Virucidal Effect of Povidone Iodine on COVID-19 In-Vivo
Condition: COVID19
MeSH terms: COVID-19
Study type: Interventional
Phase: Phase 2

Summary: 
      It is an established fact that, corona virus spread through the respiratory droplets.
      Colonization of the virus in oropharynx and/or nasopharynx is considered to be major factor
      for transmissibility of the virus through respiratory secretions. Preventing colonization of
      the virus by administrating povidone iodine in the nasal passage therefore, a rational
      thought which is supported by recent evidence of in-vitro virucidal action of povidone iodine
      in Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS CoV-2). Therefore, the study is
      designed to assess the virucidal effect of povidone iodine on COVID-19 virus in-vivo.This
      open label randomized clinical trial will be conducted at Department of Otorhinolaryngology
      and Head Neck Surgery, in collaboration with Department of Virology and Department of
      Medicine in Dhaka Medical College (DMC) Hospital. The study will be conducted from September
      2020 to October 2020. Total 175 confirmed cases of COVID-19 disease, proven by Reverse
      transcription polymerase chain reaction (RT-PCR) testing will be enrolled in this study.
      Written informed consent will be ensured before participation. In case of no literacy, finger
      print will be considered for written permission.Consent will be sought from the legal
      guardian in case of minor or underaged.Formal ethical clearance will be taken from Ethical
      Review Committee (ERC) of Dhaka Medical College. All of the Participants will be divided into
      seven groups: Group A will receive Povidone iodine (PVP-I) nasal irrigation at concentration
      of 0.4%, Group B and Group C will received 0.5% and 0.6%; Group D will receive PVP-I nasal
      spray at concentration of 0.5% and Group E will received at 0.6% concentration. Group F
      (Placebo comparator group) will receive nasal irrigation by distilled water (DW) and Group G
      (Placebo comparator group) will received nasal spray by distilled water. The contact time
      will be minimum 30 seconds. After the individual application of PVP-I and distilled water in
      respective participant, they will be tested again for RT-PCR for COVID-19 from nasopharyngeal
      and oropharyngeal sample. All patients will be subjected to detail history, physical
      examination and adverse events. Block Randomization will be followed for randomization. Data
      will be recorded in a semi-structured questionnaire and will be analyzed by 'R-4.0.2' data
      analysis software
    

Detailed description: 
      Rationale of the study

      The coronavirus disease 2019 (COVID-19) is a highly infectious disease and cause human to
      human transmission primarily by respiratory droplets from coughing, sneezing and speaking. In
      early SARS-CoV-2 infection, a greater viral titre can be found in saliva and nasal mucous;
      minimization of these titres should help to reduce cross infection. Povidone-iodine (PVP-I)
      disinfectant has better anti-viral activity than other antiseptics and has already been
      proven to be an extremely effective virucide in vitro against severe acute respiratory
      syndrome and Middle East respiratory syndrome coronaviruses (SARS-CoV and MERS-CoV). Its' in
      vivo virucidal activity is unknown, though its nasal or oral preparation can be effective in
      reducing transmission. Earlier, a very few studies have evaluated the efficacy of
      povidone-iodine as nasal antiseptics or oral rinse antiseptics against the SARS-CoV-2 virus
      but the result of those studies are not undebatable. So aim of this study is to investigate
      the virucidal activity of povidone iodine on coronavirus located on the mucosal surface of
      oropharynx and nasopharynx and is very rational in this pandemic period.

      Research Hypothesis:

      Objectives:

      General Objective:

      To determine the virucidal efficacy of povidone iodine on COVID-19 virus located in
      nasopharynx.

      Secondary objectives:

      i. To determine the efficacy of povidone iodine to clear COVID-19 virus located in
      nasopharynx ii. To assess the adverse events among the groups

      Study Design: Open label randomized clinical trial. Place of Study: Department of
      Otorhinolaryngology and Head Neck Surgery, in collaboration with Department of Virology and
      Department of Medicine, Dhaka Medical College Hospital, Dhaka, Bangladesh.

