Clinical trial NCT04363541: Local Thermotherapy for Patients With Mild-to-moderate COVID-19
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: COVID-19
Thermotherapy
Keywords: SARS-CoV-2
Hyperthermia
Lead sponsor: Instituto Nacional de Perinatologia
Sponsor class: OTHER_GOV
Collaborators: name: Direccion General de Calidad y Educacion en Salud
name: Instituto Mexicano del Seguro Social
name: Hospital Regional de Alta Especialidad Juan Graham Tabasco
name: Hospital Dr. Ángel Leaño
name: National Polytechnic Institute, Mexico
name: Universidad Juárez Autónoma de Tabasco
First posted: 2020-04-27
Enrollment: 274
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression of disease (composite outcome)
timeFrame: 28 days
Secondary outcomes:
measure: Mortality at day 15
timeFrame: 15 days
measure: Mortality at day 28
timeFrame: 28 days
measure: Time to progression to severe COVID-19
timeFrame: Up to 33 days
measure: Time to progression to critical COVID-19
timeFrame: Up to 33 days
measure: Hospitalization time
timeFrame: Up to 33 days
measure: Percentage of participants at each clinical status in the Ordinal Scale at Day 15
timeFrame: 15 days
measure: Percentage of participants at each clinical status in the Ordinal Scale at Day 28
timeFrame: 28 days
measure: Time (days) to last requiring supplementary oxygen according to modality
timeFrame: 28 days
measure: Change in National Early Warning Score 2 (NEWS-2) with respect to baseline
timeFrame: Days 1, 5, 15, and 28
measure: Proportion of patients requiring invasive mechanical ventilation
timeFrame: 28 days
measure: Proportion of patients requiring admission to intensive care unit (ICU)
timeFrame: 28 days
measure: Time to requiring invasive mechanical ventilation
timeFrame: Up to 33 days
measure: Time to requiring admission to intensive care unit (ICU)
timeFrame: Up to 33 days
measure: Proportion of patients with adverse events according to outcome
timeFrame: 28 days
measure: Proportion of patients with adverse events according to severity
timeFrame: 28 days
measure: Proportion of patients with adverse events according to causality
timeFrame: 28 days
measure: Proportion of patients tolerating the intervention (no comparison)
timeFrame: 5 days
Other outcomes:
measure: Comparison of laboratory parameters with respect to baseline (units: 10^3/microliter)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (units: milligrams/deciliter)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (units: grams/deciliter)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (units: milligrams/liter)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (units: nanograms/milliliter)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (units: International Units/liter)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (ratio: no units)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (units: percent)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (units: seconds)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of laboratory parameters with respect to baseline (units: millimeters/hour)
timeFrame: Days 1, 5, 15, and 28
measure: Comparison of cytokine levels with respect to baseline
timeFrame: Days 1, 5, 15, and 28
Locations:
city: Guadalajara
country: Mexico
facility: Hospital Dr. Ángel Leaño
state: Jalisco
city: Villahermosa
country: Mexico
facility: Hospital Regional de Alta Especialidad "Dr. Juan Graham Casasus"
state: Tabasco
city: Mexico City
country: Mexico
facility: Unidad Temporal Movil COVID-19 Autódromo Hermanos Rodríguez IMSS
Study officials:
affiliation: Instituto Nacional de Perinatología
name: Norma del Carmen Galindo Sevilla, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Cardiología
name: Javier Mancilla-Galindo, MBBS
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.