Study objectives and hypothesis
The main purpose of the proposed trial is to determine whether M. communis 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 M. communis 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.
Confidentiality
Data and source documents will be archived for the purposes of any need for monitoring or inspection by the Ethics Committee. The researchers are only allowed to publish the general and group results of this research without mentioning patients’name and details. The Research Ethics Committee can access patients’ information to monitor their rights.
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. Other inclusion criteria includ the age range of 18-65 years old, absence of 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 M. communis, diabetes, hypertension, hepatic disorder, and renal disorder. Exclusion criteria further covered recent consumption of herbal drugs. The criteria for discontinuing the trial are allergy or any other adverse effects to M. communis, applying other herbs during project, and irregular consumption of M. communis preparation.
Study design
This open label randomized controlled clinical trial will be conducted to determine the effect of M. communis preparation 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 has been started from April 2, 2020.
Randomization and allocation
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 enrolls participants to intervention groups via sequentially numbered opaque envelopes.
Intervention
The researchers obtain written informed consent from the participants, then they are randomly divided into intervention (M. communis) and control groups. Patients in both groups are permitted to take only conventional treatment which are indicated in the fifth edition of novel Corona virus pneumonia guideline of the Iranian Ministry of Health and Medical Education. According to this guideline the allowed medication for outpatients who are not high risk is supportive care such as acetaminophen, and for those who are high risk is hydroxyl chloroquin sulfate or chloroquine phosphate. It should be noted that high risk patients are excluded from this study. Patients in intervention group should take M. communis preparation in addition to classic medication. So, they received packets containing M. communis fruit and sugar. On a daily basis, they should gently boil the contents of a pack containing 10 grams of M. communis 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.
Trained assessors collect data and record them in prepared forms. The compliance of the participants will be evaluated via telephone survey to record the usage of study medication and any side effect. A team from vice-Chancellor for Research monitors the processes. The test schedule and procedures are provided in Table 1.
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
|
|
|
Ancillary and post-trial care
Patients are followed up directly for 9 days after the intervention. They can contact the researchers until a month later in case of any presenting adverse effects. Researchers are responsible for providing treatment conditions to eliminate any side effects caused by the intervention.
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 outcome and the method of measurement is as follows:
- Cough (severity and frequency), via Fisman Cough Severity Score (12)
The secondary outcomes include the following:
- Temperature, via thermometer (centigrade)
- Myalgia, via visual analog scale (VAS) (13)
- Weakness, via VAS
- Respiratory rate (the number of breaths per minute)
- Hospital admission (%)
- Taste and smell disorder (%)
- Mortality rate (%)
- Adverse effect
Sample size
Due to the lack of a similar study, the primary sample size was initially considered to be 70 (35 in each arm) (14). Then an interim analysis will be done and the final sample size will be calculated with the comparison of parameters (Mean ± Standard Deviation of cough severity) between the intervention groups at 7th day after intervention, using following formula.
Type I (α), and type II (β) errors will be set at 0.05 and 0.1, respectively.
If the primary sample size is adequate, the study will be finished, and if it is inadequate, the study will be continue (under supervision of ethics committee of Kerman University of medical Sciences)
Statistical analysis
Only the data of participants who complete the follow up will be considered. Their demographic data including gender and age will compare between the two groups using the chi-square test. Analysis of covariance (ANCOVA) will be used to adjust the quantitative data if there is a significant difference at the baseline. Meanwhile, to compare the changes in the symptoms experienced by the patients in the two groups at 7 different time points (on enrollment, 1, 2, 3, 4, 7, and 14 days), the repeated measures ANOVA will apply. The independent samples t-test will also be utilized for comparing the changes between the two groups. The statistical analysis will perform via SPSS 23 and the resultant value of p<0.05 will be considered significant.
Definition of end of the study
The end of study will be the last patient’s last visit. However, Vice-Chancellor for Research and ethics committee of Kerman University of Medical Sciences have supervision on trial and make the final decision to terminate the study.
Data management
There are no legal, ethical or security issues related to recording, collection of the data, storage, processing, and dissemination for this trial. We will not generate any sensitive data, and also we will not undersign any confidentiality contract. All data will be archived for up to 10 years after the study.
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.