      Period of study: The study period will be September 2020 to November 2020. Study population:
      Confirmed cases of COVID-19 disease proven by RT-PCR testing. Sampling and Statistical basis
      of the sample size: The sample size is determined using the following formula Sample size:
      estimated sample size 189 (twenty seven in each group) Research instruments General
      questionnaire for recording baseline information A checklist for for detecting COVID-19
      status

      Method and data collection:

      Participant selection and enrollment: All patients admitted to the medical wards through
      emergency department or Outpatient department with suspected COVID-19 cases will be initially
      approached and screened for confirmation of the COVID-19. Confirmation of the COVID-19 will
      be done by positive impression of RT-PCR result. Following confirmation of the viral
      infection, the patients will be seen by the ward doctors and clinical trial physicians
      (registered physicians). Moreover, baseline complete blood count (CBC) will be done for each
      patient. Chest X-ray/High resolution computed tomography (HRCT) will be done in necessary
      case. The ward doctors and trial physicians will together care for the patient; then the
      patients will be briefed about the aim, objective and details of the procedure of the study.
      If without capacity, their relatives will be approached about the trial and seek their
      consent for recruitment. As this study will be confined into a tertiary care hospital,
      patients will be recruited up to day 4 of illness.

      Consenting participants: It will be prioritized that the patients will be treated early for
      COVID-19 management by standard regiment and in accordance to the guidance of the national
      guidelines. And within shortest possible time preferably within 4 hours of admission,
      consenting procedure will be completed either from the patient or from the attendant/legal
      guardian of the patients to obtain the full potential benefit of the treatment. Written
      informed consent will be obtained from the patient in their own language [Bengali] by trial
      physicians working on the trial.

      Screening for eligibility: During admission, demographic and clinical details including name,
      age/date of birth, gender, duration of onset of fever and hospitalization, vital statistics
      will be recorded before randomization. RT PCR for COVID-19 will be used for confirmation of
      the COVID-19 virus infection. A screening log will be maintained including these essential
      details and the decision taken by the patient or attendant or legal guardian where
      appropriate concerning recruitment. Ineligible and non-recruited patients will also be cared
      by the ward physicians following standard treatment guidelines.

      Procedure of randomization: The study participants will be randomly assigned in this study
      into six equal groups; where each group has equal opportunity to receive any treatment
      option. Randomization will be done by block randomization methods. Randomization will be done
      quickly, with baseline information typically captured in <15 min. Recruitment & randomization
      will be performed contemporaneously with assessment/resuscitation of patients by a second
      person so that medical care is not delayed by recruitment. Patients will only be randomized
      once baseline data has been entered; after this has been done, participants will not be
      withdrawn from the study. Following completion of the randomization, the trial physicians
      reported the Principal Investigator (PI) of the trial and then the Principal Investigator
      (PI) handed over an opaque sealed envelope, which will be numbered sequentially to correspond
      to patient enrollment numbers, which will be used for concealment of treatment allocations.
      Envelopes will be kept in a locked drawer and will be opened in strictly numerical order by
      in supervisor in presence of nursing supervisor of study unit. Allocation between arms will
      initially be equal, although this may be revised following guidance of the PI and his team
      (as per the statistical plan).

      Withdrawal of study participants: Participants are free to withdraw from the study at any
      point, for any reason. If this occurs, the primary reason for withdrawal will be documented
      in the participant's case record form. The participant will have the option of withdrawal
      from:

      participant samples. Randomized patients who wish to withdraw from the study before they have
      undertaken any study-related procedures will be replaced. Data on the original participant
      will be kept on the CRF/database if the participant agrees to this.

      Investigational medicinal products:

      All of the Participants will be divided into three groups: Group A will receive Povidone
      iodine (PVP-I) nasal irrigation (NI) at three different concentration of 0.4%, Group B and
      Group C will received 0.5% and 0.6%; Group D will receive PVP-I nasal spray (NS) at
      concentration of 0.5% and Group E will received at 0.6% concentration. Group F (Placebo
      comparator group) will receive nasal irrigation by distilled water and Group G (Placebo
      comparator group) will received nasal spray by distilled water Participant compliance: The
      study team will not create any problem with compliance while the patient is under care and
      supervision in hospital. It was ensured that all recruited patients receive the appropriate
      interventions, although it could be interrupted due to the onset of potential adverse effects
      such as hypotension.

