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

Phase 2

Completed

• Conditions: COVID-19
• Interventions: Drug: Lopinavir/Ritonavir 400 mg/100 mg; Other: Placebo

• Registration Number: NCT04372628
• Lead Sponsor: Vanderbilt University Medical Center

Brief Summary

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

Detailed Description

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.

Basic Information
|
Recruitment & Eligibility
|
Study & Design
|
Trial Locations

Study Timeline

• Study First Submitted: 2020-04-30
• Study First Submitted QC: 2020-04-30
• Study First Posted: 2020-05-04
• Study Start: 2020-06-01
• Primary Completion: 2021-12-16
• Study Completion: 2022-01-18
• Results First Submitted: 2022-08-30
• Results First Submitted QC: 2023-01-09
• Results First Posted: 2023-01-26
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-23
• Last Update Posted: 2024-02-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 452

Inclusion Criteria

1. Age ≥18 years
2. 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
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.

Read More

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 severe liver disease [cirrhosis or >3 times upper limit of normal for aspartate aminotransferase (AST) or alanine aminotransferase (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 human immunodeficiency virus (HIV) infection

17. Known history of pancreatitis

18. 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]

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, 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

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, 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.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Group 1 - Lopinavir/Ritonavir	Lopinavir/Ritonavir 400 mg/100 mg	Lopinavir/Ritonavir 400 mg/100 mg orally twice daily for twenty-eight doses (Days 1-14)
Control Group	Placebo	Placebo unmatched orally twice daily for 14 days

Primary Outcome Measures

Name	Time	Method
Modified COVID Ordinal Outcomes Scale: Study Day 15 (Group 2 and Placebo Control Group)	Day 1 to Day 15	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.

Secondary Outcome Measures

Name	Time	Method
Vasopressor-free Days Through Study Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of vasopressor-free days through Study Day 29 (Group 2 and Placebo Control Group)
Number of Patients Hospitalized: Day 1 to 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of patients hospitalized from Day 1 to 29 (Group 2 and Placebo Control Group)
Fever-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of days without fever from Day 1 to Day 29 (Group 2 and Placebo Control Group)
Hospital-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of days outside the hospital from Day 1 to Day 29 (Group 2 and Placebo Control Group)
Modified COVID Ordinal Outcome Scale: Study Day 8 (Group 2 and Placebo Control Group)	on or at Day 8	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.
Modified COVID Ordinal Outcome Scale: Study Day 29 (Group 2 and Placebo Control Group)	on or at Day 29	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.
All-cause, All-location Mortality: Day 1 to Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Survival status (All-cause, all-location mortality) from Day 1 to Day 29 (Group 2 and Placebo Control Group)
Ventilator-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of days without ventilator use from Day 1 to Day 29 (Group 2 and Placebo Control Group)
Time to Hospitalization Day 1 to Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of days from enrollment to hospitalization (Group 2 and Placebo Control Group)
Time to Symptom Resolution: Day 1 to Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of days from enrollment to resolution of COVID-19 symptoms (Group 2 and Placebo Control Group)
Oxygen-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of Days without oxygen Day 1 to Day 29 (Group 2 and Placebo Control Group)
ICU-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)	Day 1 to Day 29	Number of days outside the ICU from Day 1 to Day 29 (Group 2 and Placebo Control Group)

Trial Locations

Locations (6)

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

University of Mississippi Medical Center; 🇺🇸 Jackson, Mississippi, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

University of Colorado School of Medicine; 🇺🇸 Aurora, Colorado, United States

Intermountain; 🇺🇸 Murray, Utah, United States

University of Wisconsin; 🇺🇸 Madison, Wisconsin, United States