Clinical trial NCT04403100: Hydroxychloroquine and Lopinavir/ Ritonavir to Improve the Health of People With COVID-19: "The Hope Coalition - 1"
Official title: Hydroxychloroquine and Lopinavir/ Ritonavir for Hospitalization and Mortality Reduction in Patients With COVID-19 and Mild Disease Symptoms: "The Hope Coalition"
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: COVID-19
Coronavirus Infection
Virus Disease
Acute Respiratory Infection
SARS-CoV Infection
Lead sponsor: Cardresearch
Sponsor class: OTHER
Collaborators: name: Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA
name: Cytel Inc.
First posted: 2020-05-27
Enrollment: 1968
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Patients will be randomly allocated to one of four treatment arms in a 1:1:1:1 ratio:

1. Lopinavir / Ritonavir
2. Hydroxychloroquine
3. Lopinavir / Ritonavir + Hydroxychloroquine
4. Placebo.

We will use a centralized random allocation schedule, generated by computer and implemented using an online remote access system. Randomization will be stratified by participating basic health unit.
Primary purpose: TREATMENT

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 controlling this disease in hospitalized patients with moderate and / or severe cases of this disease. Hydroxychloroquine and lopinavir / ritonavir have been shown to inhibit SARS-CoV viral replication in experimental severe acute respiratory symptoms models and have similar activity against SARS-CoV2. Although widely used in studies of critically ill patients, to date, no study has demonstrated its role on the treatment of high-risk, newly diagnosed patients with COVID-19 and mild symptoms.

Detailed description: In December 2019 a series of viral pneumonia cases were reported in the city of Wuhan, China. A new subtype of coronavirus has been identified as the causative agent of this condition. On February 11, 43,103 cases had already been described and on this day the World Health Organization (WHO) named this disease as COVID-19. With. The disease had spread out to several countries on different continents and on March 11, WHO declared a state of worldwide pandemic. Today (April 25, 2020) there are 2,719,897 cases and 187,705 deaths documented, with a global case-fatality ratio of 6.9%.

To date, no treatment has been identified as effective in combating this disease which has been identified as with high mortality, therefore there are no specific therapeutic options. So far, efforts have been focused on the treatment of patients hospitalized with dyspnea and, although several promising drugs are being evaluated, none has demonstrated effectiveness in reducing morbidity and mortality at this stage of the disease, suggesting that perhaps the best time to use medications either before the onset of severe symptoms of respiratory distress.

Thus, we propose the use of two drugs which experimentally have shown activity against SARS-CoV2 and being used in severely ill patients with COVID-19. Our hypothesis is that perhaps using such drugs before onset of complications will allow better outcomes on this patient population.

Eligibility criteria: Inclusion Criteria:

Patients with RT-PCR diagnosis of COVID-19 or a clinical condition compatible with COVID-19 and respiratory symptoms, presenting:

A. Persistent dry cough associated with axillary temperature \> 37.7 Celsius;

OR

B. Recent onset of Flu-like Respiratory Symptoms associated with dry cough

OR

C. Tomographic image compatible with COVID 19 infection;

2. Men and women aged \> 50 years OR: Patients over 18 years of age with at least one of the following criteria

* Diabetes requiring oral medication or insulin.
* Arterial hypertension requiring at least 01 oral medication for treatment
* Known cardiovascular diseases (CHF of any etiology, documented Coronary Artery Disease, Clinically overt heart disease)
* Symptomatic chronic lung disease and/ or medically controlled
* Patients with a history of transplantation
* Patient with stage IV chronic kidney disease or on dialysis.
* Patients on current Immunosuppression and/or using corticosteroid therapy (equivalent to at least 10 mg of oral prednisone per day)
* Willingness to comply with study related procedures

  3. Ability to provide informed consent before any protocol-related procedures.

Exclusion Criteria:

1. RT-PCR exam for COVID-19 negative during the screening visit.
2. Patients with an acute respiratory condition compatible with COVID-19 being hospitalized;
3. Patients with an acute respiratory condition and with moderate to high probability of not being a COVID infection 19;
4. Dyspnea secondary to other acute and chronic respiratory causes or infections (eg, decompensated Chronic Obstructive Pulmonary Disease, acute bronchitis, pneumonia, primary pulmonary arterial hypertension);
5. Severe respiratory clinical condition, presenting at least ONE of the criteria below:

   1. Respiratory Rate\> 28 / min;
   2. Arterial Oxygen Saturation \< 92% with nasal oxygen therapy at 10 l/ min;
   3. PaO2 / FIO2 \<300 mmHg

4. History of Cardiac Arrhythmia or Long QT Syndrome; 5. Use of Medications that are known to prolong QTc: Citalopram, Venlafaxine, Bupropion and with no possibility of suspension during the period of investigational medical product administration. 6. Inability to take oral medications; 7. Patients on continuous use of Amiodarone and / or PGE5 Inhibitors (Ex .: Sildenafil and similar). 8. Use of Digoxin, Cyclosporine, Cimetidine, Tamoxifen. 9. Use of anticonvulsants, antifungals, immunosuppressants other than corticotherapy. 10. Use of Hydroxychloroquine for other indications 11. Use of chemoprophylaxis for malaria. 12. Psoriasis in a form other than cutaneous 13. Porphyria 14. Use of protease inhibitors, ritonavir or Cobicistat 15. Clinical history of Liver Cirrhosis or Child-Pugh C classification; 16. Patients with a history of degenerative retinal diseases (patients with retinal diseases due to diabetes and hypertension can participate in the research); 17. Patient with a clinically relevant history of hearing loss; 18. Patients with known severe degenerative neurological diseases and / or severe mental illness; 19. Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol; 20. Known hypersensitivity and / or intolerance to Hydroxychloroquine. 21. Hypersensitivity and / or intolerance Lopinavir / Ritonavir

-

Primary outcomes:
measure: Proportion of participants who were hospitalized for progression of COVID-19 disease
timeFrame: Measuring during 28-day period since randomization (Intention to treat analysis)
measure: Proportion of participants who died due to COVID-19 progression and/ or complications
timeFrame: Measuring during 28-day period since randomization (Intention to treat analysis)
Secondary outcomes:
measure: Proportion of participants with viral load change on 03, 07, 10 and 14 after randomization
timeFrame: Measuring during 14-day period since randomization
measure: Time to clinical improvement
timeFrame: Measuring during 28-day period since randomization
measure: Time to clinical failure
timeFrame: Measuring during 28-day period since randomization
measure: Hospitalization for any cause
timeFrame: Measuring during 28-day period since randomization
measure: Proportion of participants who died due to pulmonary complications
timeFrame: Measuring during 28-day period since randomization
measure: Proportion of participants who died due to cardiovascular complications
timeFrame: Measuring during 28-day period since randomization
measure: Proportion of participants who presented with adverse events
timeFrame: Measuring during 28-day period since randomization
measure: Time to improvement on respiratory scale symptoms
timeFrame: Measuring during 28-day period since randomization
measure: proportion of non-adherent participants to any of study drugs
timeFrame: Measuring during 10-day period since randomization
Other outcomes:
Locations:
city: Belo Horizonte
country: Brazil
facility: CARDRESEARCH - Cardiologia Assistencial e de Pesquisa
state: Minas Gerais
city: Belo Horizonte
country: Brazil
facility: Pontificia Universidade Catolica de Minas Gerais
state: Minas Gerais
city: Betim
country: Brazil
facility: Fundo Municipal de Saúde de Betim
state: Minas Gerais
city: Ouro Preto
country: Brazil
facility: Universidade Federal de Ouro Preto
state: Minas Gerais
Study officials:
affiliation: Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA
name: Gilmar Reis, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Reis G, Moreira Silva EADS, Medeiros Silva DC, Thabane L, Singh G, Park JJH, Forrest JI, Harari O, Quirino Dos Santos CV, Guimaraes de Almeida APF, Figueiredo Neto AD, Savassi LCM, Milagres AC, Teixeira MM, Simplicio MIC, Ribeiro LB, Oliveira R, Mills EJ; TOGETHER Investigators. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open. 2021 Apr 1;4(4):e216468. doi: 10.1001/jamanetworkopen.2021.6468.