      Responsibility sharing of care of the patients: As the patients will remain under the care of
      the hospitals' consultant physicians/unit head who will have primary responsibility for their
      management. Management protocols will be agreed between the medical team and study team.
      Decisions about intubation, requirement of blood and blood products, transfer of patients to
      intensive care, weaning of ventilation and extubation will be made by the medical team
      independently of study doctors. All decisions will be based on the patient's clinical
      condition and the available hospital resources, as per usual hospital practice. The study
      team preferably by trial physicians will note down the record in patient's Case Record Form
      (CRF).

      Methods of data collection: data collection will be done by the trial physicians. A paper
      based semi-structured questionnaire was made and pre-tested before data collection. All
      potential participants will be recorded in this database at first contact and assigned a
      study number. This study number (eg DMC-PVP-I-0001) will be used for all data and samples
      collected from that person. Study doctors will recruit and randomize patients at the bedside
      with a randomization procedure. They will not be able to predict allocation before
      randomization. Following randomization, allocation will be done by the PI and trial
      physicians or nurse will confirm the administration of the either drug/distilled water.
      Patients will be closely monitored. Temperature will be measured in every 6 hours, blood
      pressure, respiratory rate, pulse rate will be measured in every hour. Urine output will be
      measured in every 8 hours. Drug related side effects or any adverse events will be observed
      in each group.

      If there is no reaction or unusual event, another RT-PCR sample will be collected from the
      nasopharynx and sent for further testing.

      Total duration of the follow up will be for 2 days (or person fulfills the discharge
      criteria). All clinical events will be noted in case record form by trial physicians,
      including vital status at hospital discharge. Data entry will be date/time stamped.
      Laboratory analysis data will be collected using same CRF.

      Data quality and standards: following collection, all data set and collected record form will
      be checked. A formal clinical data management plan will be written before the study starts,
      agreed by the co-investigators, and Data Monitoring Committee, and documented trail master
      file. Laboratory results will be discussed regularly between the PI and laboratory managers.

      Proposed Analysis Plan of the study:

      Data analysis will be done by data management software, R-4.0.2'. Statistical significance is
      set as 95% confidence level at 5% acceptable error level. Differences will be considered
      significant at the P < 0.05 level for all these tests. The data will be expressed as means
      ±Standard deviations (SD) for continuous variables and as frequencies (%) for categorical
      variables. Chi-square test, student t test or ANOVA or other statistical test will be used in
      case of normally distributed data and similar non-parametric data will be used whenever
      appropriate. Graph & chart will be expressed by Microsoft Excel 2016.

      Ethical consideration:

      The researcher is duly concern about the ethical issues relate to the study. In this study
      the following criteria will be followed to ensure maintaining the ethical values. All ethical
      measure will be followed in accordance to the current Declaration of the Helsinki and Good
      clinical practice (GCP) and Good laboratory practice (GLP) guidelines.

      Facilities available at study center:

      The RT-PCR and other study-related testing will be done at DMCH. DMCH was designated as a
      COVID dedicated hospital which provide multidisciplinary care.Necessary investigations are
      available here with minimal cost.
    

Intervention name(s): Povidone-Iodine 0.4% NI; Povidone-Iodine 0.5% NI; Povidone-Iodine 0.6% NI; Povidone-Iodine 0.5% NS; Povidone-Iodine 0.6% NS; Placebo comparator: DW-NI; Placebo comparator: DW-NS
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Other; Other
Intervention description(s): Povidone iodine (PVP-I) nasal irrigation at concentration of 0.4%; Povidone iodine (PVP-I) nasal irrigation at concentration of 0.5%; Povidone iodine (PVP-I) nasal irrigation at concentration of 0.6%; Povidone iodine (PVP-I) nasal spray at concentration of 0.5%; Povidone iodine (PVP-I) nasal spray at concentration of 0.6%; Nasal irrigation will be provided by Distilled water; Nasal spray will be provided by Distilled water
Other intervention name(s): Povidone-Iodine 0.4%; Povidone-Iodine 0.5%; Povidone-Iodine 0.6%; Povidone-Iodine 0.5%; Povidone-Iodine 0.6%; Distilled water (DI) in the form of Nasal Irrigation; Distilled water (DI) in the form of Nasal spray
Intervention MeSH terms: Iodine; Cadexomer iodine; Povidone-Iodine; Povidone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: COVID19; prevention; Povidone Iodine; Low and middle income countries