Efficacy and Safety of Ethanol Inhalation on COVID-19 Treatment (a Clinical Trial Study)
Condition: Clinical Infection; Outcome; Morality
MeSH terms: COVID-19; Communicable Diseases; Infections
Study type: Interventional
Phase: Phase 3

Summary: 
      Cytokine storm is the cause of many deaths in COVID -19. The antiviral in-vitro effects of
      ethanol with solving the fat layer and destroying the glycoprotein of coronavirus have
      already been established. Proven antiviral effects of ethyl alcohol on extracellular surfaces
      have been demonstrated by researchers. Immunological studies have shown that acute
      administration of ethanol can have immunomodulatory effects on innate immunity system
      mediated by TNFamRNA protein and mitogen-activated protein kinas and reduce cytokine storm by
      reducing inflammatory factors such as -TLR, TLR, TL-9, interleukin-6 and TL9. It also helps
      with the chemotaxis of bronchoalveolar macrophages. Other demonstrated effects of ethanol are
      including: inhibition of virus replication by inhibition of RNA-dependent polymerase, the
      bronchial dilation by relaxing their involuntary smooth muscles, sedating and relaxation of
      the participant, muscular analgesic effects.

      Ethanol administration has previously been reported for the treatment of methanol poisoning,
      fat embolism, prevention of preterm labor, pre-eclampsia, and pulmonary edema. The
      histological safety of inhalation ethanol therapy in the lungs and respiratory tracts of
      rabbits has been shown by Anna Castro-Balado et al. Ethanol is approved by the Food and Drug
      Administration. Given these effects of ethanol on virus wall destruction, inhibition of
      proliferation, and inhibition of immune hyperactivity, the question now is, "Can ethanol
      inhalation therapy be effective in controlling COVID-19?" There is no a prior knowledge of
      the inhalation ethanol therapy in COVID-19. This idea was first suggested and published one
      month after COVID-19 pandemic in Iran (February 2020). To find the answer, a clinical trial
      was conducted to evaluate the effectiveness of ethanol therapy on clinical state and
      prognosis of participants. The study was approved by the Medical University of Isfahan,
      research and ethics committees and is registered at https://irct.ir/trial/58201.
    

Detailed description: 
      Study Design and Oversight This study is a randomized triple-blind clinical trial with a
      control group and a parallel design that was conducted at the Isabn-e-Maryam hospital in
      Medical university of Isfhan, Iran in September 2021. participants randomly assigned in a 1:1
      ratio. The study was originally intended for participants admitted to the hospital, but due
      to amending the country's policy of setting up respiratory clinics in hospitals and
      prescribing remdesivre and dexamethasone to participants with moderate COVID-19, the study
      was conducted in this center. Physicians of hospitalized participants were informed about the
      participant's referral to the respiratory center and this study.

      Participants The study population consisted of positive SARS-CoV-2-PCR test. Participants had
      moderate COVID-19 pneumonia that was referred to the Respiratory Clinic of the Hospital.
      Inclusion criteria were: agreeing to implement the plan in the form of informed consent, age
      over 12 years, not pregnant, no history of asthma, alcoholism or epilepsy, no
      contraindications to ethanol. Exclusion criteria were: intolerance to inhaled ethanol,
      hypersensitivity or allergies to ethanol, use of drugs that interact with ethanol, and
      partial or incomplete treatment. Ethanol patch skin test was used to detect possible allergy
      to alcohol. In this experiment, a drop of ethanol was placed on a gas pad and attached to the
      participant's arm. After about seven minutes, symptoms such as redness, swelling or itching
      of the skin will be checked. These symptoms indicated the possibility of allergy or
      intolerance to alcohol.

      Intervention Both control and intervention groups were enrolled with standard treatments
      based on the national clinical guidelines of Iran. The national standard treatment was
      intramuscular dexamethasone, 8mg/day (5 days) and 200 mg of remdesivir intravenously on day
      1, followed by 100 mg of remdesivir once daily for 4 subsequent days, infused over 30 to 60
      minutes. In addition to standard treatment, after obtaining consent, distilled water spray
      (placebo) was added in the control group and 35% ethanol spray was added in the intervention
      group. Two sets of 100 ml spray were provided. All of them were instructed to spray three
      times every 6 hours from a distance of 20-30 cm from their face, while wearing a mask and
      closing their eyes, and take a deep breath as they feel nebulized liquid droplets in their
      nose, mouth, throat, larynx and lungs. Investigators emphasized participants that this
      protocol must be repeated every six hours to 7 days, depending on the persistence of
      symptoms. How to use it was first taught by investigators and after ensuring the
      participant's mastery, it was given to the participants to continue at home. In all referrals
      and follow-ups, the status of spray use was questioned and participants who did not use it or
      used it irregularly were excluded from the study.

      Clinical and Laboratory Monitoring The required information was taken from the participants'
      records. The data collection sheet had two sections. In the first part were demographic
      information and underlying diseases. In the second part, clinical information of research
      cases was written. Data collection checklist was completed by a trained nurse according to
      clinical symptoms, para-clinical results, clinical examinations and participant's file
      contents. Data related to research variables including blood oxygen saturation in pulse
      oximetry, level of inflammatory factor (CRP), need for adjunctive treatment or readmission in
      hospital and clinical symptoms in both groups were collected until discharge. The Global
      Symptomatic Score (GSS) was achieved by calculation of cumulative scores of clinical signs
      and symptoms including fever, headache, body aches, sore throat, runny nose, chills, cough,
      shortness of breath, anorexia, loss of smell and loss of taste. Any possible side effects
      were treated in both groups and reported if present. Participants' oxygenation status was
      monitored and recorded daily with a pulse oximeter. The pulse oximeter was fixed, and at the
      time of measurement, the participant was breathing room air without receiving supplemental
      oxygen.

      A modified 7-point ordinal scale was used to assess the clinical condition on day 14 of
      treatment period related to research. This scale has 7 indexes:

      1- Death 2. Hospitalized, on invasive mechanical ventilation 3. Hospitalized, on non-invasive
      ventilation or high flow oxygen devices 4. Hospitalized, requiring low flow supplemental
      oxygen 5. Hospitalized, for whatever reason, - requiring ongoing medical care (Covid 19
      related or otherwise), requiring supplemental oxygen at home.

      6. Continue signs or symptoms of Covid 19 without requiring supplemental oxygen - no longer
      requires ongoing medical care 7. Complete recovery The corrections made to these indicators
      were due to the limitations that occurred at the same time as the peak of the disease in Iran
      with the implementation of this study, and participants who needed to be hospitalized were
      followed up on an outpatient basis in the respiratory clinic. The need for hospitalization in
      the intensive care unit, drug side effects, clinical symptoms and mortality of the research
      samples were monitored in two groups. The final follow-up was performed on the 14th day of
      the disease through telephone calls and review of participants' records and hospital
      information system documents.

      Side effects were recorded after the informed consent was signed and were graded based on
      version 5.0 of the Common Terminology Criteria for Adverse Event. The required comparisons
      were performed at 0, 3, 7 and 14 days after the intervention.

      Sampling Sampling was performed by an easy random method. Computerized Random number table
      was used for random assignment. One researcher determined the sequence of random allocations
      without coordination with other investigators. This person was different from the nurses who
      assigned participants to the interventions. This person filled the sprays (nebulizer) one by
      one with 100ml of diluted distilled water or ethanol-35% and labeled them with the numbers
      coming out of the number container one by one. Investigator assigned a questionnaire and
      consent form for each spray and wrote the number on the spray in the questionnaire. Each
      spray was delivered to one of the participants in the study and his / her family or companion
      was instructed on how to use it. Blinding was performed at the level of participants,
      clinicians, nurses and analysts.

      Statistical Analysis Based on the "treatment-on" or "protocol per" strategy, analysis was
      limited to participants who, according to the study protocol and inclusion criteria, received
      full interventions and informed the outcomes. Quantitative and qualitative variables were
      reported in the form of descriptive statistics including mean standard deviation and number
      (%), respectively. Quantitative variables with normal and abnormal distributions were
      compared between groups using independent t-test and Mann-Whitney test, respectively. In
      addition, qualitative variables were compared between the two groups using Chi-square test.

      Comparisons between SPO2 values and clinical symptom scores on days 1, 3, 7 and 14 were
      performed using a mixed model. Mean changes of baseline values were measured by repeated
      measures analysis. The sphericity hypothesis was rejected with the help of Mauchly's
      Statistics and Geisser-Greenhouse correction was used for this purpose.

      The proportion of participants who needed additional medical care after 14 days was tested in
      two groups using χ2 test.

      All statistical analyzes were performed using SPSS software version 22 (SPSS Inc., Chicago,
      IL, USA) and P <0.05 was considered significant.
    

Intervention name(s): Ethanol; Water Distilled
Intervention type(s): Drug; Drug
Intervention description(s): Inhalation of 35%-ethanol spray; Inhalation of water distilled spray
Other intervention name(s): Ethyl Alcohol; Water for Injection,Sterile,30Ml
Intervention MeSH terms: Ethanol
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Based on the "treatment-on" or "protocol per" strategy, analysis was limited to participants who, according to the study protocol and inclusion criteria, received full interventions and informed the outcomes.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: COVID-19; Ethanol; Inhalation; Nebulizer