Repurposed Approved and Under Development Therapies for Patients With Early-Onset COVID-19 and Mild Symptoms

• ClinicalTrials.gov Identifier: NCT04727424
• Recruitment Status: Recruiting
• First Posted: January 27, 2021
• Last Update Posted: February 1, 2022
• Sponsor: Cardresearch
• Collaborators: Cytel Inc.; McMaster University; Fastgrants; Eiger BioPharmaceuticals; RainWater Foundation
• Information provided by (Responsible Party): Cardresearch

Tracking Information

• First Submitted Date: January 25, 2021
• First Posted Date: January 27, 2021
• Last Update Posted Date: February 1, 2022
• Actual Study Start Date: January 19, 2021
• Estimated Primary Completion Date: October 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 15, 2022)

• Rate of fluvoxamine + budesonide, peginterferon Lambda and fluvoxamine in changing the need for emergency care AND observation for more than 06 hours due to the worsening of COVID-19; [ Time Frame: 28 days ]
  Evaluation of emergency visits and observation unit stay > 06 hours
• Rate of fluvoxamine + budesonide, peginterferon Lambda and fluvoxamine in changing the need for Hospitalization due to COVID-19 progression and related complications, including lower respiratory tract infection (LRTI) [ Time Frame: 28 days ]
  Hospitalization due to COVID-19 progression and related complications

Original Primary Outcome Measures (submitted: January 26, 2021)

• To evaluate the effect of fluvoxamine, ivermectin and metformin in reducing need for emergency care AND observation for more than 12 hours due to the worsening of COVID-19; [ Time Frame: 28 days ]
  Evaluation of emergency visits and observation unit stay > 12 hours
• To evaluate the effect of fluvoxamine, ivermectin and metformin in reducing need for Hospitalization due to lower respiratory tract infection (LRTI) related to COVID-19 [ Time Frame: 28 days ]
  Hospitalization due to COVID-19 progression

Current Secondary Outcome Measures (submitted: January 15, 2022)

• Change in viral load on day 03 and 07 after randomization (interferon lambda arm) [ Time Frame: Day 3 and Day 7 ]
  Viral load
• Time to clinical changes (up to 28 days of randomization), defined as greater than 50% symptoms changing in reference to baseline symptoms) [ Time Frame: Randomization through day 28 ]
  time to > 50% clinical symptoms changes as reported on baseline visit (self reported)
• Time to clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19 or associated complications. [ Time Frame: Randomization through day 28 ]
  Time to hospitalization
• Number of days with respiratory symptoms since randomization [ Time Frame: Randomization through day 28 ]
  Days with symptoms
• Rate of all-cause hospitalizations [ Time Frame: Randomization through day 28 ]
  All cause hospitalizations
• Rate of COVID-19 related hospitalizations [ Time Frame: Randomization through day 28 ]
  COVID-19 hospitalizations
• Number of days on Mechanical Ventilator [ Time Frame: Randomization through day 28 ]
  Number of days on mechanical Ventilator
• Number of Days on Intensive Care Unit [ Time Frame: Randomization through day 28 ]
  Number of days on Intensive Care Unit
• Number of days on hospitalizations [ Time Frame: Randomization through day 28 ]
  Number of days on Hospitalization
• Health and Functioning after COVID-19 disease [ Time Frame: Day 14 and Day 28 ]
  Self evaluation of health functioning post COVID using Promis Global Health Score. Short term scale is a 10 item patient-reported questionnaire using response options as a 5-point and one 11 point rating scale. Higher scores means better global health.
• WHO ordinal scale for clinical improvement [ Time Frame: Randomization through day 28 ]
  An 8 item Ordinal Scale for clinical status on COVID-19. Higher numbers means worse clinical status.
• Number of days on respiratory Symptoms [ Time Frame: randomization through day 28 ]
  Number of days on respiratory symptoms
• Adherence of Study drug [ Time Frame: Randomization through day 14 ]
  Percentage of adherence on Study drug

Original Secondary Outcome Measures (submitted: January 26, 2021)

