Study objectives and hypothesis
The main purpose of the proposed trial is to determine whether myrtle preparation can accelerate the healing process of patients clinically suspected to COVID-19 pneumonia and decrease the hospital admission and other related complications.
Primary hypothesis: taking myrtle fruit preparation in the first days of clinically suspicion to COVID-19 will subside the sign and symptoms of the disease, as well as decrease the respiratory distress and enhance the wellbeing.
Public involvement
The present trial is designed against the uncertainties about the value of applying alternative therapy and herbal medicine for alleviating the symptoms and promoting the prognosis of the mentioned disease. This issue is a popular subject raised by both people and health professionals involving the current pandemic.
Ethical aspects
The protocol of this study is approved by the Local Medical Ethics Committee of Kerman University of Medical Sciences under the approval code IR.KMU.REC.1399.015; it is also registered at the Iranian Registry of Clinical Trials website under the code IRCT20180923041093N3. This study will be conducted in accordance with the guidelines of Declaration of Helsinki (2008 revision). The procedure will be explained to the patients complying with the inclusion criteria, and each participant will voluntarily sign an informed written consent.
Patients recruitment
Patients clinically suspected to the COVID-19 pneumonia are considered and enrolled as suspected cases if they meet either an epidemiological history and two clinical manifestations or three clinical manifestations without epidemiological history, are in the age range of 18-65 years old, without respiratory distress, and candidate for outpatient care and home isolation. They would be eligible if they do not have exclusion criteria including pregnancy, lactation, allergy to myrtle, diabetes, hypertension, hepatic disorder, and renal disorder. Exclusion criteria further covered recent consumption of herbal drugs.
Study design
This prospective randomized controlled clinical trial will be conducted to determine the effect of myrtle on subjects clinically suspected to COVID-19 pneumonia. In this trial, the allocation ratio was considered 1:1.
Study setting
This study will be conducted in referral clinic of Afzalipour Hospital affiliated to Kerman University of Medical Sciences, Kerman, southeastern Iran. A trained general physician will visit the patients. Next, in case of clinical diagnosis of COVID-19 pneumonia, they will be introduced to researchers. Finally, patients who meet eligibility criteria will be invited to the study. Patients’ recruitment started from April 2, 2020.
Randomization
All eligible patients will be randomly allocated to intervention and control groups. A biostatistician generated a randomization list via blocked randomization method (non-stratified, four patients in each block) using Microsoft Excel® software. A secretary enroll participants to intervention groups via sequentially numbered opaque envelopes.
Intervention
After obtaining the written informed consent from the participants, they were randomly divided into intervention (myrtle) and control groups. All patients will receive conventional therapy according to the fifth edition of novel Corona virus pneumonia guideline of the Iranian Ministry of Health and Medical Education. Patients in intervention group should take myrtle preparation in addition to classic medication. So, they received packets containing myrtle fruit and sugar. On a daily basis, they should gently boil the contents of a pack containing 10 grams of myrtle fruit and 10 grams of sugar in 3 glasses of water until 2 glasses of the liquid remain; next, they should percolate it and drink 1 glass in the morning and 1 glass in the evening for 5 days.
The compliance of the participants will be evaluated via telephone survey to record the usage of study medication and any side effect. The test schedule and procedures are provided in Table 1.
Outcome measures
Primary and secondary outcomes will be determined in different time points including 0,1,2,3,4,7, and14 days after the intervention.
The primary outcomes and their method of measurement are as follows:
- Temperature, via thermometer
- Cough (severity and frequency), via Fisman Cough Severity Score
- Weakness, via visual analog scale (VAS)
- Muscular pain, via VAS
- Respiratory rate, via counting the number of breaths per minute
The secondary outcomes include the following:
- Hospital admission
- Taste and smell disorder
- Mortality rate
- Adverse effect
Statistical analysis
Due to the lack of a similar study, the sample size was initially considered to be 70 (35 in each arm). Differences between treatment groups in different variables will be measured using analysis of covariance (ANCOVA).
Definition of end of the study
The end of study will be the last patient’s last visit. However, ethics committee makes the final decision to terminate the trial.
Potential weakness in study design
The protocol of this study was conceived when the PCR test was not adequately available for confirming the diagnosis of COVID-19 infection; on the other hand, the placebo-controlled setting can enhance the value of the study. Hence, it can be concluded that another placebo-controlled study on the confirmed COVID-19 patients is required and ethically justifiable.
Lack of monitoring such laboratory data as inflammatory factors, lymphocyte count, renal and liver function, as well as the lack of following the chest radiography are the other limitations of this study.
Table 1. The test schedule and procedures of suspected COVID-19 patients participating the study
Study phase
|
screening
|
Randomization/intervention phase
|
Follow up
|
Study days
|
Day 0
|
Day 1
|
Day 2
|
Day 3
|
Day 4
|
Day 5
|
Day 7
|
Day 14
|
Informed consent
|
O
|
|
|
|
|
|
|
|
Assessing the eligibility
|
O
|
|
|
|
|
|
|
|
Demographics
|
O
|
|
|
|
|
|
|
|
History and Physical examination
|
O
|
|
|
|
|
|
|
|
Assessing the variables
|
O
|
O
|
O
|
O
|
O
|
O
|
O
|
O
|
Pulse oximetery
|
O
|
|
|
|
|
|
|
|
Randomization
|
|
O
|
|
|
|
|
|
|
Recording the adverse effect
|
|
|
O
|
O
|
O
|
O
|
|
|