Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19

Study Overview
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Brief Summary
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Blinded, multicenter, placebo-controlled, randomized clinical trial evaluating lopinavir/ritonavir vs placebo in early outpatient treatment of adults with COVID-19

Detailed Description
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We will conduct an investigator-initiated, multicenter, blinded, placebo-controlled, randomized clinical trial evaluating lopinavir/ritonavir vs placebo for early treatment of adults with COVID-19 in the outpatient setting prior to hospitalization. Patients, treating clinicians, and study personnel will all be blinded to study group assignment.

Official Title
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Trial of Early Therapies During Non-hospitalized Outpatient Window (TREAT NOW) for COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Lopinavir/Ritonavir 400 mg/100 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by reverse transcription polymerase chain reaction (RT-PCR) or other molecular test collected within the past 6 days Current symptoms of acute respiratory infection for ≤6 days, defined as one or more of the following: cough, fever, shortness of breath, chest pain, abdominal pain, nausea/vomiting, diarrhea, body aches, weakness/fatigue. Exclusion Criteria: Prisoner Pregnancy Breast feeding Two individuals from the same household are not enrolled in the study Unable to randomize within 6 days after onset of acute respiratory infection symptoms Hospitalization within the 6 days prior to randomization Inability to swallow oral medications Refusal or inability to be contacted and participate in daily symptom/safety monitoring in English or Spanish during the two-week follow-up period Previous enrollment in this trial Known severe chronic kidney disease requiring dialysis Known severe liver disease [cirrhosis or >3 times upper limit of normal for aspartate aminotransferase (AST) or alanine aminotransferase (ALT) in medical record if available] Known hepatitis B or hepatitis C infection Known history of jaundice Current heavy alcohol use, defined as 8 drinks or more per week for women or 15 drinks or more per week for men Known seizure disorder Known human immunodeficiency virus (HIV) infection Known history of pancreatitis Known history of prolonged QT interval [Long QT Syndrome, patient report, or corrected QT interval (QTc) >500 milliseconds on most recently available electrocardiogram within the past 2 years] Receipt of >1 dose of lopinavir/ritonavir in the 10 days prior to enrollment Known allergy to lopinavir/ritonavir Currently prescribed (with planned continuation) or planned administration during 14-day study period of medication at high risk for QT prolongation as follows: Antiarrhythmics: Amiodarone, disopyramide, dofetilide, dronedarone, flecainide, ibutilide, procainamide, propafenone, quinidine, sotalol Anti-cancer: Arsenic trioxide, oxaliplatin, vandetanib Antidepressants: Amitriptyline, citalopram, escitalopram, imipramine Antimicrobials: azithromycin, ciprofloxacin, clarithromycin, erythromycin, fluconazole, levofloxacin, moxifloxacin, pentamidine, hydroxychloroquine Antipsychotics: haloperidol, chlorpromazine, droperidol, olanzapine, pimozide, quetiapine, thioridazine, risperidone, ziprasidone Others: cilostazol, cimetidine, cisapride, donepezil, methadone, ondansetron, sumatriptan Currently prescribed (with planned continuation) or planned administration during 14-day study period of any of the following medications: alfuzosin, apalutamide, astemizole, ergot-containing medicines (including dihydroergotamine mesylate, ergotamine tartrate, methylergonovine), lomitapide, lovastatin, lurasidone, midazolam, phenobarbital, phenytoin, ranolazine, rifampin, sildenafil, simvastatin, St. John's Wort, terfenadine, triazolam. Patients who are on warfarin or fluticasone will be advised to contact their primary care provider to advise them that they are in the trial and possibly receiving lopinavir/ritonavir which can influence levels of either drug and may require more frequent monitoring.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Blinded, multicenter, placebo-controlled randomized clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1 - Lopinavir/Ritonavir<br>Lopinavir/Ritonavir 400 mg/100 mg orally twice daily for twenty-eight doses (Days 1-14) | Drug: Lopinavir/Ritonavir 400 mg/100 mg<br>* Lopinavir/Ritonavir tablets<br>* Other names: Kaletra;|
