Randomized-controlled Trial of the Effectiveness of COVID-19 Early Treatment in Community

Randomized-controlled Trial of the Effectiveness of COVID-19 Early Treatment in Community With Fluvoxamine, Bromhexine, Cyproheptadine, and Niclosamide in Decreasing Recovery Time

There is an urgent need to identify effective treatments for SARS-CoV-2 infection that helps people recover quicker and reduces the need for hospital admission. The investigators develop an open, adaptive, platform trial to evaluate treatments, Fluvoxamine, Bromhexine, Cyproheptadine, and Niclosamide suitable for use in the community for treating COVID-like-illness that might help people recover sooner and prevent hospitalisation.

Study Overview

• Status: Completed
• Conditions: Treatment Efficacy
• Intervention / Treatment: Drug: FluvoxaMINE Maleate 50 MG; Combination product: Fluvoxamine, Bromhexine; Combination product: Fluvoxamine, Cyproheptadine; Drug: Niclosamide Pill; Combination product: Niclosamide, Bromhexine

Detailed Description

There is an urgent need to identify interventions against COVID-19 suitable for wide use in the community that have been proven to be effective in reducing symptom duration or hospitalisation. There is urgent need to know whether potential COVID-19 treatments such as Fluvoxamine, Bromhexine, Cyproheptadine, and Niclosamide that are available for rapid pragmatic evaluation might modify the course of COVID-19 infections, particularly among those who are at higher risk of complications, such as those aged 50 years and over with comorbidity and those aged 65 years and over.

Most reported trials have been conducted in hospital settings, and there is little evidence from community settings, where most people with COVID-19 receive care and where deployment of effective early treatment could speed time to recovery and reduce complications. The investigators established a multi-arm, adaptive platform, randomised controlled trial for community treatment of COVID-19 syndromic illness in people at higher risk of an adverse illness course.

• Study Type: Interventional
• Enrollment (Actual): 1200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10900
    • Vibhavadi Hospital
  • Chiangmai, Thailand, 50200
    • Chiangmai Neurological Hospital
  • Bangkok
    • Ratchathewi, Bangkok, Thailand, 10400
      • Rajvithi Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• COVID-1 9 patients with mild symptoms and the results were confirmed by Antigen Test Kit or PCR for SARS-CoV-2.
• People who have symptoms consistent with COVID-19 and test positive for SARS-CoV-2 infection within 48 hours of being known.
• Participants are 18 years of age or older.

Exclusion Criteria:

• Almost recovered (generally much improved and symptoms now mild or almost absent)
• Judgement of the recruiting clinician deems ineligible.
• Previous randomisation to an arm of the trial
• Pregnancy
• Breastfeeding
• Known severe hepatic impairment.
• Known severe renal impairment.
• Currently taking Fluvoxamine, Bromhexine, Cyproheptadine, or Niclosamide

