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

Sponsor

Cardresearch (Other)

Overall Status

Recruiting

CT.gov ID

NCT04727424

Collaborator

Cytel Inc. (Industry), McMaster University (Other), Fastgrants (Other), Eiger BioPharmaceuticals (Industry), RainWater Foundation (Other)

6,246

Enrollment

Locations

Arms

33.4

Anticipated Duration (Months)

520.5

Patients Per Site

15.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Covid19 SARS-Associated Coronavirus	Drug: Fluvoxamine Maleate 100 MG [Luvox] Drug: Budesonide Powder Drug: Placebo (mild disease) Drug: Peginterferon Lambda-1a Drug: Fluoxetine 20 MG	Phase 3

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:

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.
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 Design

Study Type:

Interventional

Anticipated Enrollment :

6246 participants

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. Fluvoxamine + Budesonide Fluoxetine + Budesonide Peginterferon Lambda Placebo Patients with SpO2 < 94% will be randomly allocated to one of two arms in a 1: ! ratio: Fluvoxamine Placebo We will use a centralized random allocation schedule, generated by computer and stratified by site and age.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. Fluvoxamine + Budesonide Fluoxetine + Budesonide Peginterferon Lambda PlaceboPatients with SpO2 < 94% will be randomly allocated to one of two arms in a 1: ! ratio:Fluvoxamine 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

Official Title:

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

Actual Study Start Date :

Jan 19, 2021

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Nov 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
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	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 Names: Fluvoxamine Maleate 100 MG [Luvox]
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	Drug: Fluvoxamine Maleate 100 MG [Luvox] One tablet every 12 hours since randomization through day 09.
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)	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)
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).	Drug: Peginterferon Lambda-1a One syringe of 180 mcg of Peginterferon Lambda SC right after randomization Day 0 (single dose SC administration).
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	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.

Outcome Measures

Primary Outcome Measures

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; [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) [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. [28 days]
Mortality due to COVID-19 associated complications

Secondary Outcome Measures

Change in viral load on day 03 and 07 after randomization (interferon lambda arm) [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) [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. [Randomization through day 28]
Time to hospitalization
Number of days with respiratory symptoms since randomization [Randomization through day 28]
Days with symptoms
Rate of all-cause hospitalizations [Randomization through day 28]
All cause hospitalizations
Rate of COVID-19 related hospitalizations [Randomization through day 28]
COVID-19 hospitalizations
Number of days on Mechanical Ventilator [Randomization through day 28]
Number of days on mechanical Ventilator
Number of Days on Intensive Care Unit [Randomization through day 28]
Number of days on Intensive Care Unit
Number of days on hospitalizations [Randomization through day 28]
Number of days on Hospitalization
Health and Functioning after COVID-19 disease [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 [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 [randomization through day 28]
Number of days on respiratory symptoms
Adherence of Study drug [Randomization through day 14]
Percentage of adherence on Study drug

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Patients over 18 years old with the ability to provide free and informed consent
Acute Flu-Like symptoms < 07 days.
Patients with at least ONE enhancement criteria:
Age > 50 years.
Diabetes mellitus requiring oral medication or insulin.
Systemic arterial hypertension requiring at least 01 oral medication for BP control.
Known cardiovascular diseases (heart failure, congenital heart disease, valvar heart valve disease, coronary artery disease, cardiomyopathies).
Symptomatic lung disease (emphysema, chronic bronchitis).
Symptomatic asthma patients requiring chronic use of agents for control of symptoms.
Fever > 38 C at baseline.
Obesity, defined as BMI> 30 kg / m2 body weight.
Transplanted patients.
Patient with stage IV chronic kidney disease or on dialysis.
Immunosuppressed patients/ using corticosteroid therapy (equivalent to maximum 10 mg of prednisone per day) and/ or immunosuppressive therapy).
Patients with a history of cancer in the last 05 years or undergoing treatment of a current cancer.
Chronic renal disease KDIGO IV or End-Stage Renal Disease on chronic ambulatory renal replacement therapy.
Patients with important limitation of daily activities due to: Dyspnea, chest pain myalgia (limited to 25% of all randomizations).
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.
Willingness to use the proposed investigative treatment and follow the protocol-related procedures foreseen in the research.
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"):

Patients over 18 years of age with the ability to provide free and informed consent.
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.
Patients over 18 years of age and a history of at least ONE of the following criteria.
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).