| Placebo Comparator: Control Group<br>Placebo unmatched orally twice daily for 14 days | Other: Placebo<br>* Unmatched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified COVID Ordinal Outcomes Scale: Study Day 15 (Group 2 and Placebo Control Group) | Improvement of clinical condition of the participant defined by the Modified COVID Ordinal Outcomes Scale (Modified from the COVID-19 WHO ordinal Outcomes score to fit the outpatient setting). This scale reflects a range of participants from dead to not hospitalized and with no limitations to activities of daily living. A score of 1 is death, 2 is Hospitalized on mechanical ventilation or extracorporeal membrane oxygenator (ECMO), 3 is Hospitalized on supplemental oxygen, 4 is Hospitalized not on supplemental oxygen, 5 is Not hospitalized with symptoms and limitation in activity, 6 is Not hospitalized with symptoms but with no limitation in activity, 7 is Not hospitalized without symptoms nor limitation in activity. COVID outcomes are more severe at the lower end of the scale and milder at the higher end of the scale for this outpatient trial. | Day 1 to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified COVID Ordinal Outcome Scale: Study Day 8 (Group 2 and Placebo Control Group) | Improvement of clinical condition of the participant defined by the Modified COVID Ordinal Outcomes Scale (Modified from the COVID-19 WHO ordinal Outcomes score to fit the outpatient setting). This scale reflects a range of participants from dead to not hospitalized and with no limitations to activities of daily living. A score of 1 is death, 2 is Hospitalized on mechanical ventilation or extracorporeal membrane oxygenator (ECMO), 3 is Hospitalized on supplemental oxygen, 4 is Hospitalized not on supplemental oxygen, 5 is Not hospitalized with symptoms and limitation in activity, 6 is Not hospitalized with symptoms but with no limitation in activity, 7 is Not hospitalized without symptoms nor limitation in activity. COVID outcomes are more severe at the lower end of the scale and milder at the higher end of the scale for this outpatient trial. | on or at Day 8 | 
| Modified COVID Ordinal Outcome Scale: Study Day 29 (Group 2 and Placebo Control Group) | Improvement of clinical condition of the participant defined by the Modified COVID Ordinal Outcomes Scale (Modified from the COVID-19 WHO ordinal Outcomes score to fit the outpatient setting). This scale reflects a range of participants from dead to not hospitalized and with no limitations to activities of daily living. A score of 1 is death, 2 is Hospitalized on mechanical ventilation or extracorporeal membrane oxygenator (ECMO), 3 is Hospitalized on supplemental oxygen, 4 is Hospitalized not on supplemental oxygen, 5 is Not hospitalized with symptoms and limitation in activity, 6 is Not hospitalized with symptoms but with no limitation in activity, 7 is Not hospitalized without symptoms nor limitation in activity. COVID outcomes are more severe at the lower end of the scale and milder at the higher end of the scale for this outpatient trial. | on or at Day 29 | 
| Number of Patients Hospitalized: Day 1 to 29 (Group 2 and Placebo Control Group) | Number of patients hospitalized from Day 1 to 29 (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| Time to Hospitalization Day 1 to Day 29 (Group 2 and Placebo Control Group) | Number of days from enrollment to hospitalization (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| Time to Symptom Resolution: Day 1 to Day 29 (Group 2 and Placebo Control Group) | Number of days from enrollment to resolution of COVID-19 symptoms (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| All-cause, All-location Mortality: Day 1 to Day 29 (Group 2 and Placebo Control Group) | Survival status (All-cause, all-location mortality) from Day 1 to Day 29 (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| Oxygen-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) | Number of Days without oxygen Day 1 to Day 29 (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| Fever-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) | Number of days without fever from Day 1 to Day 29 (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| Ventilator-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) | Number of days without ventilator use from Day 1 to Day 29 (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| ICU-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) | Number of days outside the ICU from Day 1 to Day 29 (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| Hospital-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) | Number of days outside the hospital from Day 1 to Day 29 (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 
| Vasopressor-free Days Through Study Day 29 (Group 2 and Placebo Control Group) | Number of vasopressor-free days through Study Day 29 (Group 2 and Placebo Control Group) | Day 1 to Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus