COALITION-V: Randomized Placebo-controlled Trial of Hydroxychloroquine in Outpatient Cases With Coronavirus Disease 2019 (COVID-19)

Sponsor

Hospital Alemão Oswaldo Cruz (Other)

Overall Status

Completed

CT.gov ID

NCT04466540

Collaborator

EMS S/A (Other), Hospital do Coracao (Other), Hospital Israelita Albert Einstein (Other), Hospital Sirio-Libanes (Other), Hospital Moinhos de Vento (Other), Brazilian Research In Intensive Care Network (Other)

1,372

Enrollment

Locations

Arms

16.6

Actual Duration (Months)

19.9

Patients Per Site

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In December 2019, a group of patients with pneumonia of unknown cause was identified in Wuhan, in the Hubei province, China. Despite the need of target specific therapeutic options for COVID-19, until now there is no proof of effectiveness of any specific intervention. Some limited observational trials and also evidence from randomized trials have shown no benefit of hydroxychloroquine in inpatient context. Thus, studies evaluating interventions in an outpatient setting in non-severe patients can provide important information related to prognosis and safety. In this way, the present study will evaluate the effectiveness and safety of the use of hydroxychloroquine in COVID-19 outpatients by means of a Randomized, double-blind, placebo-controlled trial

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Hydroxychloroquine Drug: Placebo	Phase 4

Detailed Description

Pragmatic, double-blind, placebo-controlled randomized parallel-group, two-arm clinical trial (with allocation ratio 1:1), evaluating hydroxychloroquine (800 mg at 1st day, and 400 mg from day 2 to 7) for prevention of hospitalization and respiratory complications in non-hospitalized confirmed or suspected COVID-19 cases. Key inclusion criteria are adults (equal to or greater tahn 18 years) seeking medical care with suspected or confirmed COVID-19, with time between symptoms and inclusion ≤ 07 days, presenting mild symptoms, without indication of hospitalization and at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; Chronic Obstructive Pulmonary Disease (COPD) or other chronic lung diseases; smoking; immunosuppression; obesity (Defined as BMI equal to or greater than 30 Kg/m2). Primary endpoint is to assess if the treatment with hydroxychloroquine is able to avoid hospitalization due to a COVID-19-related clinical reason within 30 days of randomization in an outpatient setting. Hospitalization is considered to be hospital stay for a period > 24h or an additional hospitalized calendar day. The primary endpoint is centrally adjudicated by an independent clinical events committee blinded to the assigned treatment groups. Secondary endpoints include uncontrolled asthma after ≥ 5 days of starting study medication; pneumonia; otitis media; fever resolution time; time to improve respiratory symptoms; hospitalization in the Intensive Care Unit; need for orotracheal intubation; mechanical ventilation time; mortality. Safety outcomes will be hypoglycemia; palpitations; reduced visual acuity; diarrhea; anorexia; and emotional lability. The evaluation of the primary outcome (hospitalization within 30 days) will be performed for the included population following the principle of intention-to-treat (ITT), which will consist of all randomized cases. A modified intention-to-treat analysis (mITT), in which cases definitely confirmed as negative for COVID-19 will be excluded, will also be performed.

Study Design

Study Type:

Interventional

Actual Enrollment :

1372 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Pragmatic, double-blind, placebo-controlled randomized parallel-group, two-arm clinical trial (with allocation ratio 1:1)Pragmatic, double-blind, placebo-controlled randomized parallel-group, two-arm clinical trial (with allocation ratio 1:1)

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Randomization (1:1) is generated by a validated software and performed in permuted blocks of size 8. Concealment of the randomization list is maintained through a 24-hour, centralized, automated, internet-based randomization system. Furthermore, as placebo-controlled study, the placebo will have the same structural characteristics as the active drug and will be dispensed in cartridges that do not allow the identification of what is being given

Primary Purpose:

Treatment

Official Title:

Pragmatic, Double-blind, Placebo-controlled Randomized Clinical Trial, Evaluating Hydroxychloroquine for Prevention of Hospitalization and Respiratory Complications in Non-hospitalized Patients With Confirmed or Probable COVID-19

