Clinical trial NCT04321278: Safety and Efficacy of Hydroxychloroquine Associated With Azithromycin in SARS-CoV2 Virus (Coalition Covid-19 Brasil II)
Official title: Evaluation of the Safety and Clinical Efficacy of Hydroxychloroquine Associated With Azithromycin in Patients With Pneumonia Caused by Infection by the SARS-CoV2 Virus - Coalition COVID-19 Brasil II - SEVERE - Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Coronavirus Infections
Pneumonia, Viral
Keywords: SARS-CoV2 virus
2019-nCOV
COVID-19
hydroxychloroquine
azithromycin
Lead sponsor: Hospital Israelita Albert Einstein
Sponsor class: OTHER
Collaborators: name: EMS
name: Hospital do Coracao
name: Hospital Sirio-Libanes
name: Brazilian Research In Intensive Care Network
First posted: 2020-03-25
Enrollment: 440
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1. Intervention Group: Hydroxychloroquine + azithromycin. After randomization, Hydroxychloroquine \[400mg 2x/day, 12/12h\] + azithromycin \[500mg 1x/day\]) for 10 days. Standard treatment is according to the treatment protocol for 2019-nCoV infection.
2. Active Control Group: Hydroxychloroquine. After randomization, Hydroxychloroquine \[400mg 2x/day, 12/12h\] for 10 days. Standard treatment is according to the treatment protocol for 2019-nCoV infection.
Primary purpose: TREATMENT

Brief summary: The Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV2) is a new and recognized infectious disease of the respiratory tract. Around 20% of those infected have severe pneumonia and currently there is no specific or effective therapy to treat this disease. Therapeutic options using malaria drugs chloroquine and hydroxychloroquine have shown promising results in vitro and in vivo test. But those efforts have not involved large, carefully-conducted controlled studies that would provide the global medical community the proof that these drugs work on a significant scale. In this way, the present study will evaluate the effectiveness and safety of the use of hydroxychloroquine combined with azithromycin compared to hydroxychloroquine monotherapy in patients hospitalized with pneumonia by SARS-CoV2 virus.

Detailed description: The Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV2) is a new and recognized infectious disease of the respiratory tract that is now spreading to several countries in the world, including Brazil. Mortality rates after infection are higher in adults over 60 and with a history of comorbidities. The most serious patients need care in intensive care units (ICU). Most of the time they depend on mechanical ventilation support due to acute respiratory distress syndrome (ARDS). Infection rates are higher than the capacity for intensive care, which represents a serious problem in medical care. Around 20% of those infected have severe pneumonia and so far it does not have a specific therapy, or even, an effective clinical management. Therapeutic options using malaria drugs chloroquine and hydroxychloroquine have shown promising results in vitro and in vivo test. A recent, small, non-randomized study with hydroxychloroquine in 36 patients infected with SARS-Cov-2 proved to be promising in the ability to reset the viral load in 6 days after starting treatment. Thus, the present study will evaluate the effectiveness and safety of the use of hydroxychloroquine combined with azithromycin compared to hydroxychloroquine monotherapy in the clinical evolution by the ordinal scale of 6 points in adult patients hospitalized with pneumonia caused by infection by the SARS-CoV2 virus in Brazil.

Eligibility criteria: Inclusion Criteria:

1. Males and females aged \> 18 years;
2. Suspected or confirmed infection by SARS-CoV2;

Presenting with one of the following:

* Need for oxygen supplementation \> 4 L/min, or
* Need for high-flow nasal canula, or
* Need for non-invasive ventilation, or
* Need for mechanical ventilation.

Exclusion Criteria:

1. Refusal to provide written informed consent (either the patient or a legal representative);
2. Hypersensitivity to any of the drugs used in the study (Azithromycin or Hydroxychloroquine);
3. Patients with more than 48 hours of prior study medication use;
4. Patients with onset of symptoms longer than 14 days;
5. Patients with long QT syndrome or severe ventricular arrhythmias, not protected by an implantable cardioverter defibrillators (ICD).;
6. QTc\>= 480ms;
7. Do not resuscitate order or exclusive palliative care;
8. Patients with liver disease or cirrhosis or abnormal liver enzyme tests above three times the upper limit values (alanine aminotransferase -ALT and aspartate aminotransferase - AST);
9. Patients with known retinopathy or macular degeneration;
10. Patients with history of pancreatitis;
11. Patients with concomitant use of medications that alter the absorption or excretion of azithromycin or hydroxychloroquine;
12. Breastfeeding women;
13. Pregnancy

