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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04727424
Recruitment Status : Recruiting
First Posted : January 27, 2021
Last Update Posted : July 7, 2022
Sponsor:
Collaborators:
Cytel Inc.
McMaster University
Fastgrants
Eiger BioPharmaceuticals
RainWater Foundation
Information provided by (Responsible Party):
Cardresearch

Tracking Information
First Submitted Date  ICMJE January 25, 2021
First Posted Date  ICMJE January 27, 2021
Last Update Posted Date July 7, 2022
Actual Study Start Date  ICMJE January 19, 2021
Estimated Primary Completion Date October 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2022)
  • Rate of fluvoxamine + budesonide, fluoxetine + budesonide, peginterferon Lambda, 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, fluoxetine + 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
  • Rate of fluvoxamine + budesonide, fluoxetine + budesonide, peginterferon Lambda and fluvoxamine in changing the COVID-19 associated mortality. [ Time Frame: 28 days ]
    Mortality due to COVID-19 associated complications
Original Primary Outcome Measures  ICMJE
 (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
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Repurposed Approved and Under Development Therapies for Patients With Early-Onset COVID-19 and Mild Symptoms
Official Title  ICMJE A Multicenter, Prospective, Adaptive, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effect of Interferon Lambda 1A, Fluvoxamina + Budesonida, Fluoxetina + Budesonida 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, Fluoxetine, Budesonide and Pegilatrd Interferon Lambda 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 prospective, double-blinded, randomized evaluation of potential therapies 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.

Important considerations on TOGETHER Trial:

  1. Vaccinated patients were proposed to be an exclusion criteria on amendment 3 which was received final National Ethics Committee (CONEP) decision letter number 4.747.755_E3 dated June 01, 2021. We evaluated vaccination data and outcomes on two large cities involving 150.000 individuals and based on these results we submitted to the IRB a notification request to withdraw the exclusion criteria 4 (vaccination > 14 days) on July 14, 2021, which was granted.
  2. The amendment 5 proposed a collaborative partnership with ANTICOV Consortia and incorporating the fluoxetine + budesonide and its active comparator (paracetamol) arms, as per ANTICOV protocol WHO ERC approval version 13.0. These generated data will be analyzed along with ANTICOV fluoxetine + budesonide and paracetamol arms.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

TOGETHER trial is a Multiplatform, adaptive trial started on 20 Jan 2021. this description is as per amendment five with final Brazilian National Ethics Committee final decision letter issued on 27 January 2022.

Patients with mild disease will be screened at primary and secondary care public health services and randomly allocated to one of four treatment arms in a 1:1:1:1 ratio, as per described in detail in approved protocol version 6.0 dated 03 JAN 2022.

  1. Fluvoxamine + Budesonide
  2. Fluoxetine + Budesonide
  3. Peginterferon Lambda
  4. 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  ICMJE
  • Covid19
  • SARS-Associated Coronavirus
Intervention  ICMJE
  • 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 schedule):

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

    OR

    Placebo oral tablets (10-day schedule):

    Matching tablets started 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

    OR

    Paracetamol (07-day schedule - active comparator):

    Paracetamol 500 mg tablets started after randomization using the dosing regimen of 01 tablet BID starting at Rand. Day (Day 0) until end of Day 06 (total of 07 days schedule)

    OR

    Placebo oral tablets (10-day schedule for patients with SPO2 < 94%):

    One tablet after randomization (Day 0) followed by 01 tablet BID for the following 09 days (total of 10 days schedule)

  • Drug: Peginterferon Lambda-1a
    One syringe of 180 mcg of Peginterferon Lambda SC right after randomization Day 0 (single dose SC administration).
  • Drug: Fluoxetine 20 MG

    Two Fluoxetine tablets every day starting just after randomization through day 07.

    PLUS

    01 Budesonide powder (inhalation) every 12 hours since randomization through day 07.

Study Arms  ICMJE
  • Active Comparator: Fluvoxamine Maleate + Budesonide Inhalation powder

    Fluvoxamine 100 mg oral tablets:

    One tablet 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) 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 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 schedule):

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

    OR

    Placebo oral tablets (10-day schedule):

    Matching tablets started 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

    OR

    Paracetamol (07-day schedule - active comparator):

    Paracetamol 500 mg tablets started after randomization using the dosing regimen of 01 tablet BID starting at Rand. Day (Day 0) until end of Day 06 (total of 07 days schedule)

    OR

    Placebo oral tablets (10-day schedule for patients with SPO2 < 94%):

    One tablet after randomization (Day 0) followed by 01 tablet BID for the following 09 days (total of 10 days schedule)

    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
  • Active Comparator: Fluxetine + Budesonide Inhalation powder

    Fluoxetine 20 mg oral tablets:

    Two tablets right after randomization (Day 0) followed by 40 mg MID for the following 06 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 06 days

    Intervention: Drug: Fluoxetine 20 MG
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 3, 2022)
6246
Original Estimated Enrollment  ICMJE
 (submitted: January 26, 2021)
2724
Estimated Study Completion Date  ICMJE November 1, 2023
Estimated Primary Completion Date October 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

A - Inclusion Criteria (except fluoxetine + budesonide and paracetamol arms):

  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.

B - Inclusion criteria for the Fluoxetine + Budesonide combination arm (07 days of treatment - partnership with the "ANTICOV Consortium"):

  1. Patients over 18 years of age with the ability to provide free and informed consent.
  2. Patients treated at a Basic Health Unit of the Unified Health System (SUS) or patients treated at emergency care units of the SUS or supplementary medicine with an acute clinical condition compatible with COVID 19.
  3. Patients over 18 years of age and a history of at least ONE of the following criteria.

    1. Diabetes mellitus, heart disease, chronic kidney disease, chronic obstructive pulmonary disease, cerebrovascular diseases or patients considered to be underweight or overweight according to the investigator's judgment (BMI ≤ 16 or BMI > 25).

      OR

    2. Individuals aged ≥ 60 years without co-morbidities.
  4. COVID-19 confirmed by molecular or antigenic test for SARS-CoV-2 within up to 24 hours prior to screening and a maximum of 2 days after sample collection.
  5. Viral syndrome with or without pneumonia and arterial O2 saturation > 94%.
  6. Signing the Free and Informed Consent Form before any research procedures.
  7. Willingness to use the proposed investigational treatment and follow the procedures provided for in the research.

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%. NOTE: Patients allocated to the fluvoxamine arm alone may be included if SpO2 is below 94%, with no evidence of acute respiratory failure, provided that the attending physician decides to discharge the unit and continue treatment on an outpatient basis.
  6. Exclusion criteria applicable to injectable medication arms:

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

  7. Exclusion criteria applicable to 07-day treatment arms:

    1. Abnormal findings on physical examination: Respiratory rate ≥ 25 sisters; blood pressure < 90/60 mmHg or > 160/100 mmHg; Weight < 45 kg; recent episodes of vomiting within the last 24 hours or recurrent diarrhea or serum potassium below 3.5 mEq/L.
    2. Severe organ damage that requires resuscitation and ongoing treatment.
    3. Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day
    4. Immunosuppressive treatment in progress
    5. History of known pulmonary arterial hypertension or pulmonary fibrosis
    6. Patients who have received a previous dose of SARS-CoV-2 vaccine
    7. Use of serotonin reuptake inhibitors (all).
  8. Exclusion criteria applicable to 10-day treatment arms:

    1. Chronic use of serotonin reuptake inhibitors other than sertraline
    2. Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day;
  9. Continued use of monoamine oxidative inhibitors (MAOI): Phenelzine, Tranylcypromine, Selegiline, Isocarboxazid, moclobemide.
  10. Patients with severe psychiatric disorders - schizophrenia, uncontrolled bipolar disorders, major depression with suicidal ideation.
  11. Pregnant or breastfeeding patients.
  12. History of severe ventricular cardiac arrhythmia (Ventricular tachycardia, recovered ventricular fibrillation patients) or Long QT Syndrome.
  13. 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.
  14. Surgical procedure or hospitalization planned (for other indications) to occur during treatment or up to 5 days after the last dose of study medication.
  15. Current daily and/or uncontrolled alcohol consumption, which, in the investigator's view, could compromise participation in the study.
  16. History of seizures in the last month or uncontrolled seizures.
  17. Clinical history of moderate to severe hepatic impairment or hepatic cirrhosis with Child-Pugh C classification.
  18. Patients with known serious degenerative neurological diseases and/or serious mental illnesses as assessed by the investigator.
  19. Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol.
  20. Any clinical conditions, including psychiatric conditions, which, in the investigator's view, could prevent the use of research drugs.
  21. Known hypersensitivity and/or intolerance to Fluvoxamine, Budesonide, Pegylated Interferon Lambda and Fluoxetine.
  22. Use of drugs which have a known interaction with Fluvoxamine, Budesonide, Pegylated Interferon Lambda and Fluoxetine.
  23. Inability to use the drugs and formulations provided for in this research.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Gender Based Eligibility: Yes
Gender Eligibility Description: Gender will be assumed as patient self-reported
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Gilmar Reis, MD, PhD +553132416574 administrador@cardresearch.org
Contact: Eduardo Santos, MD, PhD +553132416574 duduaugusto1@yahoo.com.br
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04727424
Other Study ID Numbers  ICMJE 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  ICMJE
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  ICMJE Cardresearch
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Cytel Inc.
  • McMaster University
  • Fastgrants
  • Eiger BioPharmaceuticals
  • RainWater Foundation
Investigators  ICMJE
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

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP