3) Hospitalized, not requiring supplementary oxygen; 4) Hospitalized, requiring low-flow supplementary oxygen; 5) Hospitalized, requiring supplementary oxygen with high-flow nasal cannula or non-invasive ventilation; 6) Hospitalized, under invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 7) Death | 28 days | 
| Time (days) to last requiring supplementary oxygen according to modality | Modalities: 1) Simple nasal cannula or face mask; 2) Face mask with reservoir; 3) High-flow nasal cannula; 4) Non-invasive mechanical ventilation; 5) Invasive mechanical ventilation | 28 days | 
| Change in National Early Warning Score 2 (NEWS-2) with respect to baseline | Change in the National Early Warning Score 2 (NEWS-2) with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. This score evaluates 7 parameters (respiratory rate, peripheral arterial oxygen saturation, supplementary oxygen requirements, systolic arterial blood pressure, heart rate, consciousness, and body temperature). Assigned values for every parameter may range from 0 to 3 points, except for supplementary oxygen for which possible values are 0 (not requiring supplementary oxygen) and 2 (requiring supplementary oxygen). The total sum of points for this score may range from 0 to 20 points. Higher scores reflect increasing clinical deterioration. | Days 1, 5, 15, and 28 | 
| Proportion of patients requiring invasive mechanical ventilation | Proportion of patients requiring invasive mechanical ventilation during the entire follow-up period | 28 days | 
| Proportion of patients requiring admission to intensive care unit (ICU) | Proportion of patients requiring admission to intensive care unit (ICU) during the entire follow-up period | 28 days | 
| Time to requiring invasive mechanical ventilation | Days from symptom onset to progression to requiring invasive mechanical ventilation | Up to 33 days | 
| Time to requiring admission to intensive care unit (ICU) | Days from symptom onset to requiring admission to intensive care unit (ICU) | Up to 33 days | 
| Proportion of patients with adverse events according to outcome | Severe: Causes death of the patient, puts the patient's life at risk in the moment of occurrence, requires hospitalization or prolongs hospitalization, causes persistent or significant disability. Non-severe adverse events: Do not meet the previously outlined criteria. | 28 days | 
| Proportion of patients with adverse events according to severity | Mild (Grade 1): Present with easily tolerated signs and symptoms, do not need specific treatment, do not prolong hospitalization, nor require suspension of the intervention Moderate (Grade 2): Interfere with daily activities (school or work), do not directly threaten life, require specific pharmacological treatment, and do not necessarily require suspension of the intervention. Severe (Grades 3, 4, and 5): Interfere with daily activities (school and work), require pharmacological treatment and suspension of the intervention. | 28 days | 
| Proportion of patients with adverse events according to causality | Certain Probable Possible Uncertain Unclassifiable | 28 days | 
| Proportion of patients tolerating the intervention (no comparison) | Proportion of patients tolerating the intervention (number of sessions and minutes per session). | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, Hyperthermia