Rationale

Most adults with SARS-CoV-2 virus who develop COVID-19 recover without a problem, but some patients develop more severe disease. The first week or so of illness typically consists of a viral syndrome (like the flu) with symptoms such as fevers and cough. Patients who experience a milder course usually start to recover after the first week; those on a more severe course may develop worse symptoms (often respiratory) which usually occurs during the second week after the onset of symptoms.

The period between onset of symptoms and the development of worsening disease is a critical treatment window that is an opportunity to intervene and slow or halt disease progression.  TREAT NOW targets treatment with early anti-viral therapy during the first week of COVID-19 to try to prevent disease worsening.

COVID-19 is an unusual and serious public health crisis, and there is significant interest in finding effective therapies, specifically in repurposing approved medications with widespread availability and known safety profiles. Efficacy and safety data for lopinavir/ritonavir from randomized trials are critical to provide evidence-based therapy for the ongoing COVID-19 pandemic.

About Lopinavir/ritonavir

Lopinavir/ritonavir (Kaletra) is an anti-viral medication that has antiviral activity and early clinical data suggesting that it may treat coronaviruses. Lopinavir/ritonavir has been extensively used as an anti-viral medicine in the U.S. across the globe (for indications outside of coronavirus treatment) with nearly 8 million patient-years of experience since its approval (patient years = a patient taking the medication for a year).  The medication is generally well tolerated by patients taking the medication over periods of time greater than the two week course used in this study.  Please see consent document for more information including potential side effects.

While a recent randomized open-label trial of lopinavir/ritonavir in hospitalized patients with COVID-19 did not demonstrate a treatment benefit. [Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020], the observed mortality in the lopinavir/ritonavir group was 5.8% lower than the control group (95% confidence interval, -17.3 to 5.7), and there was as an observed faster time to clinical improvement that was also not statistically significant (HR 1.24, 95%CI 0.90-1.72). However, the trial was underpowered for clinically important endpoints and enrolled patients at an advanced stage of disease, a median of 13 days after symptom onset, when antiviral activity is likely much less important.  Accordingly, substantial enthusiasm remains for the early treatment of COVID-19, particularly prior to hospitalization.

Full Inclusion Criteria

1. Age ≥18 years
2. Laboratory-confirmed SARS-CoV-2 by RT-PCR or other molecular test collected within the past 6 days
3. 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

Full Exclusion Criteria

1. Prisoner
2. Pregnancy
3. Breast feeding
4. Two individuals from the same household are not enrolled in the study
5. Unable to randomize within 6 days after onset of acute respiratory infection symptoms
6. Hospitalization within the 6 days prior to randomization
7. Inability to swallow oral medications
8. Refusal or inability to be contacted and participate in daily symptom/safety monitoring in English or Spanish during the two-week follow-up period
9. Previous enrollment in this trial
10. Known severe chronic kidney disease requiring dialysis
11. Known liver disease (cirrhosis or >3 times upper limit of normal for AST or ALT in medical record if available)
12. Known hepatitis B or hepatitis C infection
13. Known history of jaundice
14. Current heavy alcohol use, defined as 8 drinks or more per week for women or 15 drinks or more per week for men
15. Known seizure disorder
16. Known HIV infection
17. Known history of pancreatitis
18. Known history of prolonged QT interval (Long QT Syndrome, patient report, or QTc >500 milliseconds on most recently available electrocardiogram within the past 2 years)
19. Receipt of >1 dose of lopinavir/ritonavir in the 10 days prior to enrollment​
20. Known allergy to lopinavir/ritonavir
21. 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, sotalolAnti-cancer: Arsenic trioxide, oxaliplatin, vandetanibAntidepressants: Amitriptyline, citalopram, escitalopram, imipramineAntimicrobials: azithromycin, ciprofloxacin, clarithromycin, erythromycin, fluconazole, levofloxacin, moxifloxacin, pentamidine, hydroxychloroquineAntipsychotics: aloperidol, chlorpromazine, droperidol, olanzapine, pimozide, quetiapine, thioridazine, risperidone, ziprasidoneOthers: cilostazol, cimetidine, cisapride, donepezil, methadone, ondansetron, sumatriptan
22. 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, rivaroxaban, 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.

About the Study Team

TREAT NOW is being conducted by top medical centers from around the country, including:

Harvard Medical School and Beth Israel Deaconess Medical Center
University of Colorado
Vanderbilt Medical Center
Intermountain Medical Center
University of Mississippi Medical Center
University of Wisconsin-Madison

The study is sponsored by Vanderbilt Medical Center.

AbbVie has provided financial support and drug product at no cost for the trial.