Actual Study Start Date :

May 12, 2020

Actual Primary Completion Date :

Jul 28, 2021

Actual Study Completion Date :

Sep 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Hydroxychloroquine (HCQ) HCQ group participants will receive a dose of 400mg twice daily (BID) in the first day, and a dose of 400 mg once daily (OD) from the second day of treatment, in a total of 7 days.	Drug: Hydroxychloroquine Hydroxychloroquine pharmaceutical form will be tablets of 400 mg.
Placebo Comparator: Placebo The placebo group will follow the same regimen of administration	Drug: Placebo Hydroxychloroquine placebo

Arm

Intervention/Treatment

Experimental: Hydroxychloroquine (HCQ)

HCQ group participants will receive a dose of 400mg twice daily (BID) in the first day, and a dose of 400 mg once daily (OD) from the second day of treatment, in a total of 7 days.

Drug: Hydroxychloroquine

Hydroxychloroquine pharmaceutical form will be tablets of 400 mg.

Placebo Comparator: Placebo

The placebo group will follow the same regimen of administration

Drug: Placebo

Hydroxychloroquine placebo

Outcome Measures

Primary Outcome Measures

Hospitalization [30 days from randomization]
To assess if the treatment is able to avoid hospitalization due to a COVID-19-related clinical reason within 30 days of randomization in an outpatient setting. Hospitalization is considered to be hospital stay for a period > 24h or an additional hospitalized calendar day.

Secondary Outcome Measures

Uncontrolled asthma after ≥ 5 days of starting study medication [within 30 days from randomization]
Affirmative answer in three or four items of the Global Initiative for Asthma (GINA) questionnaire
Pneumonia [within 30 days from randomization]
Defined by clinical-radiological criteria - a history of cough and one or more of the following symptoms: sputum, dyspnea, chest pain, sweating or fever (T> 37.8o C) + Chest CT scan showing ground-glass opacity, focal consolidations or mixed opacities (including reverse halo sign), uni or bilateral
Otitis media [within 30 days from randomization]
Defined by clinical criteria - Fever (T> 37.8o C) and otalgia + bulging of the tympanic membrane
Fever resolution time [within 30 days from randomization]
Day 0 of fever resolution will be defined as the first afebrile day (T <37.5o C) after inclusion in the study followed by at least two consecutive days. The temperature will be obtained through the participant report in the patient's diary
Time to improve respiratory symptoms [within 30 days from randomization]
Time to improve respiratory symptoms (cough, runny nose)
Hospitalization in the Intensive Care Unit [within 30 days from randomization]
Admission to ICU due to clinical reasons related to COVID-19
Need for Orotracheal Intubation [within 30 days from randomization]
Clinical need for Orotracheal Intubation as assessed by the physician responsible for the case
Mechanical Ventilation Time [within 30 days from randomization]
Number of days on mechanical ventilation until extubation or death
Mortality [within 30 days from randomization]
Death due to any cause that occurred within 30 days after inclusion in the study

Other Outcome Measures

Hypoglycemia [within 30 days from randomization]
Change in the frequency of hypoglycemic episodes in diabetic patients using hypoglycemic medication, perceived by clinical signs or symptoms or measured in a capillary or blood glucose device
Palpitations [within 30 days from randomization]
Presence of cardiac arrhythmias in patients without known history of prolongation of the measure between Q wave and T wave in the heart's electrical cycle (QTc) or pre-existing heart disease;
Reduced visual acuity [within 30 days from randomization]
Change in visual acuity or new diagnosis of retinal disease not previously documented
Diarrhea [within 30 days from randomization]
Change in bowel habit greater than three (3) diarrheal episodes per day during the use of hydroxychloroquine medication and 3 days after its end
Anorexia [within 30 days from randomization]
Change in appetite during medication use hydroxychloroquine and 3 days after the end of treatment
Emotional lability [within 30 days from randomization]
Perception of change in emotional lability (mood swings) during hydroxychloroquine use and 3 days after the end of treatment
Time to hospitalization after randomization [within 30 days from randomization]
Time from randomization to hospitalization
Assessment of the patient clinical status at the time of hospitalization [within 30 days from randomization]
Clinical and vital signs assessed when admitted to hospital

