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

• ClinicalTrials.gov Identifier: NCT04372628
• Recruitment Status: Completed
• First Posted: May 4, 2020
• Results First Posted: January 26, 2023
• Last Update Posted: January 26, 2023
• Sponsor: Vanderbilt University Medical Center
• Collaborator: AbbVie
• Information provided by (Responsible Party): Todd Rice, Vanderbilt University Medical Center

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Lopinavir/Ritonavir 400 mg/100 mg; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 452 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Blinded, multicenter, placebo-controlled randomized clinical trial
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Lopinavir/Ritonavir tablets or unmatched placebo tablets
• Primary Purpose: Treatment
• Official Title: Trial of Early Therapies During Non-hospitalized Outpatient Window (TREAT NOW) for COVID-19
• Actual Study Start Date: June 1, 2020
• Actual Primary Completion Date: December 16, 2021
• Actual Study Completion Date: January 18, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Group 1 - Lopinavir/Ritonavir; Lopinavir/Ritonavir 400 mg/100 mg orally twice daily for twenty-eight doses (Days 1-14)	Drug: Lopinavir/Ritonavir 400 mg/100 mg; Lopinavir/Ritonavir tablets; Other Name: Kaletra
Placebo Comparator: Control Group; Placebo unmatched orally twice daily for 14 days	Other: Placebo; Unmatched placebo

Outcome Measures

Primary Outcome Measures :

1. Modified COVID Ordinal Outcomes Scale: Study Day 15 (Group 2 and Placebo Control Group) [ Time Frame: 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 :

1. Modified COVID Ordinal Outcome Scale: Study Day 8 (Group 2 and Placebo Control Group) [ Time Frame: 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.
2. Modified COVID Ordinal Outcome Scale: Study Day 29 (Group 2 and Placebo Control Group) [ Time Frame: 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.
3. Number of Patients Hospitalized: Day 1 to 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
   Number of patients hospitalized from Day 1 to 29 (Group 2 and Placebo Control Group)
4. Time to Hospitalization Day 1 to Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
   Number of days from enrollment to hospitalization (Group 2 and Placebo Control Group)
5. Time to Symptom Resolution: Day 1 to Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
   Number of days from enrollment to resolution of COVID-19 symptoms (Group 2 and Placebo Control Group)
6. All-cause, All-location Mortality: Day 1 to Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
   Survival status (All-cause, all-location mortality) from Day 1 to Day 29 (Group 2 and Placebo Control Group)
7. Oxygen-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
   Number of Days without oxygen Day 1 to Day 29 (Group 2 and Placebo Control Group)
8. Fever-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
   Number of days without fever from Day 1 to Day 29 (Group 2 and Placebo Control Group)
9. Ventilator-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
   Number of days without ventilator use from Day 1 to Day 29 (Group 2 and Placebo Control Group)
10. ICU-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
    Number of days outside the ICU from Day 1 to Day 29 (Group 2 and Placebo Control Group)
11. Hospital-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
    Number of days outside the hospital from Day 1 to Day 29 (Group 2 and Placebo Control Group)
12. Vasopressor-free Days Through Study Day 29 (Group 2 and Placebo Control Group) [ Time Frame: Day 1 to Day 29 ]
    Number of vasopressor-free days through Study Day 29 (Group 2 and Placebo Control Group)

Eligibility Criteria

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

Criteria

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.

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.

Contacts and Locations

Locations

United States, Colorado

University of Colorado School of Medicine

Aurora, Colorado, United States, 80045

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37203

United States, Utah

Intermountain

Murray, Utah, United States, 84107

United States, Wisconsin

University of Wisconsin

Madison, Wisconsin, United States, 53705

Sponsors and Collaborators

Vanderbilt University Medical Center

AbbVie

Investigators

• Principal Investigator: Todd Rice, MD; Vanderbilt University Medical Center

  Study Documents (Full-Text)

Documents provided by Todd Rice, Vanderbilt University Medical Center:

Study Protocol  [PDF] January 26, 2021

Statistical Analysis Plan  [PDF] December 23, 2021

Informed Consent Form  [PDF] January 21, 2021

More Information

Additional Information:

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kaizer AM, Wild J, Lindsell CJ, Rice TW, Self WH, Brown S, Thompson BT, Hart KW, Smith C, Pulia MS, Shapiro NI, Ginde AA. Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT NOW) for COVID-19: a summary of the protocol and analysis plan for a decentralized randomized controlled trial. Trials. 2022 Apr 8;23(1):273. doi: 10.1186/s13063-022-06213-z.

• Responsible Party: Todd Rice, Associate Professor of Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT04372628
• Other Study ID Numbers: 200827
• First Posted: May 4, 2020
• Results First Posted: January 26, 2023
• Last Update Posted: January 26, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Todd Rice, Vanderbilt University Medical Center:

Coronavirus

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Ritonavir; Lopinavir; HIV Protease Inhibitors; Viral 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