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Hydroxychloroquine and Lopinavir/ Ritonavir to Improve the Health of People With COVID-19: "The Hope Coalition - 1"

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ClinicalTrials.gov Identifier: NCT04403100
Recruitment Status : Recruiting
First Posted : May 27, 2020
Last Update Posted : June 9, 2020
Sponsor:
Collaborators:
Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA
Cytel Inc.
Information provided by (Responsible Party):
Gilmar Reis, Cardresearch

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.

Condition or disease Intervention/treatment Phase
COVID-19 Coronavirus Infection Virus Disease Acute Respiratory Infection SARS-CoV Infection Drug: Hydroxychloroquine Sulfate Tablets Drug: Lopinavir/ Ritonavir Oral Tablet Drug: Hydroxychloroquine Sulfate Tablets plus Lopinavir/ Ritonavir Oral Tablets Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1968 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
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.

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 A, B and C" and with different colored labels. They will be randomly allocated among the participants. The research subjects, medical assistance, administrative and health staff will not have access to the contents of the bottles. The Arm Lopinavir/ ritonavir plus hydroxychloroquine will receive two of such bottles.

At the end of the study, after the statistical analysis and DMSB meeting, it will then be requested from third party documentation on content of each bottle and then have arms identified.

Primary Purpose: Treatment
Official Title: Hydroxychloroquine and Lopinavir/ Ritonavir for Hospitalization and Mortality Reduction in Patients With COVID-19 and Mild Disease Symptoms: "The Hope Coalition"
Actual Study Start Date : June 3, 2020
Estimated Primary Completion Date : September 3, 2020
Estimated Study Completion Date : November 28, 2020


Arm Intervention/treatment
Active Comparator: Hydroxychloroquine Sulfate
Hydroxychloroquine 400 mg. Loading oral dose of 800 mg followed by orally dose of 400 mg/ day for the following 10 days
Drug: Hydroxychloroquine Sulfate Tablets
Tablets of 400 mg: Loading dose of 02 tablets followed by one tablet of 400 mg orally on the following 09 days

Active Comparator: Lopinavir/ Ritonavir
Lopinavir Ritonavir 200/ 50 mg Loading oral dose of 800/ 200 mg twice a day on day 1 followed by 400/100 mg orally twice a day for the following 9 days
Drug: Lopinavir/ Ritonavir Oral Tablet
tablets of 200/ 50 mg; Loading dose of 04 tablets twice a day on day 1 followed by two tablets twice a day on the following 09 days

Active Comparator: Hydroxychloroquine plus Lopinavir/ Ritonavir

Hydroxychloroquine 400 mg. Loading oral dose of 800 mg followed by orally dose of 400 mg/ day for the following 10 days

Plus

Lopinavir Ritonavir 200/ 50 mg Loading oral dose of 800/ 200 mg twice a day on day 1 followed by 400/100 mg orally twice a day for the following 9 days

Drug: Hydroxychloroquine Sulfate Tablets plus Lopinavir/ Ritonavir Oral Tablets

Hydroxychloroquine Oral Tablet 400 mg: Loading dose of 02 tablets followed by one tablet of 400 mg orally on the following 09 days

plus

Lopinavir/ Ritonavir Oral Tablet of 200/ 50 mg: Loading dose of 04 tablets twice a day on day 1 followed by two tablets twice a day on the following 09 days


Placebo Comparator: Placebo

Placebo

Twice a day from day 1 through day 10.

Drug: Placebo
Placebo tablets - 01 tablet twice daily from day 01 through day 10.




