Clinical trial NCT04372628: Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19
Official title: Trial of Early Therapies During Non-hospitalized Outpatient Window (TREAT NOW) for COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Keywords: Coronavirus
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: AbbVie
First posted: 2020-05-04
Enrollment: 452
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Blinded, multicenter, placebo-controlled randomized clinical trial
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Modified COVID Ordinal Outcomes Scale: Study Day 15 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 15
Secondary outcomes:
measure: Modified COVID Ordinal Outcome Scale: Study Day 8 (Group 2 and Placebo Control Group)
timeFrame: on or at Day 8
measure: Modified COVID Ordinal Outcome Scale: Study Day 29 (Group 2 and Placebo Control Group)
timeFrame: on or at Day 29
measure: Number of Patients Hospitalized: Day 1 to 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: Time to Hospitalization Day 1 to Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: Time to Symptom Resolution: Day 1 to Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: All-cause, All-location Mortality: Day 1 to Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: Oxygen-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: Fever-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: Ventilator-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: ICU-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: Hospital-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
measure: Vasopressor-free Days Through Study Day 29 (Group 2 and Placebo Control Group)
timeFrame: Day 1 to Day 29
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado School of Medicine
state: Colorado
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Murray
country: United States
facility: Intermountain
state: Utah
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Vanderbilt University Medical Center
name: Todd Rice, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Del Rio C, Malani PN. COVID-19-New Insights on a Rapidly Changing Epidemic. JAMA. 2020 Apr 14;323(14):1339-1340. doi: 10.1001/jama.2020.3072. No abstract available.
citation: Fauci AS, Lane HC, Redfield RR. Covid-19 - Navigating the Uncharted. N Engl J Med. 2020 Mar 26;382(13):1268-1269. doi: 10.1056/NEJMe2002387. Epub 2020 Feb 28. No abstract available.
citation: Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.
citation: Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4. No abstract available.
citation: Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, Ma Z, Zhang Y, Shi G, Lam TTY, Wu JT, Gao GF, Cowling BJ, Yang B, Leung GM, Feng Z. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020 Mar 26;382(13):1199-1207. doi: 10.1056/NEJMoa2001316. Epub 2020 Jan 29.
citation: Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24.
citation: Perlman S. Another Decade, Another Coronavirus. N Engl J Med. 2020 Feb 20;382(8):760-762. doi: 10.1056/NEJMe2001126. Epub 2020 Jan 24. No abstract available.
citation: Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, Liu W, Bi Y, Gao GF. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiol. 2016 Jun;24(6):490-502. doi: 10.1016/j.tim.2016.03.003. Epub 2016 Mar 21.
citation: Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019 Mar;17(3):181-192. doi: 10.1038/s41579-018-0118-9.
citation: Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270-273. doi: 10.1038/s41586-020-2012-7. Epub 2020 Feb 3.
citation: Cheng PK, Wong DA, Tong LK, Ip SM, Lo AC, Lau CS, Yeung EY, Lim WW. Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome. Lancet. 2004 May 22;363(9422):1699-700. doi: 10.1016/S0140-6736(04)16255-7.
citation: Hui DS, Azhar EI, Kim YJ, Memish ZA, Oh MD, Zumla A. Middle East respiratory syndrome coronavirus: risk factors and determinants of primary, household, and nosocomial transmission. Lancet Infect Dis. 2018 Aug;18(8):e217-e227. doi: 10.1016/S1473-3099(18)30127-0. Epub 2018 Apr 18.
citation: Wang Y, Liu Y, Liu L, Wang X, Luo N, Li L. Clinical Outcomes in 55 Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Who Were Asymptomatic at Hospital Admission in Shenzhen, China. J Infect Dis. 2020 May 11;221(11):1770-1774. doi: 10.1093/infdis/jiaa119.
citation: Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Jul 1;180(7):934-943. doi: 10.1001/jamainternmed.2020.0994.
citation: Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, Lee M. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020 Apr 28;323(16):1612-1614. doi: 10.1001/jama.2020.4326.
citation: Wilson N, Kvalsvig A, Barnard LT, Baker MG. Case-Fatality Risk Estimates for COVID-19 Calculated by Using a Lag Time for Fatality. Emerg Infect Dis. 2020 Jun;26(6):1339-1441. doi: 10.3201/eid2606.200320. Epub 2020 Jun 17.
citation: Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect. 2017 Jan 23;5(1):e00293. doi: 10.1002/prp2.293. eCollection 2017 Feb.
citation: Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS, Yuen KY; HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004 Mar;59(3):252-6. doi: 10.1136/thorax.2003.012658.
citation: Chen F, Chan KH, Jiang Y, Kao RY, Lu HT, Fan KW, Cheng VC, Tsui WH, Hung IF, Lee TS, Guan Y, Peiris JS, Yuen KY. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol. 2004 Sep;31(1):69-75. doi: 10.1016/j.jcv.2004.03.003.
citation: Wu CY, Jan JT, Ma SH, Kuo CJ, Juan HF, Cheng YS, Hsu HH, Huang HC, Wu D, Brik A, Liang FS, Liu RS, Fang JM, Chen ST, Liang PH, Wong CH. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10012-7. doi: 10.1073/pnas.0403596101. Epub 2004 Jun 28.
citation: de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, van den Hoogen BG, Neyts J, Snijder EJ. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014 Aug;58(8):4875-84. doi: 10.1128/AAC.03011-14. Epub 2014 May 19.
citation: Chan JF, Yao Y, Yeung ML, Deng W, Bao L, Jia L, Li F, Xiao C, Gao H, Yu P, Cai JP, Chu H, Zhou J, Chen H, Qin C, Yuen KY. Treatment With Lopinavir/Ritonavir or Interferon-beta1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015 Dec 15;212(12):1904-13. doi: 10.1093/infdis/jiv392. Epub 2015 Jul 21.
citation: Wang J. Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study. J Chem Inf Model. 2020 Jun 22;60(6):3277-3286. doi: 10.1021/acs.jcim.0c00179. Epub 2020 May 4.
citation: Martinez MA. Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e00399-20. doi: 10.1128/AAC.00399-20. Print 2020 Apr 21.
citation: Kim UJ, Won EJ, Kee SJ, Jung SI, Jang HC. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-alpha for Middle East respiratory syndrome. Antivir Ther. 2016;21(5):455-9. doi: 10.3851/IMP3002. Epub 2015 Oct 22.
citation: Spanakis N, Tsiodras S, Haagmans BL, Raj VS, Pontikis K, Koutsoukou A, Koulouris NG, Osterhaus AD, Koopmans MP, Tsakris A. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J Antimicrob Agents. 2014 Dec;44(6):528-32. doi: 10.1016/j.ijantimicag.2014.07.026. Epub 2014 Sep 18.
citation: Min CK, Cheon S, Ha NY, Sohn KM, Kim Y, Aigerim A, Shin HM, Choi JY, Inn KS, Kim JH, Moon JY, Choi MS, Cho NH, Kim YS. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep. 2016 May 5;6:25359. doi: 10.1038/srep25359.
citation: Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, Li PT, Dai J, Mok FK, Chen H, Hayden FG, Yuen KY. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect. 2013 Dec;67(6):606-16. doi: 10.1016/j.jinf.2013.09.029. Epub 2013 Oct 3.
citation: Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020 May 5;172(9):577-582. doi: 10.7326/M20-0504. Epub 2020 Mar 10.
citation: Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.
citation: Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73. doi: 10.5582/bst.2020.01047. Epub 2020 Feb 19.
citation: Sapp JL, Alqarawi W, MacIntyre CJ, Tadros R, Steinberg C, Roberts JD, Laksman Z, Healey JS, Krahn AD. Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society. Can J Cardiol. 2020 Jun;36(6):948-951. doi: 10.1016/j.cjca.2020.04.003. Epub 2020 Apr 8.
citation: Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
citation: Wang Y, Fan G, Salam A, Horby P, Hayden FG, Chen C, Pan J, Zheng J, Lu B, Guo L, Wang C, Cao B. Comparative Effectiveness of Combined Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza Virus Infection. J Infect Dis. 2020 Apr 27;221(10):1688-1698. doi: 10.1093/infdis/jiz656.
citation: 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.