Individuals aged ≥ 60 years without co-morbidities.
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.
Viral syndrome with or without pneumonia and arterial O2 saturation > 94%.
Signing the Free and Informed Consent Form before any research procedures.
Willingness to use the proposed investigational treatment and follow the procedures provided for in the research.

Exclusion Criteria:

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).
Patients with an acute respiratory condition compatible with COVID-19 treated in the primary care network and with a decision to be hospitalized.
Patients with acute respiratory symptoms due to other causes.
Dyspnea secondary to other acute and chronic respiratory causes or infections (eg, decompensated COPD, Acute bronchitis, Pneumonia other than viral, Primary pulmonary arterial hypertension).
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.
Exclusion criteria applicable to injectable medication arms:

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

Exclusion criteria applicable to 07-day treatment arms:
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.
Severe organ damage that requires resuscitation and ongoing treatment.
Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day
Immunosuppressive treatment in progress
History of known pulmonary arterial hypertension or pulmonary fibrosis
Patients who have received a previous dose of SARS-CoV-2 vaccine
Use of serotonin reuptake inhibitors (all).
Exclusion criteria applicable to 10-day treatment arms:
Chronic use of serotonin reuptake inhibitors other than sertraline
Chronic corticosteroid use with equivalent prednisone doses of > 40 mg/day;
Continued use of monoamine oxidative inhibitors (MAOI): Phenelzine, Tranylcypromine, Selegiline, Isocarboxazid, moclobemide.
Patients with severe psychiatric disorders - schizophrenia, uncontrolled bipolar disorders, major depression with suicidal ideation.
Pregnant or breastfeeding patients.
History of severe ventricular cardiac arrhythmia (Ventricular tachycardia, recovered ventricular fibrillation patients) or Long QT Syndrome.
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.
Surgical procedure or hospitalization planned (for other indications) to occur during treatment or up to 5 days after the last dose of study medication.
Current daily and/or uncontrolled alcohol consumption, which, in the investigator's view, could compromise participation in the study.
History of seizures in the last month or uncontrolled seizures.
Clinical history of moderate to severe hepatic impairment or hepatic cirrhosis with Child-Pugh C classification.
Patients with known serious degenerative neurological diseases and/or serious mental illnesses as assessed by the investigator.
Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol.
Any clinical conditions, including psychiatric conditions, which, in the investigator's view, could prevent the use of research drugs.
Known hypersensitivity and/or intolerance to Fluvoxamine, Budesonide, Pegylated Interferon Lambda and Fluoxetine.
Use of drugs which have a known interaction with Fluvoxamine, Budesonide, Pegylated Interferon Lambda and Fluoxetine.
Inability to use the drugs and formulations provided for in this research.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Betim	Betim	MG	Brazil	32550770
2	Hospital e Maternidade Santa Rita	Contagem	MG	Brazil	32215000
3	City of Governador Valadares	Governador Valadares	MG	Brazil	35010-000
4	City of Ibirité	Ibirité	MG	Brazil	30240528
5	City of Nova Lima	Nova Lima	MG	Brazil	34000000
6	City of Santa Luzia	Santa Luzia	MG	Brazil	33105160
7	City of Sete Lagoas	Sete Lagoas	MG	Brazil	35700-000
8	CARDRESEARCH - Cardiologia Assistencial e de Pesquisa	Belo Horizonte	Minas Gerais	Brazil	30150240
9	City of Brumadinho	Brumadinho	Minas Gerais	Brazil	35.460-000
10	City of Igarapé	Igarapé	Minas Gerais	Brazil	32900-000
11	Centro Universitário FIPMOC	Montes Claros	Minas Gerais	Brazil	39.408-007
12	Universidade Federal de Ouro Preto	Ouro Preto	Minas Gerais	Brazil	35400000