• Change in viral load on day 03 and 07 after randomization (first 600 enrolled participants) [ Time Frame: Day 3 and Day 7 ]
  Viral load
• Time to clinical improvement (up to 28 days of randomization), defined as improvement greater than 50% in reference to baseline symptoms) [ Time Frame: Randomization through day 28 ]
  time to > 50% clinical improvement (self reported)
• Time to clinical failure, defined as time to need for hospitalization due to the clinical progression of COVID-19 [ Time Frame: Randomization through day 28 ]
  Time to hospitalization
• Number of days with respiratory symptoms since randomization [ Time Frame: Randomization through day 28 ]
  Days with symptoms
• All-cause hospitalizations [ Time Frame: Randomization through day 28 ]
  All cause hospitalizations
• COVID-19 related hospitalizations [ Time Frame: Randomization through day 28 ]
  COVID-19 hospitalizations
• All-Cause Death [ Time Frame: Randomization through day 28 ]
  Death all cause
• Cardiovascular death [ Time Frame: Randomization through day 28 ]
  Cardiovascular death
• Respiratory death [ Time Frame: Randomization through day 28 ]
  REspiratory death
• Promis Global-10 scale [ Time Frame: Randomization, Day 14 and Day 28 ]
  Ordinal scale
• WHO ordinal scale for clinical improvement [ Time Frame: Randomization through day 14 ]
  Ordinal Scale
• Adverse Events [ Time Frame: randomization through day 28 ]
  Adverse events
• Adherence of Study drug [ Time Frame: Randomization through day 10 ]
  Percentage of adherence on Study drug

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Repurposed Approved and Under Development Therapies for Patients With Early-Onset COVID-19 and Mild Symptoms
• Official Title: A Multicenter, Prospective, Adaptive, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effect of Fluvoxamine, Ivermectin, Doxasozin and Interferon Lambda 1A in Mild COVID-19 and High Risk of Complications
• Brief Summary: The COVID-19 pandemic has been characterized by high morbidity and mortality, especially in certain subgroups of patients. To date, no treatment has been shown to be effective in patients with early-onset disease and mild symptoms. Experimental studies have demonstrated a potential anti-inflammatory role of Fluvoxamine, Metformin and Ivermectin in SARS-CoV-2 infections and observational studies have suggested a reduced complications in patients with COVID-19 disease.

Detailed Description

In December 2019 a series of viral pneumonia cases were reported in the city of Wuhan, China and a new subtype of coronavirus has been identified as the causative agent of this condition. On February 11, 2000 the disease has been characterized as COVID-19 and on March 11 the World Health Organization (WHO) declared a state of worldwide pandemic. On January 25, 2021 there are 98,794,942 cases and 2,124,193 documented deaths (global case-fatality ratio of 2.15%).

To date, no early treatment has been identified as effective in combating this disease which has been identified as with high morbidity and mortality. Epidemiological data suggest that despite development of vaccines we will have hundreds od thousands of cases in the next two years.

Thus, we propose the repositioning of three drugs which experimentally have shown anti-inflammatory activity against SARS-CoV2 and some clinical evidence derived from observational studies on reducing complications if used early on the disease, before inflammatory cascade is fully activated.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Patients with mild disease will be randomly allocated to one of three treatment arms in a 1:1:1 ratio:

1. Fluvoxamine + Budesonide
2. Peginterferon Lambda
3. Placebo

Patients with SpO2 < 94% will be randomly allocated to one of two arms in a 1: ! ratio:

1. Fluvoxamine
2. Placebo

We will use a centralized random allocation schedule, generated by computer and stratified by site and age.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

The investigational medical product will be packaged in similar bottles by a third party who will keep the allocation confidential until the end of the study. The bottles will be sealed and identified as "Research Product with no commercial value" and coded. They will be randomly allocated among the participants using a centralized randomization system The research subjects, medical assistance, administrative and health staff will not have access to the contents of the bottles. All arms will have a placebo counterpart with same dose schedule.

All planned Data and Safety Monitoring Board (DSMB) interim analysis will be blinded. If needed a unblinded statistician will be provided if DSMB decides to stop any arm. At the end of the study, or early termination as per DMSB interim analysis plan, the arms will then be identified.