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Fluvoxamine Arm; The subjects received fluvoxamine (immediate release) 50 mg, 1 tablet in the morning and 50 mg 2 tablets before bedtime, orally after meals. For a total of 14 days, the first two days and the last two days, 50 mg 1 tablet in the morning and 50 mg 1 tablet at bedtime.	Drug: FluvoxaMINE Maleate 50 MG; The subjects received fluvoxamine (immediate release) 50 mg, 1 tablet in the morning and 50 mg 2 tablets before bedtime, orally after meals. For a total of 14 days, the first two days and the last two days, 50 mg 1 tablet in the morning and 50 mg 1 tablet at bedtime. All enrolled patients will be provided a thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. In addition, Oropharyngeal swab samples will be collected for viral shedding as measured by PCR on days 0, 7 and 14. Fecal and blood samples will be collected for viral shedding as measured by PCR on days 0,7 and 14. A baseline fecal and oropharyngeal sample will be obtained on Day 0 prior to starting dosing of drugs.; Other Names: Telehealth monitoring
EXPERIMENTAL: Fluvoxamine in Combination with Bromhexine Arm; The subjects received fluvoxamine (immediate release) 50 mg, 1 tablet in the morning and 50 mg 2 tablets before bedtime, orally after meals. For a total of 14 days, the first two days and the last two days, 50 mg 1 tablet in the morning and 50 mg 1 tablet at bedtime. Co- administration with bromhexine 8 mg, 1 tablet twice taken after meals and taken at least 8 hours apart, for 10 days.	Combination product: Fluvoxamine, Bromhexine; The subjects received fluvoxamine (immediate release) 50 mg, 1 tablet in the morning and 50 mg 2 tablets before bedtime, orally after meals. For a total of 14 days, the first two days and the last two days, 50 mg 1 tablet in the morning and 50 mg 1 tablet at bedtime. Co- administration with bromhexine 8 mg, 1 tablet twice taken after meals and taken at least 8 hours apart, for 10 days. All enrolled patients will be provided a thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. In addition, Oropharyngeal swab samples will be collected for viral shedding as measured by PCR on days 0, 7 and 14. Fecal and blood samples will be collected for viral shedding as measured by PCR on days 0,7 and 14. A baseline fecal and oropharyngeal sample will be obtained on Day 0 prior to starting dosing of drugs.; Other Names: Telehealth monitoring
EXPERIMENTAL: Fluvoxamine in Combination with Cyproheptadine Arm; The subjects received fluvoxamine (immediate release) 50 mg, 1 tablet in the morning and 50 mg 2 tablets before bedtime, orally after meals. For a total of 14 days, the first two days and the last two days, 50 mg 1 tablet in the morning and 50 mg 1 tablet at bedtime. Co- administration with cyproheptadine 4 mg, 1 tablet, three times, orally after meals and should be taken every 8 hours apart, for 14 days.	Combination product: Fluvoxamine, Cyproheptadine; The subjects received fluvoxamine (immediate release) 50 mg, 1 tablet in the morning and 50 mg 2 tablets before bedtime, orally after meals. For a total of 14 days, the first two days and the last two days, 50 mg 1 tablet in the morning and 50 mg 1 tablet at bedtime. Co- administration with cyproheptadine 4 mg, 1 tablet, three times, orally after meals and should be taken every 8 hours apart, for 14 days. All enrolled patients will be provided a thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. In addition, Oropharyngeal swab samples will be collected for viral shedding as measured by PCR on days 0, 7 and 14. Fecal and blood samples will be collected for viral shedding as measured by PCR on days 0,7 and 14. A baseline fecal and oropharyngeal sample will be obtained on Day 0 prior to starting dosing of drugs.; Other Names: Telehealth monitoring
EXPERIMENTAL: Niclosamide Arm; The subjects received 1 tablet of niclosamide 1000 mg orally in divided doses twice a day. After meals in the morning and evening for a total of 14 days.	Drug: Niclosamide Pill; The subjects received 1 tablet of niclosamide 1000 mg orally in divided doses twice a day. After meals in the morning and evening for a total of 14 days. All enrolled patients will be provided a thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. In addition, Oropharyngeal swab samples will be collected for viral shedding as measured by PCR on days 0, 7 and 14. Fecal and blood samples will be collected for viral shedding as measured by PCR on days 0,7 and 14. A baseline fecal and oropharyngeal sample will be obtained on Day 0 prior to starting dosing of drugs.; Other Names: Telehealth monitoring
EXPERIMENTAL: Niclosamide in Combination with Bromhexine Arm; The subjects received 1 tablet of niclosamide 1000 mg orally in divided doses twice a day. After meals in the morning and evening for a total of 14 days. Co-administration with bromhexine 8 mg, 1 tablet twice taken after meals and taken at least 8 hours apart, for 10 days.	Combination product: Niclosamide, Bromhexine; The subjects received 1 tablet of niclosamide 1000 mg orally in divided doses twice a day. After meals in the morning and evening for a total of 14 days. Co-administration with bromhexine 8 mg, 1 tablet twice taken after meals and taken at least 8 hours apart, for 10 days. All enrolled patients will be provided a thermometer as well as a fingertip probe pulse oximeter, with the specific instructions to monitor both temperature at oxygen saturation at the time of daily oral administration of drug. In addition, Oropharyngeal swab samples will be collected for viral shedding as measured by PCR on days 0, 7 and 14. Fecal and blood samples will be collected for viral shedding as measured by PCR on days 0,7 and 14. A baseline fecal and oropharyngeal sample will be obtained on Day 0 prior to starting dosing of drugs.; Other Names: Telehealth monitoring
NO_INTERVENTION: Usual Care Arm; The control group received treatment according to the latest usual care medical guidelines provide by ministry of Thailand at that time.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital admission or mortality related to COVID-19	Contacts with health services reported by patients and/or captured by reports of patients' medical records	Within 28 days
Time taken to self- report recovery	Patient reports the day they feel recovered	Enrolment through final day of participation
Progression to severe COVID-19 Disease	O2 saturation <92% on room air (in two consecutive measurements at least 2 hours apart) OR 2) requirement of hospitalization OR 3) need for artificial ventilation OR 4) death.	Enrolment through final day of participation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction (change) in GI viral shedding (by PCR)	Fecal swabs	Days 0,7,14
Change in respiratory viral clearance (by PCR)	Oropharyngeal swabs	Days 0,7,14
Time to resolution of a fever	Online diary	Enrolment through final day of participation
Negative effects on well being	WHO 5 Well Being Index via online diary or telephone	Days 0,7,15,28,60

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events (AEs)	Composite counts by Adverse Events and Serious Adverse Events	Enrolment through 30 days after final day of participation

Collaborators and Investigators

• Sponsor: Chulalongkorn University
• Collaborators: Washington University School of Medicine; Mahidol University; Ramathibodi Hospital; Rajavithi Hospital; King Chulalongkorn Memorial Hospital; Ministry of Health, Thailand; QIMR Berghofer Medical Research Institute; The University of Western Australia; Yamagata Prefectural Central Hospital; Mae Fah Luang University; Vibhavadi Hospital; Thanyarak Pattani Hospital
• Investigators: Principal Investigator: Dhammika Leshan Wannigama, MD PhD, Chulalongkorn University; Study Chair: Cameron Hurst, PhD, QIMR Berghofer Medical Research Institute; Study Chair: Kanokpoj Chanpiwat, MD, Rajvithi Hospital; Study Chair: Shuichi Abe, MD, Yamagata Prefectural Central Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 1, 2021
• Primary Completion (ACTUAL): June 21, 2022
• Study Completion (ACTUAL): June 21, 2022

Study Registration Dates

• First Submitted: October 19, 2021
• First Submitted That Met QC Criteria: October 19, 2021
• First Posted (ACTUAL): October 21, 2021

Study Record Updates

• Last Update Posted (ACTUAL): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Coronavirus Infections; Treatment; Anti-Infective Agents; Coronavirus; COVID-19; Respiratory Tract Infections; Pneumonia, Viral; Fluvoxamine; Viral shedding; Niclosamide; Bromhexine; Early treatment; Cyproheptadine
• 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; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Enzyme Inhibitors; Gastrointestinal Agents; Dermatologic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Serotonin Antagonists; Anti-Anxiety Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Respiratory System Agents; Antiparasitic Agents; Anti-Allergic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Antinematodal Agents; Anthelmintics; Cytochrome P-450 CYP1A2 Inhibitors; Expectorants; Antiplatyhelmintic Agents; Cytochrome P-450 CYP2C19 Inhibitors; Anticestodal Agents; Fluvoxamine; Bromhexine; Cyproheptadine; Niclosamide
• Other Study ID Numbers: 64197

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No