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

It will be considered eligible those adults (equal to or greater than 18 years) seeking medical care with suspected or confirmed COVID-19, with time between symptoms and inclusion ≤ 07 days, presenting mild symptoms, without indication of hospitalization and at least 1 risk factor for complication:

65 years;
Hypertension;
Diabetes mellitus;
Asthma;
COPD or other chronic lung diseases;
Smoking;
Immunosuppression;
Obesity (Defined as BMI equal to or greater than 30 Kg/m2).

Exclusion Criteria:

Patients under 18 years old;
Hospitalization at the first medical care;
Positive test for influenza at the first medical care;
Known hypersensitivity to hydroxychloroquine / chloroquine;
Previous diagnosis of retinopathy or macular degeneration;
Previous diagnosis of Long QT-syndrome, history of sudden death in close family members (parents and siblings), decompensated heart failure, unstable coronary artery disease, use of anti-arrhythmic drugs or other drugs that can increase the hydroxychloroquine bioavailability or enhance its effect;
Evidence of known liver disease, reported by the patient;
Evidence of known chronic kidney disease, reported by the patient;
Patients with pancreatitis;
Baseline ECG with QTc interval ≥ 480ms;
Chronic use of hydroxychloroquine/chloroquine for other reasons;
Pregnancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centro de Pesquisas Clínicas Dr. Marco Mota HCOR	Maceió	Alagoas	Brazil
2	Hospital e Clínica São Roque	Ipiaú	Bahia	Brazil
3	Clínica Otorhinus	Salvador	Bahia	Brazil
4	Hospital da Bahia	Salvador	Bahia	Brazil
5	Hospital Santa Izabel	Salvador	Bahia	Brazil
6	Instituto Cárdio Pulmonar da Bahia	Salvador	Bahia	Brazil
7	Hospital SAMUR	Vitória Da Conquista	Bahia	Brazil
8	Hospital Maternidade São Vicente de Paulo	Barbalha	Ceará	Brazil
9	Hospital Unimed Cariri	Juazeiro Do Norte	Ceará	Brazil
10	Unimed Sul Capixaba	Cachoeiro De Itapemirim	Espírito Santo	Brazil
11	Hospital das Clínicas Universidade Federal de Goiás	Goiânia	Goiás	Brazil
12	Santa Casa de Misericórdia de Passos	Passos	Minas Agerais	Brazil
13	Hospital Júlia Kubitschek	Belo Horizonte	Minas Gerais	Brazil
14	Instituto da Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa	Belo Horizonte	Minas Gerais	Brazil
15	Casa de Caridade de Carangola	Carangola	Minas Gerais	Brazil
16	Hospital Maternidade e Pronto Socorro Santa Lucia	Poços De Caldas	Minas Gerais	Brazil
17	Hospital da Unimed	São João Del Rei	Minas Gerais	Brazil
18	Santa Casa de Misericórdia de São João Del Rei	São João Del Rei	Minas Gerais	Brazil
19	Hospital de Clínicas da Universidade Federal do Triangulo Mineiro	Uberaba	Minas Gerais	Brazil
20	Hospital de Clínicas da Universidade Federal de Uberlândia	Uberlândia	Minas Gerais	Brazil
21	Hospital do Rocio	Campo Largo	Paraná	Brazil
22	Clínica Clinilive	Maringá	Paraná	Brazil
23	Hospital Universitário Regional de Maringá	Maringá	Paraná	Brazil
24	PROCAPE	Recife	Pernambuco	Brazil
25	Real Hospital Português de Beneficência em Pernambuco	Recife	Pernambuco	Brazil
26	SECRETARIA MUNICIPAL DE SAÚDE DE SAIRÉ (Unidade Mista Olília Mendonça Souto Maior)	Sairé	Pernambuco	Brazil
27	Complexo Hospitalar de Niterói	Niterói	Rio De Janeiro	Brazil
28	Hospital Unimed Volta Redonda	Volta Redonda	Rio De Janeiro	Brazil
29	Associação Dr. Bartholomeu Tacchini	Bento Gonçalves	Rio Grande Do Sul	Brazil
30	Hospital São Vicente de Paulo	Passo Fundo	Rio Grande Do Sul	Brazil
31	Hospital Moinhos de Vento	Porto Alegre	Rio Grande Do Sul	Brazil
32	Santa Casa de Misericórdia de Porto Alegre (ISCMPA)	Porto Alegre	Rio Grande Do Sul	Brazil
33	Universidade Federal de Santa Maria	Santa Maria	Rio Grande Do Sul	Brazil
34	CEPEM Centro de Pesquisa de Medicina Tropical de Rondônia	Porto Velho	Rondônia	Brazil
35	Irmandade de Misericórdia Do Hospital Da Santa Casa de Monte Alto	Monte alto	Salto Alto	Brazil
36	Maestri e Kormann Consultoria Medico Cientifica	Blumenau	Santa Catarina	Brazil
37	Imigrantes Hospital e Maternidade	Brusque	Santa Catarina	Brazil
38	Hospital São José	Criciúma	Santa Catarina	Brazil
39	Hospital Regional Hans Dieter Schmidt	Joinville	Santa Catarina	Brazil
40	Santa Casa de Araras	Araras	São Paulo	Brazil
41	Hospital de Amor	Barretos	São Paulo	Brazil
42	Santa Casa de Misericórdia de Barretos	Barretos	São Paulo	Brazil
43	Alphacor Cardiologia Clinica E Diagnóstica LTDA	Barueri	São Paulo	Brazil
44	Faculdade de Medicina de Botucatu, UNESP	Botucatu	São Paulo	Brazil
45	Hospital Regional do Litoral Norte	Caraguatatuba	São Paulo	Brazil
46	Hospital de Cordeirópolis	Cordeirópolis	São Paulo	Brazil
47	Centro de Combate ao Coronavírus de Itapevi	Itapevi	São Paulo	Brazil
48	Dux Medicina	Jundiaí	São Paulo	Brazil
49	Hospital Carlos Fenando Malzoni	Matão	São Paulo	Brazil
50	Centro de Atendimento Para O Enfrentamento A Covid-19 Da Prefeitura Municipal de Monte Altoprefeitura de Monte Alto	Monte alto	São Paulo	Brazil
51	Faculdade de Medicina de Ribeirão Preto	Ribeirão Preto	São Paulo	Brazil
52	Unimed Ribeirão Preto	Ribeirão Preto	São Paulo	Brazil
53	Hospital Casa de Saúde de Santos	Santos	São Paulo	Brazil
54	Kaiser Clínica e Hospital Dia	São José Do Rio Preto	São Paulo	Brazil
55	Hospital Policlin	São José Dos Campos	São Paulo	Brazil
56	Hospital Regional de São José dos Campos	São José Dos Campos	São Paulo	Brazil
57	Santa Casa de Misericórdia de Votuporanga	Votuporanga	São Paulo	Brazil
58	ESF Dr. João Paccola Primo	Lençois Paulista		Brazil
59	Cardioclinica da Ilha do Governador	Rio De Janeiro		Brazil
60	International Research Center - Hospital Alemão Oswaldo Cruz	São Paulo		Brazil	01323-903
61	Hospital do Coração	São Paulo		Brazil
62	Hospital Israelita Albert Einstein	São Paulo		Brazil
63	Hospital Leforte	São Paulo		Brazil
64	Hospital Moriah	São Paulo		Brazil
65	Hospital Samaritano	São Paulo		Brazil
66	Hospital Santa Paula	São Paulo		Brazil
67	Hospital São Camilo Pompéia	São Paulo		Brazil
68	Hospital São Paulo - UNIFESP	São Paulo		Brazil
69	Hospital Sírio-Libanês	São Paulo		Brazil