Primary Purpose: Treatment

Condition

• Covid19
• SARS-Associated Coronavirus

Intervention

• Drug: Fluvoxamine Maleate 100 MG [Luvox]
  One tablet every 12 hours since randomization through day 09.
• Drug: Budesonide Powder

  One Fluvoxamine tablet every 12 hours since randomization through day 09. PLUS

  01 Budesonide powder (inhalation) every 12 hours since randomization through day 09.

  Other Name: Fluvoxamine Maleate 100 MG [Luvox]
• Drug: Placebo (mild disease)

  Placebo SC normal saline syringe (single day dosing schedule):

  Matching syringes containing 0,5 ml normal saline will be administered by SC route just after randomization Day 0 (single dose SC administration).

  OR

  Placebo oral tablets (10-day dosing schedule):

  Matching tablets started right after randomization using the dosing regimen of 01 tablet every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule) PLUS Matching inhalation therapy started right after randomization using the dosing regimen of 01 inhalation every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule)

• Drug: Peginterferon Lambda-1a
  One syringe of 180 mcg of Peginterferon Lambda SC right after randomization Day 0 (single dose SC administration).
• Drug: Placebo (SpO2 < 94%)
  One tablet every 12 hours starting at Randomization day (day 0) until end of day 09.

Study Arms

• Active Comparator: Fluvoxamine Maleate + Budesonide Inhalation powder

  Fluvoxamine 100 mg oral tablets:

  One tablet right after randomization (Day 0) followed by 100 mg BID for the following 09 days PLUS

  Budesonide Inhalation powder 400 mcg capsule:

  One 400 mcg capsule (inhalation) right after randomization (Day 0) followed by 400 mcg BID for the following 09 days

  Intervention: Drug: Budesonide Powder
• Active Comparator: Fluvoxamine Maleate

  Fluvoxamine 100 mg oral tablets:

  One tablet right after randomization (Day 0) followed by 100 mg BID for the following 09 days

  Intervention: Drug: Fluvoxamine Maleate 100 MG [Luvox]
• Placebo Comparator: Placebo (mild disease)

  Placebo SC normal saline syringe (single day dosing schedule):

  Matching syringes containing 0,5 ml normal saline will be administered by SC route just after randomization Day 0 (single dose SC administration).

  OR

  Placebo oral tablets (10-day dosing schedule):

  Matching tablets started right after randomization using the dosing regimen of 01 tablet every 12 hs starting at Randomization Day (Day 0) until end of Day 09 (total of 10 day schedule) PLUS

  Placebo Inhalation Therapy:

  One dosing (inhalation) right after randomization (Day 0) followed by one dose BID for the following 09 days

  Intervention: Drug: Placebo (mild disease)
• Active Comparator: Peginterferon Lambda

  Peginterferon Lambda 180 mcg syringe:

  One syringe of Peginterferon Lambda will be administered by SC route just after randomization (Day 0 - single dose SC administration).

  Intervention: Drug: Peginterferon Lambda-1a
• Placebo Comparator: Placebo (SpO2 < 94%)
  One tablet right after randomization (Day 0) followed by 100 mg BID for the following 09 days
  Intervention: Drug: Placebo (SpO2 < 94%)

