A Preventive Treatment for Migrant Workers at High-risk of COVID-19
Condition: Covid-19
MeSH terms: COVID-19
Study type: Interventional
Phase: Phase 3

Summary: 
      In December 2019, a novel coronavirus, now called COVID-19, emerged as a global health threat
      from Wuhan, China. Within weeks, the contagious virus spread within and between communities,
      causing a lower respiratory tract infection dominated by symptoms of fever, cough and sore
      throat. The incubation period was estimated at between 5 to 7 days, but could last as long as
      14 days. Although COVID-19 causes a mostly mild and self-limiting disease, respiratory
      involvement has been reported in about 5% of the population, requiring supplemental oxygen
      and even ventilatory support to relieve hypoxia. Alveolar damage, fibrosis and consolidation
      have been reported in radiologic and post-mortem studies. Existing data suggest a mortality
      rate of COVID-19 is approximately 1-2%, higher among individuals with pre-existing
      comorbidities and in healthcare systems with suboptimal access to ventilatory support.

      Given its high transmissibility, COVID-19 has quickly spread across the globe within a short
      interval. By 27 April 2020, over 3 million people around the world have been diagnosed with
      COVID-19, and more 200,000 have succumbed to the disease. As a proportion of patients
      manifest mild or no symptoms, these numbers are likely an underestimate of the actual number
      of patients with COVID-19. More disconcertingly, patients are known to shed viruses despite
      mild or no symptoms, making it essential that a collective approach against COVID-19
      incorporate active pharmacological treatment to prevent or mitigate virus pathogenesis prior
      to its potential evolution to cause respiratory distress. To date, clinical trials have
      focused on the treatment of hospitalised patients diagnosed with COVID-19; only few have
      examined the clinical benefits of pharmacological agents despite few compelling in vitro
      data.

      The relatively high transmission of COVID-19 in a closed dormitory environment of migrant
      workers in Singapore presents a real-life scenario where a prophylaxis treatment could reduce
      the impact of the disease. In Singapore, there are well grounded concerns an excess in cases
      could pose the possibility of strain in healthcare system and mentally drain her workers. The
      availability of an effective prophylaxis treatment is highly desirable to potentially reduce
      this burden. Data from the current study could also have implications on how future outbreaks
      in high-density areas should be managed, especially when residents are subjected to
      quarantine and isolation.
    

Detailed description: 
      This is a pragmatic, open-label, randomised study with 4 interventional and 1 control arms.
      Individuals will be recruited from migrant worker dormitories, and written informed consent
      taken prior to enrolment. Randomisation will be done by the level within the dormitory
      building and predetermined each day according to a randomisation schema done by an
      independent statistician. This will obviate the potential for bias due to drug exchange
      between study individuals.

      The 5 arms consist of:

        -  Experimental arms

             1. Hydroxychloroquine tablet 400mg loading dose, followed by 200mg daily for 42 days
                (1,000 study subjects)

             2. Ivermectin tablet 12mg single dose (1,000 study subjects)

             3. Zinc tablet 80 mg/vitamin C 500mg daily for 42 days (1,000 study subjects)

             4. Povidone-iodine throat spray (3 times daily) for 42 days (1,000 study subjects)

        -  Control arm 5) Vitamin C tablet 500mg daily for 42 days (1,000 study subjects)

      Study information sheet will be circulated in selected buildings within the dormitory 1-4
      days before recruitment starts. All publicity materials and informed consent form will be
      translated to the different languages (e.g. Tamil, Bengali, Chinese, Burmese and Malay). A
      translator will be present to aid translation if necessary. Study subjects will be given
      ample time to ask questions relating to the study. Prospective participants will respond by
      showing up to recruitment stations at designated dates and times. Facilitators from the
      dormitory will be engaged to assist with the ground crowd-control. Prospective videos will be
      shown to inform the subject on the purpose, study inclusion and exclusion criteria, study
      medications, blood taking, reporting of adverse effects and follow-up visits. Informed
      consent will be taken before all study-related procedures are performed, including study
      eligibility. Translators will also help translate the daily questionnaires.