Primary Outcome Measures :
  1. Proportion of participants who were hospitalized for progression of COVID-19 disease [ Time Frame: Measuring during 28-day period since randomization (Intention to treat analysis) ]
    Hospitalization is defined as at least 24 hours of acute care in a hospital or similar acute care facility (emergency settings, temporary emergency facilities created for acute care of COVID-19 pandemic)

  2. Proportion of participants who died due to COVID-19 progression and/ or complications [ Time Frame: Measuring during 28-day period since randomization (Intention to treat analysis) ]

Secondary Outcome Measures :
  1. Proportion of participants with viral load change on 03, 07, 10 and 14 after randomization [ Time Frame: Measuring during 14-day period since randomization ]
    Viral load change on 03, 07, 10 and 14 after randomization (200 patients per arm)

  2. Time to clinical improvement [ Time Frame: Measuring during 28-day period since randomization ]
    Proportion of participants with clinical improvement, defined as normalization of temperature, Respiratory rate, SaO2, and cough relief (> 50% compared to baseline measured on a visual analog scale) in the last 72 hours.

  3. Time to clinical failure [ Time Frame: Measuring during 28-day period since randomization ]
    Proportion of participants with clinical improvement, defined as as time to need for hospitalization due to dyspnea, death, need for mechanical ventilation, shock and need for vasoactive amines;

  4. Hospitalization for any cause [ Time Frame: Measuring during 28-day period since randomization ]
    Proportion of participants with hospitalization for any cause

  5. Proportion of participants who died due to pulmonary complications [ Time Frame: Measuring during 28-day period since randomization ]
  6. Proportion of participants who died due to cardiovascular complications [ Time Frame: Measuring during 28-day period since randomization ]
  7. Proportion of participants who presented with adverse events [ Time Frame: Measuring during 28-day period since randomization ]
    Evaluation of adverse events evaluated as associated to any of study arms

  8. Time to improvement on respiratory scale symptoms [ Time Frame: Measuring during 28-day period since randomization ]
    Proportion of participants who presented sustained improvement on respiratory scale defined as at least 48 hours of improvement.

  9. proportion of non-adherent participants to any of study drugs [ Time Frame: Measuring during 10-day period since randomization ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

-


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04403100


Contacts
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Contact: Gilmar Reis, MD, PhD +5531332416574 greisbh@uol.com.br
Contact: Rosemary Oliveira, SC +5531992636703 roliveira@cardresearch.org

Locations
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Brazil
CARDRESEARCH - Cardiologia Assistencial e de Pesquisa Recruiting
Belo Horizonte, Minas Gerais, Brazil, 30150240
Contact: Izabel Silva, SC    553132416574    coordpesq@cardresearch.org   
Principal Investigator: Gilmar Reis, MD,PhD         
Pontificia Universidade Catolica de Minas Gerais Not yet recruiting
Belo Horizonte, Minas Gerais, Brazil, 30535901
Contact: Eduardo Silva, MD, PhD       duduaugusto1@gmail.com   
Principal Investigator: Eduardo Silva, MD, PhD         
Fundo Municipal de Saúde de Betim Recruiting
Betim, Minas Gerais, Brazil, 32600412
Contact: Daniela Silva, MD, PhD    5531984923130    daninhamed@yahoo.com.br   
Principal Investigator: Daniela Silva, MD, PhD         
Universidade Federal de Ouro Preto Not yet recruiting
Ouro Preto, Minas Gerais, Brazil, 35400000
Contact: Leonardo Savassi, MD, PhD       leosavassi@gmail.com   
Principal Investigator: Leonardo Savassi, MD, PhD         
Sponsors and Collaborators
Cardresearch
Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA
Cytel Inc.
Investigators
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Principal Investigator: Gilmar Reis, MD, PhD Cardresearch - Cardiologia Assistencial e de Pesquisa LTDA
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Responsible Party: Gilmar Reis, Director - Outpatient Research Clinic, Cardresearch
ClinicalTrials.gov Identifier: NCT04403100    
Other Study ID Numbers: COVID19_AMB_Brasil
First Posted: May 27, 2020    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Respiratory Tract Infections
Coronavirus Infections
Severe Acute Respiratory Syndrome
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Respiratory Tract Diseases
Ritonavir
Lopinavir
Hydroxychloroquine
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Antirheumatic Agents