Primary outcomes:
measure: Evaluation of the clinical status
timeFrame: 15 days after randomization
Secondary outcomes:
measure: All-cause mortality
timeFrame: 29 days after randomization
measure: Evaluation of the clinical status
timeFrame: 7 and 29 days after randomization
measure: Number of days free from mechanical ventilation
timeFrame: 29 days after randomization
measure: Duration of mechanical ventilation
timeFrame: 29 days after randomization
measure: Duration of hospitalization
timeFrame: 29 days after randomization
measure: Other secondary infections
timeFrame: 29 days after randomization
measure: Time from treatment start to death
timeFrame: 29 days after randomization
measure: Medium and long-term outcomes of SARS-CoV2 infection on morbimortality, daily life activities, mental health, and quality of life
timeFrame: 3, 6, 9 and 12 months
measure: Assess whether the tested therapies may be affected by leucocyte phenotype
timeFrame: Baseline
Other outcomes:
measure: QT interval prolongation
timeFrame: 29 days after randomization
measure: Gastrointestinal intolerance
timeFrame: 29 days after randomization
measure: Laboratory abnormalities
timeFrame: 29 days after randomization
measure: Adverse events
timeFrame: 29 days after randomization
Locations:
city: Rio Branco
country: Brazil
facility: Hospital de Urgência e Emergência de Rio Branco
state: AC
city: Ipiaú
country: Brazil
facility: Hospital e Clínica São Roque
state: BA
city: Salvador
country: Brazil
facility: Hospital da Cidade
state: BA
city: Barbalha
country: Brazil
facility: Hospital Maternidade São Vicente de Paulo
state: CE
city: Fortaleza
country: Brazil
facility: Hospital de Messejana Dr. Carlos Alberto Studart Gomes
state: CE
city: Juazeiro Do Norte
country: Brazil
facility: Hospital Unimed Cariri
state: CE
city: Brasilia
country: Brazil
facility: Hospital Brasilia
state: DF
city: Serra
country: Brazil
facility: Hospital Estadual Jayme dos Santos Neves
state: ES
city: Vila Velha
country: Brazil
facility: Hospital Evangélico de Vila Velha
state: ES
city: Goiânia
country: Brazil
facility: Secretaria de Estado de Saúde de Goias
state: GO
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericórdia de Belo Horizonte Santa Casa de BH
state: MG
city: Passos
country: Brazil
facility: Hospital Santa Paula
state: MG
city: São João Del Rei
country: Brazil
facility: Santa Casa da Misericordia - UTI (São João Del Rey)
state: MG
city: Poços De Caldas
country: Brazil
facility: Hospital Maternidade E Pronto Socorro Santa Lucia Ltda
state: Minas Gerais
city: Londrina
country: Brazil
facility: Universidade Estadual de Londrina
state: Paraná
city: Belém
country: Brazil
facility: Hospital Adventista de Belém
state: Pará
city: Belem
country: Brazil
facility: Hospital Adventista de Belem
state: PA
city: Recife
country: Brazil
facility: Procape - Pronto S.Cardiologico de Pe.Prof.Luiz Tavares-
state: PE
city: Curitiba
country: Brazil
facility: Liga Paranaense de Combate ao Câncer
state: PR
city: Natal
country: Brazil
facility: Hospital Giselda Trigueiro
state: Rio Grande Do Norte
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Irmandade da Santa Casa de Misericordia de Porto Alegre
state: Rio Grande Do Sul
city: Rio de Janeiro
country: Brazil
facility: Hospital Naval Marcílio Dias
state: RJ
city: Rio De Janeiro
country: Brazil
facility: Hospital São Lucas
state: RJ
city: Natal
country: Brazil
facility: Hospital Maternidade PROMATER
state: RN
city: Bento Gonçalves
country: Brazil
facility: Associação Dr. Bartholomeu Tacchini
state: RS
city: Caxias Do Sul
country: Brazil
facility: Hospital Geral de Caxias do Sul
state: RS
city: Lajeado
country: Brazil
facility: Hospital Bruno Born
state: RS
city: Passo Fundo
country: Brazil
facility: Hospital São Vicente de Paulo
state: RS
city: Blumenau
country: Brazil
facility: Maestri E Kormann Consultoria Medico-Cientifica
state: Santa Catarina
city: Criciúma
country: Brazil
facility: Sociedade Literaria e Caritativa Santo Agostinho
state: Santa Catarina
city: Florianópolis
country: Brazil
facility: Hospital Nereu Ramos
state: SC
city: Florianópolis
country: Brazil
facility: Hospital Universitário Polydoro Ernani de São Thiago/HU - UFSC
state: SC
city: Joinville
country: Brazil
facility: Centro Hospitalar Unimed
state: SC
city: Joinville
country: Brazil
facility: Hospital Dona Helena
state: SC
city: Joinville
country: Brazil
facility: Hospital Municipal Sao Jose
state: SC
city: Joinville
country: Brazil
facility: Hospital Regional Hans Dieter Schmidt
state: SC
city: Botucatu
country: Brazil
facility: Faculdade de Medicina de Botucatu
state: SP
city: Campinas
country: Brazil
facility: nstituto de Pesquisa Clínica de Campinas
state: SP
city: Santo André
country: Brazil
facility: Fundação do ABC (Hospital Estadual Mário Covas)
state: SP
city: São Paulo
country: Brazil
facility: AC Camargo Cancer Center - Fundação Antonio Prudente
state: SP
city: São Paulo
country: Brazil
facility: Casa de Saude Santa Marcelina
state: SP
city: São Paulo
country: Brazil
facility: Hospital Alemão Oswaldo Cruz
state: SP
city: São Paulo
country: Brazil
facility: Hospital Moriah
state: SP
city: São Paulo
country: Brazil
facility: Hospital Nove de Julho
state: SP
city: São Paulo
country: Brazil
facility: Hospital Santa Paula
state: SP
city: São Paulo
country: Brazil
facility: Hospital São Camilo Pompeia
state: SP
city: Barretos
country: Brazil
facility: Fundação Pio XII
state: São Paulo
city: Votuporanga
country: Brazil
facility: Santa Casa de Misericordia de Votuporanga
state: São Paulo
city: São Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein
city: São Paulo
country: Brazil
facility: A Beneficência Portuguesa de São Paulo - BP
city: São Paulo
country: Brazil
facility: Associacao Beneficente Siria
city: São Paulo
country: Brazil
facility: Hospital Vila Santa Catarina
city: São Paulo
country: Brazil
facility: Real e Benemérita Associação Portuguesa de Beneficência/SP - 1
city: São Paulo
country: Brazil
facility: Secretaria de Saúde do Estado de São Paulo
city: São Paulo
country: Brazil
facility: Serv Social da Industria do papel, papelão e cortiça do estado de SP
city: São Paulo
country: Brazil
facility: Sociedade Beneficente de Senhoras Hospital Sírio-Libanês
city: São Paulo
country: Brazil
facility: Universidade Federal de São Paulo
Study officials:
affiliation: Hospital Israelita Albert Einstein
name: Otávio Berwanger, PhD
role: STUDY_DIRECTOR
References:
citation: Furtado RHM, Berwanger O, Fonseca HA, Correa TD, Ferraz LR, Lapa MG, Zampieri FG, Veiga VC, Azevedo LCP, Rosa RG, Lopes RD, Avezum A, Manoel ALO, Piza FMT, Martins PA, Lisboa TC, Pereira AJ, Olivato GB, Dantas VCS, Milan EP, Gebara OCE, Amazonas RB, Oliveira MB, Soares RVP, Moia DDF, Piano LPA, Castilho K, Momesso RGRAP, Schettino GPP, Rizzo LV, Neto AS, Machado FR, Cavalcanti AB; COALITION COVID-19 Brazil II Investigators. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020 Oct 3;396(10256):959-967. doi: 10.1016/S0140-6736(20)31862-6. Epub 2020 Sep 5.
citation: Lasheras I, Santabarbara J. Use of antimalarial drugs in the treatment of COVID-19: A window of opportunity? Med Clin (Barc). 2020 Jul 10;155(1):23-25. doi: 10.1016/j.medcli.2020.04.004. Epub 2020 Apr 22. No abstract available. English, Spanish.