Publications *

• Rayner CR, Dron L, Park JJH, Decloedt EH, Cotton MF, Niranjan V, Smith PF, Dodds MG, Brown F, Reis G, Wesche D, Mills EJ. Accelerating Clinical Evaluation of Repurposed Combination Therapies for COVID-19. Am J Trop Med Hyg. 2020 Oct;103(4):1364-1366. doi: 10.4269/ajtmh.20-0995.
• Park JJH, Mogg R, Smith GE, Nakimuli-Mpungu E, Jehan F, Rayner CR, Condo J, Decloedt EH, Nachega JB, Reis G, Mills EJ. How COVID-19 has fundamentally changed clinical research in global health. Lancet Glob Health. 2021 May;9(5):e711-e720. doi: 10.1016/S2214-109X(20)30542-8. Review.
• Forrest JI, Rawat A, Duailibe F, Guo CM, Sprague S, McKay P, Reis G, Mills EJ. Resilient Clinical Trial Infrastructure in Response to the COVID-19 Pandemic: Lessons Learned from the TOGETHER Randomized Platform Clinical Trial. Am J Trop Med Hyg. 2022 Jan 7;106(2):389-393. doi: 10.4269/ajtmh.21-1202.
• Reis G, Dos Santos Moreira-Silva EA, Silva DCM, Thabane L, Milagres AC, Ferreira TS, Dos Santos CVQ, de Souza Campos VH, Nogueira AMR, de Almeida APFG, Callegari ED, de Figueiredo Neto AD, Savassi LCM, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Forrest JI, Ruton H, Sprague S, McKay P, Glushchenko AV, Rayner CR, Lenze EJ, Reiersen AM, Guyatt GH, Mills EJ; TOGETHER investigators. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2022 Jan;10(1):e42-e51. doi: 10.1016/S2214-109X(21)00448-4. Epub 2021 Oct 28. Erratum in: Lancet Glob Health. 2022 Apr;10(4):e481.
• Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, Thabane L, Cruz Milagres A, Ferreira TS, Quirino Dos Santos CV, de Figueiredo Neto AD, Diniz Callegari E, Monteiro Savassi LC, Campos Simplicio MI, Barra Ribeiro L, Oliveira R, Harari O, Bailey H, Forrest JI, Glushchenko A, Sprague S, McKay P, Rayner CR, Ruton H, Guyatt GH, Mills EJ. Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial. Lancet Reg Health Am. 2022 Feb;6:100142. doi: 10.1016/j.lana.2021.100142. Epub 2021 Dec 14.
• Reis G, Silva EASM, Silva DCM, Thabane L, Milagres AC, Ferreira TS, Dos Santos CVQ, Campos VHS, Nogueira AMR, de Almeida APFG, Callegari ED, Neto ADF, Savassi LCM, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Forrest JI, Ruton H, Sprague S, McKay P, Guo CM, Rowland-Yeo K, Guyatt GH, Boulware DR, Rayner CR, Mills EJ; TOGETHER Investigators. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med. 2022 May 5;386(18):1721-1731. doi: 10.1056/NEJMoa2115869. Epub 2022 Mar 30.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 15, 2022): 4669
• Original Estimated Enrollment (submitted: January 26, 2021): 2724
• Estimated Study Completion Date: November 1, 2023
• Estimated Primary Completion Date: October 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patients over 18 years old with the ability to provide free and informed consent
2. Acute Flu-Like symptoms < 07 days.

3. Patients with at least ONE enhancement criteria:

   1. Age > 50 years;
   2. Diabetes mellitus requiring oral medication or insulin
   3. Systemic arterial hypertension requiring at least 01 oral medication for BP control;
   4. Known cardiovascular diseases (heart failure, congenital heart disease, valvar heart valve disease, coronary artery disease, cardiomyopathies)
   5. Symptomatic lung disease (emphysema, chronic bronchitis)
   6. Symptomatic asthma patients requiring chronic use of agents for control of symptoms.
   7. Fever > 38 C at baseline
   8. Obesity, defined as BMI> 30 kg / m2 body weight
   9. Transplanted patients
   10. Patient with stage IV chronic kidney disease or on dialysis.
   11. Immunosuppressed patients/ using corticosteroid therapy (equivalent to maximum 10 mg of prednisone per day) and/ or immunosuppressive therapy)
   12. Patients with a history of cancer in the last 05 years or undergoing treatment of a current cancer
   13. Chronic renal disease KDIGO IV or End-Stage Renal Disease on chronic ambulatory renal replacement therapy
   14. Patients with important limitation of daily activities due to: Dyspnea, chest pain myalgia (limited to 25% of all randomizations)
4. Patient with positive rapid test for SARS-CoV2 antigen performed on occasion of the screening or patient with a positive SARS-CoV2 diagnostic test within 07 days of the onset of symptoms.
5. Willingness to use the proposed investigative treatment and follow the protocol-related procedures foreseen in the research
6. Specific inclusion criteria for the fluvoxamine arm: Present significant dyspnea, arterial hypotension, severe dehydration or SpO2 between 85 to 93% in room air at admission and medical decision to discharge patient home, with an observation period at ER not exceeding 12 hours.

Exclusion Criteria:

1. Diagnostic test for negative SARS-CoV2 associated with acute flu symptoms (patient with a negative test collected early and becomes positive a few days \.

   later is eligible, as long as it is < 07 days since the onset of flu symptoms);

2. Patients with an acute respiratory condition compatible with COVID-19 treated in the primary care network and with a decision to be hospitalized;
3. Patients with acute respiratory symptoms due to other causes;
4. Dyspnea secondary to other acute and chronic respiratory causes or infections (eg, decompensated COPD, Acute bronchitis, Pneumonia other than viral, Primary pulmonary arterial hypertension);
5. Patients requiring hospitalization due to COVID-19 or SpO2 ≤ 93%.

6. Exclusion criteria applicable to injectable medication arms:

   a) Patients on chronic use of prednisone, prednisolone or other corticosteroid, with doses > 10 mg/day equivalent to prednisone,

7. Exclusion criteria applicable to 10-day treatment arms:

   1. Chronic use of serotonin reuptake inhibitors (SSRI),
   2. Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day
8. Continued use of monoamine oxidase inhibitors (MAOI): Phenelzine, Tranylcypromine, Selegiline, Isocarboxazid, moclobemide;
9. Patients with severe psychiatric disorders - schizophrenia, uncontrolled bipolar disorders, major depression with suicidal ideation.
10. Pregnant or breastfeeding patients;
11. History of severe ventricular cardiac arrhythmia (Ventricular tachycardia, recovered ventricular fibrillation patients) or Long QT Syndrome;
12. Known history of decompensated heart failure (NYHA III or IV), recent myocardial infarction (event < 90 days of screening), unstable angina, recent coronary bypass surgery (procedure < 90 days of screening), recent stroke ( event < 90 days from screening), symptomatic carotid disease, or moderate to severe mitral or aortic stenosis;
13. Surgical procedure or hospitalization planned (for other indications) to occur during treatment or up to 05 days after the last dose of study medication;
14. Current daily and/or uncontrolled alcohol consumption, which, in the investigator's view, could compromise participation in the study;
15. History of seizures in the last month or uncontrolled seizures;
16. Clinical history of moderate to severe hepatic impairment or hepatic cirrhosis with Child-Pugh C classification;
17. Patients with known serious degenerative neurological diseases and/or serious mental illnesses as assessed by the investigator;
18. Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol;
19. Any clinical conditions, including psychiatric conditions, which, in the investigator's view, could prevent the use of research drugs
20. Known hypersensitivity and/or intolerance to Fluvoxamine, Budesonide or Pegylated Interferon Lambda;
21. Use of drugs which have a known interaction with Fluvoxamine, Budesonide or Pegylated Interferon Lambda;
22. Inability to use the drugs and formulations provided for in this research;

Sex/Gender

• Sexes Eligible for Study: All
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Gender will be assumed as patient self-reported

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Gilmar Reis, MD, PhD; +553132416574; administrador@cardresearch.org

Contact: Eduardo Santos, MD, PhD; +553132416574; duduaugusto1@yahoo.com.br

• Listed Location Countries: Brazil

Administrative Information

• NCT Number: NCT04727424
• Other Study ID Numbers: TOGETHER_2
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Patient tables and main data.
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: As of protocol termination
• Access Criteria: Upon request

• Current Responsible Party: Cardresearch
• Original Responsible Party: Same as current
• Current Study Sponsor: Cardresearch
• Original Study Sponsor: Same as current

Collaborators

• Cytel Inc.
• McMaster University
• Fastgrants
• Eiger BioPharmaceuticals
• RainWater Foundation

Investigators

• Study Chair: Gilmar Reis, MD,PhD.; Cardresearch - Cardiologia Assistencial e de Pesquisa
• Study Director: Edward J Mills, FRCP; McMaster University

• PRS Account: Cardresearch
• Verification Date: January 2022