Local Thermotherapy for Patients With Mild-to-moderate COVID-19 (TherMoCoV)

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

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.

Study Overview

• Status: Unknown
• Conditions: COVID-19; Thermotherapy
• Intervention / Treatment: Device: Electric pad for human external pain therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 274
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Norma del Carmen Galindo Sevilla, PhD; Phone Number: +525539968217; Email: ngalindosevilla@gmail.com
• Study Contact Backup: Name: Javier Mancilla-Galindo, MBBS; Email: javimangal@gmail.com

Study Locations

• Mexico
  • Mexico City, Mexico, 08400
    • Recruiting
    • Unidad Temporal Movil COVID-19 Autódromo Hermanos Rodríguez IMSS
    • Contact: Javier Michael García Acosta, MD; Email: michxal1@gmail.com
    • Contact: Yanira Saralee Nava Serrano, MD, MSc; Email: male.sevilla.25@gmail.com
    • Principal Investigator: Javier Michael García Acosta, MD
    • Sub-Investigator: Yanira Saralee Nava Serrano, MD, MSc
    • Sub-Investigator: Óscar Santiago Martínez, MSc
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 45200
      • Recruiting
      • Hospital Dr. Ángel Leaño
      • Contact: Juan Pablo Cuellar Robledo, MD
      • Contact: Alfonso Gutiérrez Padilla, MD
      • Principal Investigator: Juan Pablo Cuellar Robledo, MD
      • Sub-Investigator: Alfonso Gutiérrez Padilla, MD
  • Tabasco
    • Villahermosa, Tabasco, Mexico, 86126
      • Recruiting
      • Hospital Regional de Alta Especialidad "Dr. Juan Graham Casasus"
      • Contact: Julio César Robledo Pascual, MD; Email: jrobledopascual@yahoo.com
      • Contact: Víctor Manuel Narváez Osorio, MD; Email: vnarvaezosorio@hotmail.com
      • Principal Investigator: Julio César Robledo Pascual, MD
      • Sub-Investigator: Víctor Manuel Narváez Osorio, MD
      • Sub-Investigator: Iván Daniel Narváez Morales, MBBS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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:

   1. 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.
   2. 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.
2. Patient with less than or equal to 5 days from symptom onset
3. Participant understands the intervention and procedures and accepts randomization.

Exclusion Criteria:

1. Suspected or confirmed pregnancy at evaluation
2. Severe decompensation of any of the patient's underlying diseases
3. Previous diagnosis of COVID-19 with complete resolution of symptoms for at least 2 days.

4. Patients meeting criteria for severe or critical COVID-19 at evaluation:

   1. 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.
   2. Critical COVID-19 - Patient with ARDS, shock, multiorgan failure, or any other condition requiring admission to an intensive care unit.

Elimination Criteria:

1. Participant retires consent to participate in the study
2. 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)
3. Two negative tests against SARS-CoV-2 (a sequential diagnostic strategy will be implemented to reduce losses due to false negative tests).
4. Patient that do not tolerate thermotherapy and requests to stop receiving the intervention.
5. Transfer to another medical unit in the first 5 days of inclusion in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Thermotherapy; 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; An electric pad for local heat production will be put on the back of the patient for two hours
No Intervention: Control; Usual in-hospital care

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of laboratory parameters with respect to baseline (units: 10^3/microliter)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: total leucocytes, neutrophils, lymphocytes, monocytes, and platelets	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (units: milligrams/deciliter)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: glucose, urea, blood urea nitrogen, creatinine, total bilirubin, direct bilirubin, and indirect bilirubin.	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (units: grams/deciliter)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: hemoglobin, and albumin	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (units: milligrams/liter)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: C-reactive protein	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (units: nanograms/milliliter)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: D-dimer, and procalcitonin	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (units: International Units/liter)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and creatinine phosphokinase (CPK).	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (ratio: no units)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: neutrophil-to-lymphocyte ratio, and international normalized ratio (INR).	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (units: percent)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: hematocrit	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (units: seconds)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: prothrombin time (PT), and partial thromboplastin time (PTT)	Days 1, 5, 15, and 28
Comparison of laboratory parameters with respect to baseline (units: millimeters/hour)	Change in laboratory parameters with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized. Parameters to be included are: erythrocyte sedimentation rate (ESR)	Days 1, 5, 15, and 28
Comparison of cytokine levels with respect to baseline	Change in cytokine levels with respect to baseline (Day 1), measured at day 5 for all patients, and days 15 & 28 only for patients that remain hospitalized.	Days 1, 5, 15, and 28

Collaborators and Investigators

• Sponsor: Instituto Nacional de Perinatologia
• Collaborators: Instituto Mexicano del Seguro Social; National Polytechnic Institute, Mexico; Universidad Juárez Autónoma de Tabasco; Direccion General de Calidad y Educacion en Salud; Hospital Regional de Alta Especialidad Juan Graham Tabasco; Hospital Dr. Ángel Leaño
• Investigators: Principal Investigator: Norma del Carmen Galindo Sevilla, PhD, Instituto Nacional de Perinatología; Study Director: Javier Mancilla-Galindo, MBBS, Instituto Nacional de Cardiologia

Publications and helpful links

General Publications

• Liu J, Zhang X, Zhang F, Hong N, Wang G, Wang A, Wang L. Identification and characterization of microRNAs from in vitro-grown pear shoots infected with Apple stem grooving virus in response to high temperature using small RNA sequencing. BMC Genomics. 2015 Nov 16;16:945. doi: 10.1186/s12864-015-2126-8.
• Wang MR, Cui ZH, Li JW, Hao XY, Zhao L, Wang QC. In vitro thermotherapy-based methods for plant virus eradication. Plant Methods. 2018 Oct 6;14:87. doi: 10.1186/s13007-018-0355-y. eCollection 2018.
• Zhu LL, Gao XH, Qi R, Hong Y, Li X, Wang X, McHepange UO, Zhang L, Wei H, Chen HD. Local hyperthermia could induce antiviral activity by endogenous interferon-dependent pathway in condyloma acuminata. Antiviral Res. 2010 Nov;88(2):187-92. doi: 10.1016/j.antiviral.2010.08.012. Epub 2010 Aug 24.

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2020
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): June 1, 2022

Study Registration Dates

• First Submitted: April 23, 2020
• First Submitted That Met QC Criteria: April 23, 2020
• First Posted (Actual): April 27, 2020

Study Record Updates

• Last Update Posted (Actual): November 5, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Hyperthermia
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: U1111-1250-7416

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes