Eucalyptus Oil as Adjuvant Therapy for Coronavirus Disease 19 (COVID-19)

Eucalyptus Oil as Adjuvant Therapy for Coronavirus Disease 19 (COVID-19), a Randomized Open-label Clinical Trial

Background :

Based on several clinical trials, eucalyptus oil can suppress edema formation and reduce inflammation, where the effect of 1,8-cineole is due to the inhibition of cytokine secretion by T lymphocytes. This but not limited to the reduction of interleukin (IL) of IL-4, IL-5, and IL-10 in nasal lavage fluids and levels of IL- 1β, IL-6, Tumor Necrosis Factor-α (TNF-α), and Interferon-γ (IFN-γ) in lung tissue of mice infected with influenza virus. Hence the researchers assume that Eucalyptus may possess benefits in COVID-19 as adjuvant therapy.

Objectives :

The primary objective of this study is to evaluate the efficacy of Eucalyptus oil as adjuvant therapy in mild-moderate COVID-19 patients.

Hypothesis :

Eucalyptus oil may reduce the inflammatory cytokines which eventually improves clinical symptoms

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Eucalyptus Oil; Drug: Standard COVID medication

Detailed Description

Detailed Objectives :

1. To assess the safety of Eucalyptus oil as an adjuvant to the standard of care in treating patients with mild to moderate COVID-19 symptoms.
2. To document the effect of Eucalyptus oil on clinical symptoms improvement, including cough, anosmia, and sore throat.
3. To assess the effect of Eucalyptus oil on viral load indirectly reflected by the Real Time-Polymerase Chain Reaction/RT-PCR cycle threshold (CT)
4. To assess the effect of Eucalyptus oil on NLR, Interleukin-6, Interleukin-10, and Tumor Growth Factor-β (TGF-β) as inflammatory marker
5. To assess the effect of Eucalyptus oil on immunoglobulin (Ig) M and G in patient's serum

Target population:

Patients with mild-moderate COVID-19

Setting:

Hospital and outpatient care

Intervention:

External use of Eucalyptus oil

Subject Recruitment and Screening :

1. A written, signed, and dated (ICF) consent form will be obtained from the patient before the study's inclusion. Assessment and records of patient's clinical report forms including demographic data, comorbidities and concurrent medications, symptoms experienced by the patient, body weight, height of the body, body mass index, vital signs, and fingertip oxygen saturation.
2. Baseline laboratory tests including complete blood count (CBC), neutrophil-lymphocyte ratio (NLR), liver (alanine aminotransferase (ALT), aspartate aminotransferase (AST), kidney function tests (serum creatinine), serum ferritin, blood glucose, coagulation test (prothrombin time and activated partial thromboplastin time), cytokine level (IL-6, IL-10, and TGF-β) will be assessed. On admission, computed tomography (CT) scan of the chest will also be performed.

Detailed procedures :

Eucalyptus oil will be applied to the surgery mask, 4 times a day, which is 45 minutes duration in each session for 14 days. Clinical assessment and vital signs, and follow-up RT-PCR tests by nasopharyngeal swab will be documented on days 5, 10, and 15. Follow-up laboratory results for blood, liver function, kidney function, blood glucose, cytokine level, and CT scan will be performed on Day 15. If moderate COVID-19 patients confirmed negative RT-PCR test results in 2 consecutive tests, the patient is allowed to be discharged and continue their adjuvant treatment at home (in the intervention group).

Sample size estimation :

following the sample size estimation of two different means

1. Type 1 error 5%
2. Power of study 80%
3. superiority trial hypothesis
4. equal allocation for two arms

f. effect size is estimated at 0.7 total sample required : 52

Statistical Analysis

1. Intention to treat
2. Descriptive statistic
3. Repeated measurement analysis using mixed model analysis.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• Indonesia
  • South Sulawesi
    • Makassar, South Sulawesi, Indonesia, 90245
      • Hasanuddin University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. SARS-COV-2 infections were confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) from the nasopharyngeal swab.
2. Mild to moderate clinical symptoms or with nasal cannula oxygen modality maximal oxygen 4 liters/minute (Moderate COVID-19 patients mean patients with clinical signs of pneumonia (fever, cough, shortness of breath, rapid breathing) but no signs of severe pneumonia including Oxygen Saturation ≥ 95%)
3. Sign the informed consent
4. Have not received the COVID-19 medicine yet

Exclusion Criteria:

1. They have or develop severe COVID-19 symptoms according to the COVID-19 diagnosis and treatment guidelines of Indonesian society of respiratory; respiratory distress (RR ≥30 breaths/min, oxygen saturation <95% at a rest state)
2. History of hepatitis or impaired liver function
3. Patients with or had a history of comorbid such as coronary heart disease, congestive heart disease, renal insufficiency, chronic liver disease, diabetes mellitus, uncontrolled hypertension or grade II hypertension or hypertensive crisis, immunocompromised, Central Nervous System disorders (such as stroke, epilepsy, Alzheimer's, and meningitis)
4. Pregnant or lactating women
5. Allergy to any of the components of the test product
6. Participated in other clinical studies

Withdraw from the study:

The protocol treatment will be discontinued if the patient

1. Withdraw their consent based on the patient's demand
2. Patient's compliance of the use of test product <90% or >5 times not using the product according to the predetermined schedule
3. Severe adverse events occurred
4. After undergoing clinical trials, the patient experienced things that caused him/her to no longer meet the criteria set out in this protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intervention Group; The group will receive standard COVID medication + Eucalyptus oil on external use for 14 days	Drug: Eucalyptus Oil; The Eucalyptus Oil pack contains Oleum Eucalyptus citriodora, Oleum Eucalyptus globulus, and Peppermint oil, given 4 times daily for 45 minutes each frequency, applied to the mask.; Other Names: Herbal Roll On; Drug: Standard COVID medication; This standard treatment is personalized according to the severity but is not limited to standard antiviral therapy, azithromycin 500 mg a day, vitamin C 500 mg 8 hourly a day, zinc 20 mg a day, tablet of complex vitamin B, and other symptomatic treatments.; Other Names: COVID Medication
ACTIVE_COMPARATOR: Comparator Group; The group will receive standard COVID medication only	Drug: Standard COVID medication; This standard treatment is personalized according to the severity but is not limited to standard antiviral therapy, azithromycin 500 mg a day, vitamin C 500 mg 8 hourly a day, zinc 20 mg a day, tablet of complex vitamin B, and other symptomatic treatments.; Other Names: COVID Medication

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Symptoms	The patient will be asked for clinical improvement (three symptoms, sore throat, anosmia and cough) with a 6-likert scale question for each symptoms. Higher number (5) indicates very severe symptoms whereas 0 indicates no symptoms.	change of score for each symptoms from baseline to day 15
Viral clearance	level of Severe Acute Respiratory Corona Virus 2 (SARS-COV2) on nasopharyngeal sample measured by RT-PCR in Cycle Threshold Unit (CT)	change of CT Value from baseline to day 15
Neutrophil-Lymphocyte Ratio (NLR)	This ratio is used as a marker of subclinical inflammation. It is calculated by dividing the number of neutrophils by number of lymphocytes from the blood sample	change of NLR from baseline to day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiology improvement	the Radiology improvement of lung Computed Tomography (CT-Scan) on day 15 indicates by resolution or absence of inflammatory sign or abnormal findings (binary response)	change of radiology feature from baseline to day 15
Cytokine level	reduction of pro-inflammatory cytokine level in blood samples (Interleukin-6, Interleukin-10, Tumor Growth Factor/TGF-β)	change of cytokine level from baseline to day 15

Collaborators and Investigators

• Sponsor: Hasanuddin University
• Collaborators: Ministry of Agriculture, Republic of Indonesia
• Investigators: Principal Investigator: Arif Santoso, MD, Ph.D, Hasanuddin University; Principal Investigator: Idrus Paturusi, Prof., Hasanuddin University; Principal Investigator: Firdaus Hamid, MD. PhD, Hasanuddin University; Principal Investigator: Andi Rofian Sultan, MD. Ph.D, Hasanuddin University; Principal Investigator: Munawir Munawir, MD, Hasanuddin University; Principal Investigator: Rasiha Rasiha, Hasanuddin University

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 18, 2020
• Primary Completion (ACTUAL): January 28, 2021
• Study Completion (ACTUAL): March 1, 2022

Study Registration Dates

• First Submitted: May 31, 2022
• First Submitted That Met QC Criteria: May 31, 2022
• First Posted (ACTUAL): June 1, 2022

Study Record Updates

• Last Update Posted (ACTUAL): June 1, 2022
• Last Update Submitted That Met QC Criteria: May 31, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; Eucalyptus; Viral Clearance; Cytokine Level; Clinical Improvement
• 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: 3105221321

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No