      During the baseline recruitment,

        1. History of symptoms, comorbidities and prior illnesses will be asked. Specific questions
           include presence or absence of the following symptoms: Fever, chills, myalgia, headache,
           diarrhoea, running nose, anosmia, loss of taste, sore throat, dry cough, shortness of
           breath.

        2. Measurements of study subjects' parameters such as weight, height, temperature, pulse
           rate and blood pressure will be recorded. Subjects randomised to Ivermectin arm and
           subsequently found to weigh below 60 kg will be randomised to other treatment arms.
           Subjects randomised to hydroxychloroquine arm and found to have systolic blood pressure
           >150 mmHg and/or diastolic blood pressure >90 mmHg and/or heart rate >100 beats per
           minute will also be randomized to other treatment arms.

        3. 12-lead electrocardiogram (ECG) will be performed in patients randomised to receive
           hydroxychloroquine. Only those with corrected QT values less than 450 ms, no cardiac
           arrhythmia and no ventricular hypertrophy will be allowed to receive hydroxychloroquine.
           Those with corrected QT values more than 450 ms, cardiac arrhythmia and ventricular
           hypertrophy will be randomised to other treatment arms.

        4. Blood sample (20 mL) will be obtained to test Immunoglobulin G/M against SARS-CoV-2.
           Depending on the findings, additional tests will be performed to explore potential
           biological reasons underpinning these observations. The choice of markers may include
           pathway-specific biomarkers targeting inflammation, oxidative stress, lipid parameters,
           as well as organ-specific ones such as renal and liver parameters. Given the large
           sample size and high costs of analysis, the study team will prioritise more detailed
           investigations in a targeted group of patients depending on the final findings. None of
           these blood results is a screening criteria for study participation. The investigator
           will share abnormal to the study subjects abnormal results of their renal and liver
           parameters should these tests are tested following study completion. The extent on
           investigation, however, depends on funding support. In this study, renal and hepatic
           dysfunction will be based on physician-diagnosed and self-declaration on the part of the
           study subject. All clinical information will be verified by a senior physician on-site.

        5. Study medications will be packed with clear instructions written on the packing bag. The
           package will be distributed to each subject based on the randomised treatment assigned.

        6. Study participants will be given a study card to remind them to submit their symptoms
           daily and to record the times when they consume their medications. They will also be
           asked to present this card to doctors at the medical post or hospital should they seek
           medical assistance. In the events of acute respiratory infection and hospitalization,
           lab testing will be done as clinically indicated. Subjects on ventilator support who are
           not able to take oral medications may discontinue taking the study drug. However,
           subjects will remain in the study for collection of data on duration of mechanical
           ventilation for analysis.

      During final study visit,

        1. The study team, including investigators, will be present at the dormitory. A repeated
           blood sample (20mL) will be collected for serological tests. Measurements of study
           subjects' parameters such as weight (using Tanita BC-418 and Tanita BC-420MA for
           bio-electrical impedance analysis), height, blood pressure will be taken. ECG will be
           done only for subjects in hydroxychloroquine arm. History will be taken including
           symptoms of fever, chills, myalgia, headache, diarrhoea, running nose, anosmia, loss of
           taste, sore throat, dry cough, shortness of breath and the duration of such symptoms, if
           any.

        2. Balance medication and packaging retrieval to do medication accounting and checking for
           adherence to assigned treatment arm

        3. Discharged from study if no adverse events to follow-up.
    

Intervention name(s): Hydroxychloroquine Sulfate Tablets; Ivermectin 3mg Tab; Zinc; Povidone-Iodine; Vitamin C
Intervention type(s): Drug; Drug; Drug; Drug; Dietary Supplement
Intervention description(s): Hydroxychloroquine tablet 400mg loading dose, followed by 200mg daily for 42 days; Ivermectin tablet 12mg single dose; Zinc tablet 80 mg/vitamin C 500mg daily for 42 days; Povidone-iodine throat spray (3 times daily) for 42 days; Vitamin C tablet 500mg daily for 42 days
Intervention MeSH terms: Hydroxychloroquine; Ivermectin; Povidone-Iodine; Povidone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention